LEUKEMIA COMMITTEE 2020/ROS... · 2020. 3. 19. · leukemia in their peripheral blood or bone marrow. Patients must have ≥ 5% blasts in the peripheral blood or bone marrow. At least

APRIL 22 - 25, 2020 SWOG LEUKEMIA 1

LEUKEMIA COMMITTEE


CONTENTS

S1312 Phase I ................................................................................................................................................................ 6

S1318 Phase I-II .......................................................................................................................................................... 13

S1612 Phase II-III ........................................................................................................................................................ 19

S1712 Phase II ............................................................................................................................................................. 25

S1905 Phase II ............................................................................................................................................................. 28

S1925 Phase III ............................................................................................................................................................ 29


Patient Registrations to Studies

by 12 Month Intervals

LEUKEMIA COMMITTEE

Screening registrations and registrations to Biologic only studies are excluded.

SWOG LAPS MEMBER NCORP NON-SWOG

600

403

109

60

120136

0

100

200

300

400

500

600

700

Time of Registration

Jan 2014Dec 2014

Jan 2015Dec 2015

Jan 2016Dec 2016

Jan 2017Dec 2017

Jan 2018Dec 2018

Jan 2019Dec 2019

116

143

85

256

100

88

81

134

40

40 3537

45

4736


Patient Registrations by Study and Arm LEUKEMIA COMMITTEE

Jul 2019

Dec 2019

Jan 2019

Jun 2019

Jul 2018

Dec 2018

All

Patients

S1312 ALL, CD22+, REL/REF, Inotuzumab+CVP

Initial Registration

CVP + Inotuzumab dose level 1 0 0 0 5





CVP + Inotuzumab MTD 0 4 7 13

0 4 7 50

S1318 ALL, Age 65+, Ph±, Blinatumomab

Initial registration

Induction: Ph- 0 0 0 31

Induction: Ph+/Ph-like 4 0 0 20

4 0 0 51

S1612 AML/MDS, Age 60+, Aza/Novel Therapeutics

Specimen Submission

FLT3 Testing 0 0 67 113

Randomization

Azacitidine 0 0 14 26

Azacitidine + Nivolumab 0 0 16 26

Azacitidine + Midostaurin 0 0 14 26

0 0 44 78

S1712 CML, Chronic Phase, TKI +/- Ruxolitinib

Randomization

Single Agent TKI 4 3 1 8

TKI + Ruxolitinib 5 2 1 8

9 5 2 16


Non-SWOG Studies with SWOG-Credited Registrations LEUKEMIA COMMITTEE

Studies with Accrual from July 2018 - December 2019

SWOG Accrual

SWOG

Champion

Jul 2019

Dec 2019

Jan 2019

Jun 2019

Jul 2018

Dec 2018

SWOG

Total

Total

Accrued

A041501 B-Cell ALL, Frontline Tx +/- Intuzumab Ozo A Advani 3 1 0 4 85

Date Activated: 06/01/17

Most Recent Progress Report

A041701 AML, Age 60+, Conv Chemo +/- Uproleselan L Liesveld 4 2 0 6 63



A041702 CLL, Stg I-IV, IO with IM versus IVO B Hill 14 5 0 19 101



E1910 BCR-ABL-neg, B ALL, Blinatumomab M Liedke 4 13 15 119 488

Date Activated: 12/23/13 Date Closed: 10/22/19


EA9161 CLL, untreated, IOV vs IO in younger pts M Shadman 41 27 0 68 297




S1312/I

S1312 Phase I

A Phase I Study of Inotuzumab (NSC-772518) in Combination with CVP

(Cyclophosphamide, Vincristine, Prednisone) for Patients with

Relapsed/Refractory CD22-Positive Acute Leukemia (including B-ALL,

Mixed Phenotypic Leukemia, and Burkitt's Leukemia)

Study Chairs:

A Advani, M Liedtke

Statisticians:

M Othus, A Moseley

Data Coordinator:

L Highleyman

Date Activated:

04/01/2014

Date Closed:

08/02/2019

Objectives To assess the safety of inotuzumab in combination

with cyclophosphamide, vincristine and prednisone

(CVP) and to determine the maximum tolerated dose

(MTD) of inotuzumab in this regimen for patients

with relapsed or refractory CD22-positive acute

leukemia (B-ALL, mixed phenotype, and Burkitt's).

To estimate the preliminary activity [response rate:

complete remission (CR) + complete remission with

incomplete count recovery (CRi)] of this combination

in the expansion cohort.

To estimate the frequency and severity of toxicities

of this combination in this patient population.

Patient Population Patients must have a diagnosis of relapsed or

refractory CD22-positive acute leukemia including

B-ALL, mixed phenotype leukemia (bilineal and

biphenotypic), or Burkitt's leukemia based on WHO

classification. Patients with bilineal leukemia are

excluded. Patients must have evidence of acute

leukemia in their peripheral blood or bone marrow.

Patients must have ≥ 5% blasts in the peripheral

blood or bone marrow. At least ≥ 20% of those blasts

must be CD22-positive (surface) based on local

immunophenotyping and histopathology. Patients

must be refractory or have relapsed following prior

induction therapy.

Patients may have received prior allogeneic

transplant or autologous transplant. Patients with

prior allogeneic bone marrow transplant will be

eligible only if the conditions stated in the protocol

are met. Patients known to have Ph+ ALL must have

either failed treatment or been intolerant to treatment

with at least one second or third generation tyrosine

kinase inhibitor. Patients must not have received

prior treatment with inotuzumab. Previous treatment

with other anti-CD22 antibodies must have been

completed at least 90 days prior to registration.

Patients must not have received any chemotherapy,

investigational agents, or undergone major surgery

within 14 days prior to registration with the following

exceptions: (1) Monoclonal antibodies must not have

been received for one week prior to registration; (2)

Chimeric antigen receptor (CAR) T-cells must not

have been received for 28 days prior to registration;

(3) Steroids, hydroxyurea, vincristine, 6-

mercaptopurine, methotrexate, thioguanine and

intrathecal chemotherapy are permitted within any

time frame prior to registration. FDA-approved

tyrosine kinase inhibitors may also be administered

until one day prior to start of study therapy (C1, D1).

All drug-related toxicities must have resolved to ≤

Grade 2. Treatment with hydroxyurea and steroids is

permitted to bring down peripheral blast count.

Patients must be at least 18 years of age and have

Zubrod performance status of 0-2. Patients must not

have a systemic bacterial, fungal, or viral infection

that is not controlled. Patients must not have active


S1312/I

CNS involvement. Patients must have < Grade 2

neuropathy (sensory/motor). Patients must not have a

history of chronic or active hepatitis B or C infection.

Patients must not have evidence or history of veno-

occlusive disease or sinusoidal obstruction syndrome.

Patients who are known to be HIV+ are eligible

providing they meet all of the criteria in the protocol.

Patients with a history of a serious allergic or

anaphylactic reaction to humanized monoclonal

antibodies are not eligible. Patients must have

adequate hematologic, renal, hepatic, and cardiac

function.

Accrual Goals Patient enrollment will follow the traditional "3+3"

algorithm until the MTD for inotuzumab is reached

or the highest dose tested is judged tolerable. This

study will accrue 3-30 eligible and evaluable patients

in the Phase I portion and 12 additional eligible

patients in the expansion cohort.

Summary Statement

Determination of MTD

This study evaluated five dose levels if inotuzumab.

The initial dose level of 0.4 mg/m2 inotuzumab

closed on November 1, 2014 with five eligible

patients registered. Two patients were not evaluable

for DLTs because they went off treatment before

their counts recovered and before prolonged

myelosuppression could be ruled out. There were no

DLTs in the first dose level.

The second dose level of inotuzumab at 0.6 mg/m2 on

day 1 and 0.4 mg/m2 on day 15 closed on May 15,

2015 with five patients registered. One patient was

ineligible due to inadequate liver function; another

patient was not evaluable for DLTs due to going off

treatment before counts recovered and before

prolonged myelosuppression could be ruled out.

There were no DLTs in the second dose level.

The third dose level of inotuzumab at 0.8 mg/m2 on

day 1 and 0.4 mg/m2 on day 15 closed on April 15,

2016 with 11 patients registered. One patient was

ineligible due to inadequate liver function. Four other

patients were not evaluable for DLTs: two went off

treatment before their counts recovered and before

prolonged myelosuppression could be ruled out, one

died before receiving a full cycle of treatment, and

one continued to take tyrosine kinase inhibitor (TKI)

while on protocol and is coded as a major protocol

deviation. Six of the 10 eligible patients were

evaluable for DLTs. One of the first three evaluable

patients experienced a DLT (prolonged

myelosuppression), so three additional patients were

evaluated at this dose level. None of these additional

patients experienced a DLT.

The fourth dose level of inotuzumab at 0.8 mg/m2 on

day 1 and 0.4 mg/m2 on days 8 and 15 closed on

August 22, 2016 with five patients registered. Two

patients were not evaluable for DLTs because they

went off treatment before their counts recovered and

before prolonged myelosuppression could be ruled

out. There were no DLTs in the fourth dose level.

The fifth dose level of inotuzumab at 0.8 mg/m2 on

day 1 and 0.5 mg/m2 on days 8 and 15 closed on July

31, 2017 with 11 patients registered. Five patients

went off treatment before their counts recovered and

before prolonged myelosuppression could be ruled

out and are not evaluable for DLTs. One patient

experienced a DLT: Grade 3 ascites, an event

considered clinically significant regardless of

duration. The fifth dose level was established as the

MTD for the expansion cohort.

There were no Grade 5 treatment-related non-

hematologic toxicities at any dose level. Two patients

treated at the third dose level experienced Grade 4

treatment-related non-hematologic toxicities: one

patient experienced Grade 4 treatment-related

hyperglycemia and another experienced Grade 4

treatment-related hyperglycemia and oral mucositis.

Expansion Cohort

The expansion cohort opened to accrual on October

25, 2017 and accrued 13 patients. The study

permanently closed to accrual on August 2, 2019.

One patient went off protocol after only one day of

treatment and was not evaluable for response. Two

patients in this cohort experienced treatment-related

Grade 4 non-hematologic toxicities: one with febrile

neutropenia and sepsis and another with sepsis (also

coded as Infections/infestations-Other). No other

Grade 4 or 5 treatment-related non-hematologic

toxicities were reported.

Though the MTD has been established and toxicities

in this cohort are not dose limiting, DLTs in the

expansion cohort will also be described in order to

better understand toxicities at this dose. Four patients

are not evaluable for DLTs: one received only one

day of treatment and three others went off treatment

before their counts recovered and before prolonged


S1312/I

myelosuppression could be ruled out. None of the

nine patients evaluable for DLTs experienced a DLT.

In all, 27 patients went off treatment for non-protocol

specified reasons, due to lack of treatment benefit

(10), physician decision (2) or to receive transplant

(15).

Results

The primary objective of this trial was to assess the

safety of inotuzumab ozogamicin in combination

with CVP and to determine the MTD of inotuzumab

in this treatment combination. The MTD was found

to be 0.8 mg/m2 on day 1 and 0.5 mg/m

2 on days 8

and 15. One out of 15 evaluable patients treated at

this dose (including the expansion cohort)

experienced a DLT (Grade 3 ascites). No Grade 4 or

Grade 5 treatment-related non-hematologic toxicities

were observed at this dose in the dose-finding portion

of the trial. Two patients in the expansion cohort

experienced Grade 4 treatment-related non-

hematologic toxicities.

A secondary objective was to estimate the response

rate (CR + CRi) in the expansion cohort. Of the 12

patients in the expansion cohort who were evaluable

for response, 10 achieved a CR or CRi (83%, 95% CI

52% - 98%). Of the 23 patients treated at the MTD

who were evaluable for response, 14 achieved a CR

or CRi (61%, 95% CI 39% - 80%).

Median overall survival (OS) is 7.7 months for all

eligible patients and 10.9 months for eligible patients

treated at the MTD. OS for patients treated at the

MTD was significantly higher than for patients

treated at lower dose levels (log-rank p = 0.02).

Median follow-up for patients who were alive at last

contact is 1.4 years.

Registration by Institution

Institutions Total Reg

City of Hope Med Ctr 18

Rochester, Univ of 12

Cleveland Clinic OH 11

Baylor College 7

Stanford University 2

Total (5 Institutions) 50

Registration, Eligibility, and Evaluability

TOTAL

CVP +

Inotuzumab

dose level 1

CVP +

Inotuzumab

dose level 2

CVP +

Inotuzumab

dose level 3

CVP +

Inotuzumab

dose level 4

CVP +

Inotuzumab

dose level 5

CVP +

Inotuzumab

MTD

NUMBER REGISTERED 50 5 5 11 5 11 13

INELIGIBLE 2 0 1 1 0 0 0

ELIGIBLE 48 5 4 10 5 11 13

RESPONSE ASSESSMENT

Determinable 45 5 4 8 5 11 12

Not Determinable 3 0 0 2 0 0 1

ADVERSE EVENT ASSESSMENT

Evaluable 48 5 4 10 5 11 13

DLT ASSESSMENT

Evaluable 30 3 3 6 3 6 9

Not Evaluable 18 2 1 4 2 5 4


S1312/I

Patient Characteristics

CVP +

Inotuzumab

dose level 1

(n=5)

CVP +

Inotuzumab

dose level 2

(n=4)

CVP +

Inotuzumab

dose level 3

(n=10)

CVP +

Inotuzumab

dose level 4

(n=5)

CVP +

Inotuzumab

dose level 5

(n=11)

CVP +

Inotuzumab MTD

(n=13)

AGE

Median 48.8 42.3 42.8 49.6 37.9 43.5

Minimum 22.3 20.6 22.4 33.0 25.0 21.6

Maximum 73.7 56.4 75.3 50.1 58.7 79.8

SEX

Males 4 80% 0 0% 6 60% 3 60% 6 55% 8 62%

Females 1 20% 4 100% 4 40% 2 40% 5 45% 5 38%

HISPANIC

Yes 2 40% 2 50% 2 20% 4 80% 3 27% 3 23%

No 3 60% 2 50% 7 70% 1 20% 6 55% 9 69%

Unknown 0 0% 0 0% 1 10% 0 0% 2 18% 1 8%

RACE

White 4 80% 3 75% 6 60% 5 100% 7 64% 8 62%

Black 1 20% 1 25% 2 20% 0 0% 1 9% 0 0%

Asian 0 0% 0 0% 0 0% 0 0% 1 9% 3 23%

Unknown 0 0% 0 0% 2 20% 0 0% 2 18% 2 15%

Treatment Summary

TOTAL

CVP +

Inotuzumab

dose level 1

CVP +

Inotuzumab

dose level 2

CVP +

Inotuzumab

dose level 3

CVP +

Inotuzumab

dose level 4

CVP +

Inotuzumab

dose level 5

CVP +

Inotuzumab

MTD

NUMBER ON PROTOCOL TREATMENT 0 0 0 0 0 0 0

NUMBER OFF PROTOCOL TREATMENT 48 5 4 10 5 11 13

REASON OFF TREATMENT

Treatment completed as planned 6 0 2 1 0 0 3

Adverse Event or side effects 6 0 0 2 0 1 3

Refusal unrelated to adverse event 1 1 0 0 0 0 0

Progression/relapse 7 1 1 4 0 0 1

Death 1 0 0 1 0 0 0

Other - not protocol specified 27 3 1 2 5 10 6

MAJOR PROTOCOL DEVIATIONS 1 0 0 1 0 0 0

LOST TO FOLLOW-UP 0 0 0 0 0 0 0

CONSENT WITHDRAWAL AFTER

TREATMENT INITIATION

1 0 0 1 0 0 0


S1312/I

Number of Patients with a Given Type and Grade of Adverse Event

Adverse Events Unlikely or Not Related to Treatment Excluded

Hematologic Adverse Events Only

Adverse Events with No Entries for Grades 3 to 5 Have Been Suppressed

CVP +

Inotuzumab

dose level 1

CVP +

Inotuzumab

dose level 2

CVP +

Inotuzumab

dose level 3

CVP +

Inotuzumab

dose level 4

CVP +

Inotuzumab

dose level 5

CVP +

Inotuzumab

MTD

(n=5) (n=4) (n=10) (n=5) (n=11) (n=13)

Grade Grade Grade Grade Grade Grade

ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5

Anemia 3 1 1 0 2 1 1 0 3 7 0 0 2 3 0 0 6 5 0 0 8 5 0 0

Lymphocyte count decreased 3 0 2 0 3 1 0 0 7 2 1 0 2 1 2 0 5 2 4 0 7 3 3 0

Neutrophil count decreased 2 0 3 0 1 0 3 0 1 0 9 0 1 2 2 0 3 4 4 0 5 1 7 0

Platelet count decreased 3 0 2 0 2 0 2 0 3 1 6 0 1 1 3 0 6 1 4 0 3 2 8 0

White blood cell decreased 2 0 3 0 0 1 3 0 0 1 9 0 0 0 5 0 4 1 6 0 4 0 9 0

MAX. GRADE ANY

ADVERSE EVENT 2 0 3 0 0 0 4 0 0 0 10 0 0 0 5 0 0 3 8 0 1 1 11 0



Non-Hematologic Adverse Events Only


CVP +

Inotuzumab

dose level 1

CVP +

Inotuzumab

dose level 2

CVP +

Inotuzumab

dose level 3

CVP +

Inotuzumab

dose level 4

CVP +

Inotuzumab

dose level 5

CVP +

Inotuzumab MTD

(n=5) (n=4) (n=10) (n=5) (n=11) (n=13)


ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5

Ascites 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 10 1 0 0 12 1 0 0

Dysphagia 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 11 0 0 0 13 0 0 0

Encephalopathy 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 11 0 0 0 13 0 0 0

Enterocolitis 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 10 1 0 0 13 0 0 0

Fatigue 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 11 0 0 0 12 1 0 0

Febrile neutropenia 5 0 0 0 2 2 0 0 8 2 0 0 2 3 0 0 10 1 0 0 6 6 1 0

Fever 4 1 0 0 3 1 0 0 9 1 0 0 5 0 0 0 11 0 0 0 12 1 0 0

GI disorders-Other, specify 5 0 0 0 3 1 0 0 10 0 0 0 5 0 0 0 11 0 0 0 13 0 0 0

Gastric hemorrhage 3 2 0 0 4 0 0 0 10 0 0 0 5 0 0 0 11 0 0 0 13 0 0 0

Headache 5 0 0 0 3 1 0 0 10 0 0 0 5 0 0 0 11 0 0 0 13 0 0 0

Hyperglycemia 5 0 0 0 4 0 0 0 6 2 2 0 1 4 0 0 9 2 0 0 13 0 0 0

Hypertension 5 0 0 0 4 0 0 0 9 1 0 0 4 1 0 0 11 0 0 0 12 1 0 0

Hypoalbuminemia 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 11 0 0 0 13 0 0 0

Hypocalcemia 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 11 0 0 0 13 0 0 0

Hypokalemia 5 0 0 0 4 0 0 0 10 0 0 0 4 1 0 0 11 0 0 0 13 0 0 0

Infections/infestations-Other 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 10 1 0 0 9 3 1 0

Intracranial hemorrhage 4 1 0 0 4 0 0 0 10 0 0 0 5 0 0 0 11 0 0 0 13 0 0 0

Lipase increased 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 11 0 0 0 12 1 0 0

Lung infection 5 0 0 0 4 0 0 0 10 0 0 0 3 2 0 0 11 0 0 0 13 0 0 0


S1312/I

CVP +

Inotuzumab

dose level 1

CVP +

Inotuzumab

dose level 2

CVP +

Inotuzumab

dose level 3

CVP +

Inotuzumab

dose level 4

CVP +

Inotuzumab

dose level 5

CVP +

Inotuzumab MTD

(n=5) (n=4) (n=10) (n=5) (n=11) (n=13)


ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5

Mucositis oral 5 0 0 0 4 0 0 0 9 0 1 0 5 0 0 0 11 0 0 0 12 1 0 0

Renal/urinary disorders-Other 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 11 0 0 0 12 1 0 0

Sepsis 5 0 0 0 4 0 0 0 10 0 0 0 5 0 0 0 11 0 0 0 11 0 2 0

Skin infection 5 0 0 0 4 0 0 0 9 1 0 0 5 0 0 0 11 0 0 0 13 0 0 0

MAX. GRADE ANY

ADVERSE EVENT 1 4 0 0 2 2 0 0 3 5 2 0 0 5 0 0 8 3 0 0 3 8 2 0

Response

CVP +

Inotuzumab

dose level 1

CVP +

Inotuzumab

dose level 2

CVP +

Inotuzumab

dose level 3

CVP +

Inotuzumab

dose level 4

CVP +

Inotuzumab

dose level 5

CVP +

Inotuzumab

MTD

N % N % N % N % N % N %

Complete Response 1 20 1 25 3 38 1 20 1 9 5 42

CR w/Incomplete Hem. Recovery 2 40 1 25 2 25 0 0 3 27 5 42

Partial Response 0 0 0 0 0 0 0 0 1 9 0 0

Resistant Disease 2 40 2 50 3 38 4 80 6 55 2 17

Total 5 100 4 100 8 100 5 100 11 100 12 100

The LIFETEST Procedure

Stratum 1: rowno = Total


S1312/I

48 13 5 2

At Risk

0 1 2 3

Years After Registration

0%

20%

40%

60%

80%

100%

At Risk

7.73548

in MonthsDeathsAt Risk

Median

Overall Survival - All Eligible PatientsData as of February 19, 2020

Stratum 1: rowno = Total

24 9 3 0

At Risk

0 1 2 3

Years After Registration

0%

20%

40%

60%

80%

100%

At Risk

10.91424

in MonthsDeathsAt Risk

Median

Overall Survival - Eligible Patients Treated at MTDData as of February 19, 2020


S1318/I-II

S1318 Phase I-II

Coordinating Group: SWOG

A Phase II Study of Blinatumomab (NSC-765986) and POMP (Prednisone,

Vincristine, Methotrexate, 6-Mercaptopurine) for Patients ≥ 65 Years of Age with

Newly Diagnosed Philadelphia-Chromosome Negative (Ph-) Acute Lymphoblastic

Leukemia (ALL) and of Dasatinib (NSC-732517), Prednisone and Blinatumomab

for Patients ≥ 65 Years of Age with Newly Diagnosed Philadelphia-Chromosome

Positive (Ph+) ALL, Relapsed/Refractory Philadelphia-Chromosome Positive

(Ph+) ALL, and Philadelphia-Chromosome-Like Signature (Ph-Like) ALL (Newly

Diagnosed or Relapsed/Refractory) with Known or Presumed Activating

Dasatinib-Sensitive Mutations or Kinase Fusions (DSMKF)

Participants:

SWOG, CTSU (Supported by Alliance, ECOG-ACRIN)

Study Chairs:

A Advani, K O'Dwyer, M Wiedewult (Alliance), J Park

(ECOG-ACRIN)

Statisticians:

M Othus, A Moseley

Data Coordinator:

T Maher

Date Activated:

01/12/2015

SCHEMA

REGISTRATION Step 1

D28 CR/CRi?

Dasatinib / Prednisone Induction

Continue Induction Cycle

YES

Blinatumomab

Re-induction 1

Ph-positive/Ph-like DSMKF Patients

NO

Until intolerance or progression for up to 10 years from registration, then

Protocol Therapy Complete

CR/CRi?

YES

NO

Off Protocol Therapy

REGISTRATION Step 2: Post-remission therapy

Blinatumomab/Dasatinib

REGISTRATION Step 3: Maintenance

Dasatinib/Prednisone

Ph-negative Patients:

Blinatumomab Induction

CR/CRi?

REGISTRATION Step 1

YES NO

REGISTRATION Step 2:

Post-remission therapy

Blinatumomab

Continued CR/Cri?

REGISTRATION Step 3:

Maintenance

POMP Chemotherapy

Protocol Therapy Complete

Blinatumomab

Re-induction

D56 CR/CRi?

YESNO

Continue Dasatinib

to Day 84

Continued CR/Cri?

YES

Blinatumomab

Re-induction 2

CR/CRi?

NO

YESYES

Continued CR/Cri?

NO

NO

CR/CRi?

YES NO

Off Protocol Therapy

YES NO


S1318/I-II

Objectives To evaluate the three-year survival rate in elderly

patients with newly diagnosed Philadelphia

chromosome (Ph) negative ALL treated with

blinatumomab followed by POMP maintenance.

To evaluate in a preliminary manner (feasibility

study) the safety of dasatinib-steroid based induction

followed by blinatumomab treatment in combination

with dasatinib followed by dasatinib-based

maintenance in elderly patients with newly diagnosed

Ph-positive ALL, relapsed/refractory Ph-positive

ALL, and Ph-like DSMKF ALL (newly-diagnosed

relapsed or refractory).

To evaluate toxicities in these patient populations

treated with these regimens.

To estimate the rates of complete response (CR),

complete response with incomplete count recovery

(CRi), and disease-free survival in Ph-negative

patients.

To estimate disease-free and overall survival in Ph-

positive ALL and Ph-like DSMKF ALL.

To estimate in each cohort the rate of minimal

residual disease (MRD) negativity, and the time to

achieve MRD negativity (exploratory analysis).

To determine whether anti-idiotype antibodies

directed against blinatumomab develop with

blinatumomab treatment in this study.

To estimate the incidence of the Ph-like signature in

elderly patients (≥ 65 years of age) with newly

diagnosed Philadelphia-chromosome negative ALL.

To estimate the incidence of the various tyrosine-

kinase fusions, making up the Ph-like signature in

elderly patients with newly diagnosed Philadelphia-

chromosome negative ALL.

To evaluate outcomes (event-free survival and

overall survival) in patients with the Ph-like signature

versus those without the Ph-like signature in Ph-

negative ALL.

Patient Population Patients must have a new morphologic diagnosis of

precursor B cell acute lymphoblastic leukemia (ALL)

(non-T cell) based on WHO criteria as defined in the

protocol. Patients with Burkitt's (L3) are not eligible

for this study. Patients with Ph-positive or Ph-like

ALL with dasatinib-sensitive mutations or kinase

fusions (DSMKF) may have relapsed or refractory

diagnoses. Patients must have a diagnosis of Ph-

negative ALL or Ph-positive ALL by cytogenetics,

FISH or polymerase chain reaction (PCR). If not

already known, BCR-ABL status (p190 or p210)

must be evaluated in Ph-positive patients by PCR. To

be registered under the Ph-like DSMKF criterion, the

patient must have a known or presumed activating

Ph-like signature and dasatinib-sensitive mutation or

kinase fusion as defined in the protocol. Patients must

have evidence of ALL in their marrow or peripheral

blood with at least 20% lymphoblasts (at least 5% for

relapsed/refractory patients) within 14 days prior to

registration. At registration, relapsed/refractory

patients must submit pathology and cytogenetics

reports from time of original diagnosis.

Immunophenotyping of the blood or marrow

lymphoblasts must be performed to determine lineage

within 14 days prior to registration. Patients with

only extramedullary disease in the absence of bone

marrow or blood involvement are not eligible.

Patients must not have testicular involvement.

Patients must not have received any prior

chemotherapy, radiation therapy, or other therapy for

the treatment of ALL (other than those noted below)

and must not be receiving any immunosuppressive

therapy. Patients must not have received any prior

investigational therapy within 28 days prior to

registration. Patients may have received the following

within any time prior to registration: low dose

chemotherapy, TKI therapy, steroids, hydroxyurea,

leukapheresis, intrathecal chemotherapy, or

vincristine. Patients must not have received any

monoclonal antibody therapy within 42 days of

registration.

Patients must be at least 65 years of age and have a

Zubrod performance status of 0-2. Patients must have

adequate hepatic, cardiac and renal function. Patients

must not have a history or presence of clinically

relevant CNS pathology and must have a lumbar

puncture to determine CNS involvement of ALL

within 14 days prior to registration. Patients must not

have systemic fungal, bacterial, viral, or other

infection that is not controlled. Patients must not have

Grade 2 or higher neuropathy (cranial, motor or

sensory) within 14 days prior to registration. Patients

known to be positive for HIV may be eligible,

providing they meet the criteria in the protocol.

Patients must not be candidates for allogeneic

hematopoietic stem cell transplant. Patients must not

have any known autoimmune disease. Ph-negative

patients must have PT/PTT/INR/fibrinogen and


S1318/I-II

neurologic assessment tests within 28 days prior to

registration. Ph-positive patients must not have active

pericardial effusion, ascites, or pleural effusion of

any grade.

Stratification/Descriptive Factors Patients are stratified by Registration Cohort: Ph-

negative vs Ph-positive/Ph-like DSMKF.

Accrual Goals This study will accrue up to 26 eligible Ph-negative

patients. An interim analysis will be performed

among the first 11 patients. If at least five complete

remissions (CR or CRi) are observed, then the study

will continue to full accrual. The study will continue

accruing while the remission data is being reviewed.

This study will initially accrue six eligible and

evaluable Ph-positive/Ph-like DSMKF patients. If the

regimen is considered safe, then the study will accrue

14 additional eligible and evaluable Ph-positive/Ph-

like DSMKF patients.

Summary Statement The study was activated on January 12, 2015. The

Ph-positive/Ph-like DSMKF cohort was temporarily

closed to Step 1 accrual on April 15, 2017 to assess

the safety profile. During this closure, on September

29, 2017 the FDA placed a temporary clinical hold

on this cohort. The hold was lifted on December 1,

2017, but the cohort remains closed to accrual while

the study team and NCI discuss whether to expand

this cohort. A protocol revision approved in

September 2019 added translational medicine (TM)

objectives and expanded the Ph-positive/Ph-like

DSMKF cohort to 20 eligible patients who receive

post-remission therapy. The Ph-positive/Ph-like

DSMKF cohort re-opened to accrual on September

16, 2019.

Ph-negative cohort:

The Ph-negative cohort permanently closed to

accrual on September 15, 2017 after reaching its

accrual goal with 31 patients. Two patients in this

cohort were ineligible: one due to elevated alkaline

phosphatase and another due to a final diagnosis of

follicular lymphoma. One patient went off treatment

to receive an alternate therapy per physician decision.

Two patients withdrew consent for further treatment

or follow-up.

Of the 29 patients evaluable for toxicities during

induction, one patient died of treatment-related

respiratory failure. Two other patients experienced

treatment-related non-hematologic Grade 4 toxicities.

There were no Grade 4 or higher treatment-related

non-hematologic toxicities reported during post-

remission. Two patients experienced Grade 4

treatment-related non-hematologic events during

maintenance: one with sepsis and hypertension and

one with sepsis and respiratory failure.

Ph-positive/Ph-like DSMKF cohort:

As of December 31, 2019, 20 patients have enrolled

to the Ph-positive/Ph-like DSMKF cohort, all of

whom are eligible and evaluable for toxicities. Two

patients experienced treatment-related non-

hematologic Grade 4 toxicities. There have been no

Grade 4 or higher treatment-related non-hematologic

toxicities reported during post-remission or

maintenance. Four patients remain on induction

treatment.



Registrations ending December 31, 2019

Institutions

Total

Reg Institutions

Total

Reg

Cleveland Clinic OH 5 Rochester, Univ of 1

City of Hope Med Ctr 4 San Diego, U of CA 1

Irvine, U of CA 3 UF Cancer Center/Arkansas, U of 1

So Calif, U of 3 Wichita NCORP 1

Michigan, U of 2 Yale University 1

Birmingham, U of AL 1 ALLIANCE 16

Greenville NCORP 1 ECOG-ACRIN 6

Heartland NCORP 1 NRG 2

Loma Linda Univ 1 Total (18 Institutions) 51

New Mexico MU-NCORP 1


S1318/I-II



Registrations ending December 31, 2019; Data as of February 18, 2020

TOTAL

Induction:

Ph-

Induction:

Ph+/Ph-like

NUMBER REGISTERED 51 31 20

INELIGIBLE 2 2 0

ELIGIBLE 49 29 20

Analyzable, Pend. Elig. 2 0 2

RESPONSE ASSESSMENT

Determinable 43 28 15

Not Determinable 2 1 1

Too Early 4 0 4


Evaluable 49 29 20




Induction:

Ph-

(n=29)

Induction:

Ph+/Ph-like

(n=20)

AGE

Median 75.4 73.1

Minimum 66.3 48.1

Maximum 84.0 87.2

SEX

Males 22 76% 5 25%

Females 7 24% 15 75%

HISPANIC

Yes 2 7% 4 20%

No 27 93% 15 75%

Unknown 0 0% 1 5%

RACE

White 28 97% 15 75%

Black 0 0% 1 5%

Asian 1 3% 2 10%

Unknown 0 0% 2 10%


S1318/I-II

Treatment Summary

Induction


TOTAL

Induction:

Ph-

Induction:

Ph+/Ph-like

NUMBER ON PROTOCOL TREATMENT 4 0 4

NUMBER OFF PROTOCOL TREATMENT


45 29 16

Treatment completed as planned 36 24 12

Adverse Event or side effects 3 1 2

Refusal unrelated to adverse event 1 1 0

Progression/relapse 1 1 0

Death 3 1 2

Other - not protocol specified 1 1 0

MAJOR PROTOCOL DEVIATIONS 0 0 0

LOST TO FOLLOW-UP 0 0 0



2 2 0


Induction





Induction: Ph-

(n=29)

Grade

Induction: Ph+/Ph-like

(n=20)

Grade

ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5

ALT increased 28 1 0 0 20 0 0 0

Catheter related infection 29 0 0 0 19 1 0 0

Confusion 28 1 0 0 20 0 0 0

Cytokine release syndrome 28 1 0 0 20 0 0 0

Dehydration 29 0 0 0 19 1 0 0

Diarrhea 28 1 0 0 19 1 0 0

Dysarthria 28 1 0 0 20 0 0 0

Dyspnea 26 2 1 0 19 1 0 0

Edema limbs 29 0 0 0 19 1 0 0

Fatigue 28 1 0 0 20 0 0 0

Febrile neutropenia 26 3 0 0 19 0 1 0

Fever 28 0 1 0 20 0 0 0

Gen disorders/admin site cond 29 0 0 0 19 1 0 0

Generalized muscle weakness 29 0 0 0 19 1 0 0

Heart failure 29 0 0 0 19 1 0 0

Hematoma 29 0 0 0 19 1 0 0


S1318/I-II

Induction: Ph-

(n=29)

Grade

Induction: Ph+/Ph-like

(n=20)

Grade

ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5

Hyperglycemia 25 4 0 0 19 1 0 0

Hypertension 26 3 0 0 20 0 0 0

Hypocalcemia 28 1 0 0 20 0 0 0

Hypokalemia 29 0 0 0 19 1 0 0

Hyponatremia 29 0 0 0 19 1 0 0

Hypophosphatemia 28 1 0 0 20 0 0 0

Hypotension 28 1 0 0 19 1 0 0

Hypoxia 28 1 0 0 19 1 0 0

Infections/infestations-Other 28 1 0 0 19 1 0 0

Infusion related reaction 28 1 0 0 20 0 0 0

Lung infection 27 1 1 0 18 1 1 0

Nausea 29 0 0 0 19 1 0 0

Nervous sys disorders-Other 28 1 0 0 20 0 0 0

Pneumonitis 28 1 0 0 20 0 0 0

Respiratory failure 28 0 0 1 20 0 0 0

Sepsis 29 0 0 0 19 0 1 0

TTP 28 1 0 0 20 0 0 0

Urinary tract infection 29 0 0 0 19 1 0 0

MAX. GRADE ANY ADVERSE

EVENT

13 13 2 1 11 7 2 0


S1612/II-III

S1612 Phase II-III


A Randomized Phase II/III Trial of "Novel Therapeutics" Versus Azacitidine

in Newly Diagnosed Patients with Acute Myeloid Leukemia (AML) or High-

Risk Myelodysplastic Syndrome (MDS), Age 60 or Older LEAP: LEss-Intense

AML Platform Trial

Participants:

SWOG, CTSU (Supported by CCTG, ECOG-ACRIN)

Study Chairs:

L Michaelis, R Walter, S Assouline (CCTG), A Im

(ECOG-ACRIN)

Statisticians:

M Othus, A Moseley

Data Coordinator:

T Maher

Date Activated:

12/22/2017

Date Closed*:

10/19/2018

*Temporary closure

SCHEMA

Objectives Phase II Component: To select, based on overall

survival, any or all of the "Novel Therapeutic"

regimens for further testing against azacitidine in

patients age 60 and older with newly diagnosed acute

myeloid leukemia (AML) or myelodysplastic

syndrome with excessive blasts-2 (MDS-EB-2).

Phase III Component: To compare overall survival of

the "Novel Therapeutic" regimens selected in the

Phase II portion of the trial to azacitidine in these

patient populations.


of the regimens in these patient populations.

R

E

G

I

S

T

R

A

T

I

O

N

R

A

N

D

O

M

I

Z

A

T

I

O

N

Arm A (control):

Azacitidine

Arm B:

Azacitidine + Nivolumab

Arm C:

Azacitidine + Midostaurin

Arm D*:

Decitabine/Cytarabine

*Arm D will open to accrual when Arms B and C have met Phase II accrual

and are temporarily closed for Phase II analysis

FLT3 Testing


S1612/II-III

To estimate response rates, event-free survival, and

relapse-free survival for these regimens in these

patient populations.

Patient Population Patients must have morphologically confirmed,

previously untreated AML or MDS-EB-2. Patients

with acute promyelocytic leukemia, biphenotypic

leukemia, blastic transformation of chronic

myelogenous leukemia are not eligible. Patients must

have disease present in the blood or bone marrow;

patients with only extramedullary disease are not

eligible. Patients must not be known to have AML in

the CNS. Patients must be deemed, in the judgment

of the treating physician, to be ineligible for intensive

induction therapy or must have refused intensive

induction therapy.

Patients who have received prior therapy with

midostaurin, any anti-PD-1 or anti-PD-L1 therapy,

any DNA-methyltransferase inhibitor, or prior 7+3

therapy for MDS are not eligible. Patients who are

transfusion-dependent and patients receiving growth

factor support are eligible; patients must discontinue

growth factor support prior to initiation of protocol

therapy. Prior malignancy is allowed providing

concurrent therapy is not required; active hormonal

therapy is allowed.

Patients must be at least 60 years old and must be

able to swallow oral medications. Clinical evaluation

at baseline including hematologic, hepatic, renal,

cardiac, and coagulation parameters must be

completed per protocol. Women and men must be

willing to use contraception as outlined in the

protocol. Patients must not have active infection

(systemic bacterial, fungal, or viral infection) that is

not controlled. Patients must be eligible for at least

one of the currently enrolling investigational

treatment arms. Refer to the protocol for arm-specific

eligibility criteria.

Patients must have specimens submitted for FLT3

testing as outlined in the protocol for randomization

stratification. Pretreatment cytogenetics must be

performed on all patients as outlined in the protocol.

Stratification/Descriptive Factors Patient randomization will be stratified by the

following factors: (1) Zubrod performance status: 0-1

vs 2-4; (2) FLT3-ITD status based on central

laboratory results: wild type FLT3 vs mutated FLT3-

ITD vs non-evaluable; and (3) baseline blast

percentage: MDS-EB-2 (< 20%) vs AML (20% or

higher).

Up to 100 eligible patients will be enrolled to each

arm for Phase II analysis. Up to 200 additional

eligible patients will be enrolled to each arm for

Phase III analysis. If all three experimental arms

complete full Phase III accrual, this study will enroll

approximately 1,500 eligible patients.

The Phase II interim analysis to evaluate for stopping

for futility will be performed when 52 events have

been observed. For arms carried forward for Phase III

testing, two additional interim analyses will be

performed when 50% and 75% of the expected

events have been observed (207 and 311 events,

respectively).

Summary Statement This trial opened on December 22, 2017. On October

22, 2018, the study team temporarily closed all arms

to accrual after observing unexpected toxicities on

the Azacitidine + Nivolumab (Aza + Nivo) arm

during the first two cycles of therapy. The FDA

placed a partial clinical hold on this trial on October

25, 2018, mandated that all patients discontinue

nivolumab, and later denied the study team's request

to reopen the Aza + Nivo arm with revised eligibility

criteria. A protocol revision was submitted to re-open

the trial with the Azacitidine (Aza), Azacitidine +

Midostaurin (Aza + Mido), and Decitabine +

Cytarabine arms. This revision includes a quality of

life component, and was disapproved for reasons

primarily related to this component. A response to

CTEP's review is in progress. The trial remains

closed to accrual.

As of October 22, 2018, 78 patients had been

randomized (26 per arm).

Aza arm: One patient withdrew from protocol

therapy before starting treatment. This patient is

considered major protocol deviation and is not

analyzable for adverse events but will be analyzed for

other endpoints. Of the 25 patients who have been

evaluated for adverse events, two experienced Grade

5 treatment-related non-hematologic toxicities: sepsis

(1 patient) and small intestinal perforation (1). Two

others experienced Grade 4 treatment-related non-


Aza + Nivo arm: One patient was ineligible due to

low baseline blast count. Of the 25 patients who have

been evaluated for adverse events, five experienced

Grade 5 treatment-related non-hematologic toxicities:

sepsis (2), respiratory failure (2), and sudden death

NOS (1). One patient who died of respiratory failure

also experienced Grade 4 treatment-related lung


S1612/II-III

infection (coded as Infections/infestation-Other). Five

others experienced Grade 4 treatment-related non-

hematologic toxicities, including one with

hemophagocytic lymphohistiocytosis (coded as

Immune sys disorders-Other).

Aza + Mido arm: One patient was ineligible due to

low baseline blast count. One patient withdrew from

protocol therapy before starting treatment and

another died before starting treatment. These two

patients are considered major protocol deviations and

are not analyzable for adverse events but will be

analyzed for other endpoints. Of the 23 patients who

have been evaluated for adverse events, three


hematologic toxicities: respiratory failure (1), lung

infection (1), and heart failure (1). Two others



Across all arms, 27 patients went off protocol

treatment for reasons other than those specified in the

protocol, primarily due to treatment futility,

physician decision, or to receive different therapy

(24). Two patients on the Aza+Nivo arm went off

protocol treatment because of the FDA mandate to

stop nivolumab. One patient went off protocol

treatment because the patient did not wish to hold

study drug per protocol for a Grade 3 toxicity.


Randomization

Institutions

Total

Reg Institutions

Total

Reg

Kaiser Perm NCORP 9 Arizona CC, Univ of 1

Heartland NCORP 6 Carle CC NCORP 1

H Lee Moffitt CC 3 Davis, U of CA 1

Montana NCORP 3 Georgia NCORP 1

New Mexico MU-NCORP 3 Loyola University 1

Rochester, Univ of 3 Southeast COR NCORP 1

Greenville NCORP 2 ALLIANCE 23

Michigan CRC NCORP 2 NRG 12

PCRC NCORP 2 ECOG-ACRIN 2

Wayne State Univ 2 Total (19 Institutions) 78


Data as of February 18, 2020

TOTAL Azacitidine

Azacitidine +

Nivolumab

Azacitidine +

Midostaurin

NUMBER REGISTERED 78 26 26 26

INELIGIBLE 2 0 1 1

ELIGIBLE 76 26 25 25


Evaluable 73 25 25 23

Not Evaluable 3 1 0 2


S1612/II-III



Azacitidine

(n=26)

Azacitidine +

Nivolumab

(n=25)

Azacitidine +

Midostaurin

(n=25)

AGE

Median 75.4 76.4 76.2

Minimum 61.9 66.4 65.7

Maximum 86.3 86.5 85.8

SEX

Males 15 58% 17 68% 16 64%

Females 11 42% 8 32% 9 36%

HISPANIC

Yes 0 0% 1 4% 1 4%

No 25 96% 23 92% 23 92%

Unknown 1 4% 1 4% 1 4%

RACE

White 23 88% 21 84% 21 84%

Black 2 8% 3 12% 2 8%

Asian 1 4% 0 0% 0 0%

Unknown 0 0% 1 4% 2 8%

BASELINE BLAST PERCENTAGE

<20% (MDS-EB-2) 8 31% 6 24% 6 24%

≥20% (AML) 18 69% 19 76% 19 76%

FLT3 - CENTRALLY REVIEWED

Wild type FLT3-ITD 25 96% 21 84% 22 88%

Mutated FLT3-ITD 1 4% 4 16% 3 12%

ZUBROD PERFORMANCE STATUS

0-1 21 81% 21 84% 20 80%

2-4 5 19% 4 16% 5 20%

Treatment Summary


TOTAL

NUMBER ON PROTOCOL TREATMENT 2



74

Adverse Event or side effects 9

Refusal unrelated to adverse event 9

Progression/relapse 15

Death 14

Other - not protocol specified 27

MAJOR PROTOCOL DEVIATIONS 3

LOST TO FOLLOW-UP 0

CONSENT WITHDRAWAL AFTER TREATMENT INITIATION 0


S1612/II-III






Azacitidine

(n=25)

Grade


(n=25)

Grade


(n=23)

Grade

ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5

ALT increased 25 0 0 0 24 1 0 0 23 0 0 0

AST increased 25 0 0 0 24 0 1 0 23 0 0 0

Acidosis 24 1 0 0 25 0 0 0 23 0 0 0

Acute kidney injury 25 0 0 0 24 1 0 0 23 0 0 0

Anorexia 25 0 0 0 25 0 0 0 22 1 0 0

Arthralgia 25 0 0 0 24 1 0 0 23 0 0 0

Atrial fibrillation 25 0 0 0 25 0 0 0 22 1 0 0

Back pain 25 0 0 0 25 0 0 0 22 1 0 0

Cardiac troponin I increased 24 1 0 0 25 0 0 0 23 0 0 0

Catheter related infection 24 1 0 0 25 0 0 0 23 0 0 0

Chest pain - cardiac 25 0 0 0 25 0 0 0 22 1 0 0

Colitis 25 0 0 0 25 0 0 0 22 1 0 0

Constipation 25 0 0 0 24 1 0 0 23 0 0 0

Dry mouth 25 0 0 0 25 0 0 0 22 1 0 0

Dyspnea 25 0 0 0 24 1 0 0 22 1 0 0

ECG QT corrected int prolong 25 0 0 0 25 0 0 0 22 1 0 0

Ejection fraction decreased 25 0 0 0 24 1 0 0 23 0 0 0

Epistaxis 24 1 0 0 25 0 0 0 23 0 0 0

Fatigue 24 1 0 0 24 1 0 0 19 4 0 0

Febrile neutropenia 15 9 1 0 18 6 1 0 15 7 1 0

Fever 25 0 0 0 24 1 0 0 23 0 0 0

GI disorders-Other, specify 24 1 0 0 25 0 0 0 23 0 0 0

Generalized muscle weakness 25 0 0 0 24 1 0 0 22 1 0 0

Heart failure 24 1 0 0 24 0 1 0 21 1 0 1

Hyperglycemia 25 0 0 0 25 0 0 0 22 1 0 0

Hypertension 25 0 0 0 25 0 0 0 22 1 0 0

Hypoalbuminemia 24 1 0 0 24 1 0 0 23 0 0 0

Hypokalemia 24 1 0 0 24 0 1 0 23 0 0 0

Hyponatremia 25 0 0 0 24 1 0 0 22 1 0 0

Hypophosphatemia 25 0 0 0 24 1 0 0 23 0 0 0

Hypotension 25 0 0 0 23 2 0 0 19 4 0 0

Hypoxia 24 0 1 0 24 1 0 0 23 0 0 0

INR increased 25 0 0 0 25 0 0 0 22 1 0 0

Immune sys disorders-Other 25 0 0 0 24 0 1 0 23 0 0 0

Infections/infestations-Other 25 0 0 0 23 1 1 0 20 3 0 0

Joint infection 25 0 0 0 25 0 0 0 22 1 0 0

Lung infection 23 1 1 0 19 4 2 0 19 3 0 1

Mucositis oral 25 0 0 0 25 0 0 0 21 2 0 0

Pneumonitis 25 0 0 0 24 0 1 0 23 0 0 0

Pruritus 24 1 0 0 25 0 0 0 23 0 0 0

Pulmonary edema 25 0 0 0 25 0 0 0 22 0 1 0

Rash maculo-papular 24 1 0 0 25 0 0 0 23 0 0 0

Respiratory failure 25 0 0 0 23 0 0 2 22 0 0 1


S1612/II-III

Azacitidine

(n=25)

Grade


(n=25)

Grade


(n=23)

Grade

ADVERSE EVENTS ≤2 3 4 5 ≤2 3 4 5 ≤2 3 4 5

Sepsis 23 0 1 1 21 0 2 2 22 0 1 0

Skin infection 25 0 0 0 24 1 0 0 23 0 0 0

Small intestinal perforation 24 0 0 1 25 0 0 0 23 0 0 0

Sudden death NOS 25 0 0 0 24 0 0 1 23 0 0 0

Supraventricular tachycardia 24 1 0 0 25 0 0 0 23 0 0 0

Typhlitis 25 0 0 0 25 0 0 0 22 1 0 0

MAX. GRADE ANY ADVERSE

EVENT

10 11 2 2 9 6 5 5 8 10 2 3


S1712/II

S1712 Phase II


A Randomized Phase II Study of Ruxolitinib (NSC-752295) in Combination

with BCR-ABL Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

(CML) Patients with Molecular Evidence of Disease

Participants:

SWOG, CTSU

Study Chairs:

K Sweet, J Radich

Statisticians:

M Othus, A Moseley

Data Coordinator:

L Highleyman

Date Activated:

07/20/2018

SCHEMA

Objectives To compare the rate of molecular response 4.5

(MR4.5) after 12 months of combination therapy

with ruxolitinib plus a TKI (bosutinib, dasatinib or

nilotinib) versus a TKI alone, based on local PCR

testing to measure BCR-ABL transcripts in chronic

phase CML patients with molecular evidence of

disease.


of each regimen in this patient population.

To estimate progression-free survival and overall

survival of each regimen in this patient population.

Patient Population Patients must have a diagnosis of chronic phase

chronic myeloid leukemia (CML) without any history

of progression to accelerated or blast phase CML as

defined in the protocol. Patients must have detectable

BCR-ABL transcripts measured by RT-PCR at a

CLIA-approved laboratory as outlined in the

protocol.

R

A

N

D

O

M

I

Z

A

T

I

O

N

Arm 1:

Single-agent TKI

Arm 2:

Single-agent TKI

+Ruxolitinib


S1712/II

Patients must have received treatment with one of

bosutinib, dasatinib or nilotinib for a minimum of six

months prior to registration and must be expected to

remain on the same TKI for the next 12 months. If

patients have received more than one TKI, the reason

for changing treatment must have been intolerance to

the prior TKI. Patients must have been receiving TKI

treatment for CML for at least one year and for no

more than 10 years prior to randomization. Prior

malignancy is allowed providing it does not require

concurrent therapy; active hormonal therapy is

allowed.

Patients must have adequate hematologic, hepatic,

renal, and cardiac function. Patients known to be

HIV+ are allowed provided they have undetectable

HIV viral loads on their most recent viral load test

within six months prior to randomization.

Patients must be offered participation in specimen

banking for future research. With patient consent,

specimens must be submitted as outlined in the

protocol.

Stratification/Descriptive Factors Patient randomization will be stratified by the

following factors: (1) time on any TKI therapy prior

to randomization: ≥ 1 and < 4 years vs ≥ 4 and ≤ 10

years; and (2) current TKI: bosutinib vs.dasatinib vs

nilotinib.

Accrual Goals The accrual goal is 84 patients to achieve 74 eligible

patients (37 per arm).

One interim analysis is planned at the time when 12-

month MR4.5 data are available from 19 patients on

each arm.

Summary Statement This study activated on July 20, 2018. As of

December 31, 2019, 16 patients had been

randomized. Two patients (one on each arm) are

ineligible because they changed prior TKI treatment

due to lack of response.

One patient on the TKI+Ruxolitinib arm withdrew

consent after initiating treatment due to extra visits

and associated costs. No patient has experienced a

Grade 3 or higher treatment-related adverse event.


Registrations ending December 31, 2019

Institutions

Total

Reg Institutions

Total

Reg

Heartland NCORP 4 Utah, U of 1

Duke Univ Med Ctr 2 ALLIANCE 2

H Lee Moffitt CC 2 NRG 2

Hawaii MU-NCORP 1 ECOG-ACRIN 1

New Mexico MU-NCORP 1 Total (9 Institutions) 16



TOTAL

Single Agent

TKI

TKI +

Ruxolitinib

NUMBER REGISTERED 16 8 8

INELIGIBLE 2 1 1

ELIGIBLE 14 7 7

Analyzable, Pend. Elig. 1 0 1


Evaluable 10 7 3

Too Early 4 0 4


S1712/II



Single Agent

TKI

(n=7)

TKI +

Ruxolitinib

(n=7)

AGE

Median 61.5 41.5

Minimum 19.7 21.7

Maximum 75.5 71.0

SEX

Males 4 57% 2 29%

Females 3 43% 5 71%

HISPANIC

Yes 1 14% 0 0%

No 5 71% 7 100%

Unknown 1 14% 0 0%

RACE

White 5 71% 7 100%

Black 1 14% 0 0%

Pacific Islander 1 14% 0 0%

TKI TIME

≥ 1 and < 4 years 3 43% 4 57%

≥ 4 and ≤ 10 years 4 57% 3 43%

CURRENT TKI

Dasatinib 3 43% 5 71%

Nilotinib 4 57% 2 29%

Treatment Summary


TOTAL

NUMBER ON PROTOCOL TREATMENT 13



1

Refusal unrelated to adverse event 1

MAJOR PROTOCOL DEVIATIONS 0

LOST TO FOLLOW-UP 0



1


S1905/II

S1905 Phase II


A Phase II Study of AKR1C3-Activated Prodrug OBI-3424 in Patients with

Relapsed/Refractory T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Participants:

SWOG, CTSU

Study Chairs:

A Advani, N Papadantonakis, C Yeung

Statisticians:

M Othus, M Duong

Data Coordinator:

L Highleyman

Objectives To assess the response rate [complete remission (CR)

or CR with incomplete count recovery (CRi)] of

OBI-3424 in patients with relapsed/refractory T-cell

acute lymphoblastic leukemia (TALL).


of OBI-3424 in this patient population.

To estimate event-free survival, relapse-free survival,

and overall survival in this patient population.

To estimate minimal/measurable residual disease

(MRD) negativity (among patients who achieve CR

or CRi).

Patient Population Patients must have a diagnosis of relapsed or

refractory T-ALL based on WHO classification.

Patients must have evidence of acute leukemia in

their peripheral blood or bone marrow with at least

5% lymphoblasts in the peripheral blood or bone

marrow. Patients with only extramedullary disease

are not eligible. Patients must be refractory to or have

relapsed following prior standard induction therapy.

Patients must have no evidence of central nervous

system (CNS) disease including a negative lumbar

puncture for patients with clinical signs or symptoms

consistent with CNS involvement.

Patients must have received prior treatment with

nelarabine as described in the protocol. Patients must

not have had chemotherapy within 14 days prior to

registration except for steroids, oral

60mercaptopurine, oral methotrexate, vincristine,

intrathecal chemotherapy, or hydroxyurea. Patients

must not have undergone allogeneic hematopoietic

transplant within 90 days prior to registration.

Patients must be at least 18 years of age, adequate

renal and hepatic functions, and a Zubrod

performance status of 0-3. Patients must not have

uncontrolled systemic fungal, bacterial, viral or other

infection. Patients must have no evidence of Grade 2

or greater acute graft versus host disease (GVHD) or

moderate or severe limited chronic GVHD and must

have no history of extensive GVHD of any severity.

Patients must agree to have bone marrow and blood

specimens submitted for MRD testing and must be

offered the opportunity to participate in specimen

banking.

Accrual Goals The accrual goal is 43 patients to achieve 35

evaluable patients. Enrollment will be paused for

additional toxicity monitoring and to evaluate

response after 10 and then 20 patients are enrolled in

a three-stage design.


S1925/III

S1925 Phase III


Randomized Phase III Study of Early Intervention with Venetoclax and

Obinutuzumab Versus Delayed Therapy with Venetoclax and Obinutuzumab

in Newly Diagnosed Asymptomatic High-Risk Patients with Chronic

Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL):

EVOLVE CLL/SLL Study

Participants:

SWOG, CTSU (Supported by ECOG-ACRIN)

Study Chairs:

D Stephens, B Hill, J Pagel, A Mato (ECOG-ACRIN)

Statisticians:

A Moseley, M Othus

Data Coordinators:

T Maher, L Kingsbury

SCHEMA

Objectives To evaluate whether early treatment with venetoclax

and obinutuzumab (V-O) extends overall survival

compared with delayed treatment with V-O in high-

risk (chronic lymphocytic leukemia [CLL]

international prognostic indicator [CLL-IPI] ≥4 or

complex cytogenetics), newly diagnosed

asymptomatic CLL/SLL patients.

R

A

N

D

O

M

I

Z

A

T

I

O

N

Early Arm:

Venetoclax + Obinutuzumab

Delayed Arm:

Venetoclax + Obinutuzumab*

*Treatment on Delayed Arm begins when the 2018 International

Workshop on CLL (IWCLL) indication is met.


S1925/III

To compare overall response rates (complete

response [CR] + partial response), CR rates,

progression-free survival, and event-free survival

between arms.

To evaluate safety and tolerability of each arm.

To compare time to second CLL-directed treatment

(from randomization and from response) between

arms.

To compare relapse-free survival and time to second

objective disease progression between arms.

To compare the rates of Richter’s transformation

between arms.

To describe distribution of Cumulative Illness Rating

Scale across the study, in each treatment arm, and to

estimate the interaction between the scale and

treatment arm and OS.

To assess the impact of early intervention with V-O

versus delayed therapy with V-O in CLL patients in

relation to Health-Related Quality of Life (HRQoL)

using the FACT-Leukemia scale.

To assess the impact of the two treatment arms on the

specific domains of the FACT-Leukemia, including

physical, social, emotional, and functional well-being

and leukemia-specific HRQoL.

Patient Population Patients must have a confirmed diagnosis of CLL or

small lymphocytic lymphoma (SLL) (collectively

referred to as CLL) according to the 2018

International Workshop on CLL (IWCLL) within 12

months prior to registration. Patients must not meet

any of the IWCLL specified criteria for active CLL

therapy. Patients must have CLL-IPI Score ≥ 4 or

complex cytogenetics.

Patients must not have received any prior CLL-

directed therapy, and the treating physician must

have the intent of using V-O as initial therapy.

Treatment with high dose corticosteroids or

intravenous immunoglobulin for autoimmune

complications of CLL must be completed at least

four weeks prior to enrollment. Palliative steroids

must be at a dose ≤ 20 mg/day at registration. Prior

therapy with anti CD20 monoclonal antibodies is not

allowed.

Patients must have performance status 0 - 2 and have

adequate hematologic, renal, and hepatic function.

FISH and cytogenetic analyses, IgVH mutational

status, and serum beta-2 microglobulin levels must be

obtained prior to registration according to the timing

in the protocol. Patients must not have current

clinically significant gastrointestinal malabsorption

and must be able to take oral medications. Patients

must not have uncontrolled autoimmune hemolytic

anemia, idiopathic thrombocytopenia purpura,

bleeding disorder, or history of cardiac disease,

stroke, or intracranial hemorrhage per the timing

specified in the protocol. Patients must not have

uncontrolled active infection with hepatitis B or C,

and those with latent hepatitis B must agree to

prophylaxis during and for six months following V-O

therapy. HIV-infected patients on effective anti-

retroviral therapy are allowed provided they have

undetectable HIV viral loads on their most recent

viral load test within six months prior to

randomization. Patients must not require continued

therapy with a strong inhibitor or inducer of

CYP3A4/5.

Patients must be offered participation in specimen

banking for future research. Patients who are able to

complete patient reported outcome forms in English,

Spanish, French, German, Russian, or Mandarin must

agree to participate in the quality of life assessments

as outlined in the protocol.

Stratification/Descriptive Factors Patient randomization will be stratified by CLL-IPI

risk score status: high risk (4-6 points) vs very high

risk (≥ 7 points or complex cytogenetics).

Accrual Goals The accrual goal is 247 patients to achieve 222

eligible patients randomized in a 2:1 ratio (148 on the

Early Arm and 74 on the Delayed Arm).

Formal interim analyses for efficacy and futility are

planned after approximately 40%, 60%, and 80% of

the expected events have occurred across both arms.

A041501 November 2019

Template Version Date: September 24, 2013

Alliance Study A041501 – A Phase III Trial to Evaluate the Efficacy of the Addition of Inotuzumab ozogamicin (a conjugated anti-CD22 Monoclonal Antibody) to Frontline Therapy in Young Adults

(Ages 16-39 years) with Newly Diagnosed Precursor B-Cell ALL

Data as of 09/16/2019

Committee: Leukemia Study Statisticians: Jun (Vivien) Yin, Ph.D. Gabriela Perez Burbano, M.S Study Chair: Daniel J. DeAngelo, M.D., Ph. D. 1.0 OBJECTIVES Primary

1. To confirm tolerability of the combination regimen with the addition of inotuzumab ozogamicin to the pediatric-inspired regimen of CALGB 10403.

2. To determine whether the addition of inotuzumab ozogamicin significantly improves the event-free survival (EFS) in patients who achieve an induction response achieved with the pediatric-inspired regimen of CALGB 10403, without censoring for transplant.

Secondary

1. To determine the impact of inotuzumab ozogamicin on disease-free (DFS) and overall survival (OS) in patients who achieve an induction response.

2. To determine whether the addition of inotuzumab ozogamicin significantly improves the event-free survival (EFS) in patients who achieve an induction response achieved with the pediatric-inspired regimen of CALGB 10403, with censoring for transplant.

3. To determine the impact of inotuzumab ozogamicin on minimal residual disease (MRD) and correlate this with the EFS, DFS and OS.

4. To determine the prognosis based on patients’ LDA gene signature in terms of EFS, DFS, and OS after treatment with or without inotuzumab ozogamicin when added to the C10403 backbone regimen.

5. To evaluate the toxicity and tolerability of the addition of inotuzumab ozogamicin to the pediatric-inspired regimen of CALGB 10403.



2.0 CURRENT SCHEMA

3.0 ELIGIBILITY CRITERIA Pre-registration Eligibility Criteria (Step 0)



• Bone marrow submission for LDA Assay

Registration Eligibility Criteria (Step 1) • Newly diagnosed patients with CD-22 positive B-cell acute lymphoblastic leukemia (WHO

criteria). Burkitt type ALL is NOT eligible. Patients who have BCR-ABL fusion transcript determined by FISH or RT-PCR or t(9;22)(q34;q11) by cytogenetics are not eligible for this trial and should be considered for enrollment on studies that incorporate imatinib or other tyrosine kinase inhibitors during induction.

• Prior Treatment (Section 3.3.3) o No prior therapy for acute leukemia except emergency therapy (corticosteroids or

hydroxyurea for ≤ 7 days) for blast cell crisis, or renal failure due to leukemia infiltration of the kidneys

o Single-dose intrathecal cytarabine is allowed prior to registration (see also Section 7.1.1.2).

o Prior steroid therapy is allowed. • Not pregnant and not nursing. • Age ≥ 18 years and < 40 years. • ECOG Performance Status 0-2 • Patients with Down Syndrome are excluded from this study due to the likelihood of excessive

toxicity. These patients should be treated in consultation with a pediatric oncologist. Randomization Eligibility Criteria (Step 2)

• Completion of remission induction therapy (per Section 7.2). • Patients with M2 marrow or better are eligible. Patients with M3 or M4 marrow (greater than

25% lymphoblasts) will not be eligible to be randomized. • Lab values

o Absolute Neutrophil Count (ANC) ≥ 1,000/mm3 o Platelet Count ≥ 100,000/mm3 o Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), except for patients with known

Gilbert’s syndrome o AST ≤ 8 x upper limit of normal (ULN)

4.0 TREATMENT SCHEDULE Table 4a. Safety Run-in: Course I and Inotuzumab

Induction Inotuzumab Course I (Remission Induction) Arm 3: Cycle1 Arm 3: Cycle 2

Allopurinol 300 mg PO daily until peripheral

blasts and extramedullary disease are reduced.

-

-

IT-Ara-C 70 mg IT on Day 1. - -

Dexamethasone 5mg/m2 PO or IV BID on Days 1-7 and 15-21

-

-

Vincristine 1.5 mg/m2 (maximum 2 mg) IV on Days 1, 8, 15, and 22

-

-

Daunorubicin -25 mg/m2 IV on Days 1, 8, 15, and 22

- -



PEG-asparaginase 2000 IU/m2 IV x 1 dose on Day 4 (OR Day 5 OR Day 6). (cap dose

at 3750 IU) *

-

-

IT Methotrexate

15 mg IT on Day 8 and Day 29. For patients with CNS3 disease, IT-MTX is also administered on

Day 15 and 22.

-

-

Bone marrow aspirate and biopsy

specimen Day 29

Day 28

Day 28

Inotuzumab - 0.5 mg/m2/day IV

on Day 1, 8 and 15 of a 28-day cycle. *

0.5 mg/m2/day IV on Day 1, 8 and 15 of a 28-day cycle. *

Table 4b. Safety Run-in: Course II-V

Course II: Remission

Consolidation Course III: Interim

Maintenance Course IV: Delayed

Intensification Course V:

Maintenance Therapy Cyclophosphamide 1000 mg/m2 IV on Day 1

and 29 -

1000 mg/m2 IV on

Day 29 -

Cytarabine

75 mg/m2 IV or SC on Days 1-4, 8-11, 29-32,

and 36-39

-

75 mg/m2 IV or SC on Days 29-32 and 36-39

-

6-Mercaptopurine 60 mg/m2 PO on Days 1-14 and 29-42. **

- - 75 mg/m2/day PO on Days 1-84. **

IT Methotrexate

15 mg IT (addition of 50 mg of hydrocortisone

optional per institutional guidelines) on Days 1, 8, 15, and 22 [omit dose on Day 15 and 22 for CNS3

patients].

15 mg IT on Days 1 and 31

15 mg IT (addition of 50 mg of

hydrocortisone optional per

institutional guidelines) on Days 1, 29, and 36



institutional guidelines) on Day 1. IT

methotrexate also is given on Day 29 of the

first 4 courses of maintenance therapy

PO Methotrexate

-

-

-

20 mg/m2 PO weekly on Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71,

and 78. Round to nearest 2.5 mg dose. PO methotrexate is

held on Day 29 of the first 4 courses of

maintenance therapy (when IT methotrexate

is given).

IV Methotrexate

-

100 mg/m2 IV (escalate by 50 mg/m2/dose) on

Days 1, 11, 21, 31, and 41.

-

-



Rituximab for CD20+ patients only *

375 mg/m2 IV on Days 1 and 8 and then again on

Days 29 and 36. *

375 mg/m2 IV on Days 1 and 11. *


-

Vincristine 1.5 mg/m2 (maximum 2 mg) IV on Days 15, 22,

43, and 50.

1.5 mg/m2 (maximum 2 mg) IV push on Days 1, 11,

21, 31, and 41.

1.5 mg/m2 (maximum 2 mg) IV on Days 1, 8,

15, 43, and 50.

1.5 mg/m2 (maximum dose 2 mg) IV on

Days 1, 29, and 57

PEG-Asparaginase

2000 IU/m2 IV on Days 15 and 43. (cap dose at

3750 IU) *

2000 IU/m2 IV on Days 2 and 22. Cap dose at 3750 IU. *

2000 IU/m2 IV on Day 4 (OR Day 5 OR Day 6) AND Day 43. (cap

dose at 3750 IU) *

-

Bone marrow aspirate and biopsy specimen

Day 56

-

One week after completion of Course

IV

-

Dexamethasone

-

-

5 mg/m2 PO or IV BID on Days 1-7 and 15-

21

6 mg/m2/day PO or IV divided BID every 4 weeks on Days 1-5,

29-33, and 57-61 Doxorubicin - - 25 mg/m2 IV on Days

1, 8, and 15 -

Thioguanine

-

-

60 mg/m2/day PO on Days 29-42, at least 1 hour after the evening

meal.

-

*Premedicate with 650 mg acetaminophen, 100 mg hydrocortisone and 25-50 mg diphenhydramine (or equivalent) prior to PEG-asparaginase ** Not to be taken with milk or citrus products Table 4c. Phase III: Course I, Randomization, and Inotuzumab

Induction Randomization: M0, M1, M2 <=25% blasts Course I (Remission

Induction) Arm 1 Arm 2: Cycle1 Arm 2: Cycle 2

Allopurinol

300 mg PO daily until peripheral blasts and

extramedullary disease are reduced.

-

-

-

IT-Ara-C 70 mg IT on Day 1. - - -

Dexamethasone 5mg/m2 PO or IV BID on Days 1-7 and 15-21

-

-

-

Vincristine 1.5 mg/m2 (maximum 2 mg) IV on Days 1, 8, 15, and 22

-

-

-

Daunorubicin -25 mg/m2 IV on Days 1, 8, 15, and 22

- - -

PEG-asparaginase 2000 IU/m2 IV x 1 dose on Day 4 (OR Day 5 OR Day 6). (cap dose at 3750 IU) *

-

-

-



IT Methotrexate

15 mg IT on Day 8 and Day 29. For patients with CNS3

disease, IT-MTX is also administered on Day 15 and

22.

-

-

-

Bone marrow aspirate and biopsy specimen Day 29

Day 28

Day 28

Inotuzumab - -

0.5 mg/m2/day IV on Day 1, 8 and 15 of a

28-day cycle. *

0.5 mg/m2/day IV on Day 1, 8 and 15 of a

28-day cycle. * Table 4d. Phase III: Course II-V

Course II: Remission Consolidation

Course III: Interim Maintenance

Course IV: Delayed Intensification

Course V: Maintenance Therapy

Cyclophosphamide 1000 mg/m2 IV on Day 1 and 29

-

1000 mg/m2 IV on Day 29

-

Cytarabine

75 mg/m2 IV or SC on Days 1-4, 8-11, 29-32,

and 36-39

-

75 mg/m2 IV or SC on Days 29-32 and 36-39

-

6-Mercaptopurine 60 mg/m2 PO on Days 1-14 and 29-42. **

- - 75 mg/m2/day PO on Days 1-84. **

IT Methotrexate

15 mg IT (addition of 50 mg of hydrocortisone

optional per institutional guidelines) on Days 1, 8, 15, and 22 [omit dose on Day 15 and 22 for CNS3

patients].

15 mg IT on Days 1 and 31



institutional guidelines) on Days 1, 29, and 36



institutional guidelines) on Day 1. IT

methotrexate also is given on Day 29 of the

first 4 courses of maintenance therapy

PO Methotrexate

-

-

-

20 mg/m2 PO weekly on Days 8, 15, 22, 29, 36, 43, 50, 57, 64, 71,

and 78. Round to nearest 2.5 mg dose. PO methotrexate is

held on Day 29 of the first 4 courses of

maintenance therapy (when IT methotrexate

is given).

IV Methotrexate

-

100 mg/m2 IV (escalate by 50 mg/m2/dose) on

Days 1, 11, 21, 31, and 41.

-

-

Rituximab for CD20+ patients only *

375 mg/m2 IV on Days 1 and 8 and then again on

Days 29 and 36. *



-

Vincristine 1.5 mg/m2 (maximum 2 mg) IV on Days 15, 22,

43, and 50.

1.5 mg/m2 (maximum 2 mg) IV push on Days 1, 11,

21, 31, and 41.

1.5 mg/m2 (maximum 2 mg) IV on Days 1, 8,

15, 43, and 50.

1.5 mg/m2 (maximum dose 2 mg) IV on

Days 1, 29, and 57



PEG-Asparaginase

2000 IU/m2 IV on Days 15 and 43. (cap dose at

3750 IU) *

2000 IU/m2 IV on Days 2 and 22. Cap dose at 3750 IU. *

2000 IU/m2 IV on Day 4 (OR Day 5 OR Day 6) AND Day 43. (cap

dose at 3750 IU) *

-

Bone marrow aspirate and biopsy specimen

Day 56

-

One week after completion of Course

IV

-

Dexamethasone

-

-

5 mg/m2 PO or IV BID on Days 1-7 and 15-

21

6 mg/m2/day PO or IV divided BID every 4 weeks on Days 1-5,

29-33, and 57-61 Doxorubicin - - 25 mg/m2 IV on Days

1, 8, and 15 -

Thioguanine

-

-

60 mg/m2/day PO on Days 29-42, at least 1 hour after the evening

meal.

-

*Premedicate with 650 mg acetaminophen, 100 mg hydrocortisone and 25-50 mg diphenhydramine (or equivalent) prior to PEG-asparaginase ** Not to be taken with milk or citrus products 5.0 STUDY DESIGN 5.1 Study Phase/Type of Design/Stratification Factors This study has two separate components: an upfront tolerability confirmation portion and then a full phase III evaluation of the two treatment regimens. Randomization will be stratified on the following stratification factors: LDA gene signature (BCR-ABL1-like versus not), age (≤25 vs >25), CD20+ status (CD20+ or not) and BM Response (M0/M1 vs. M2). Patients will be randomized to receive one of the two treatment regimens with equal allocation using a dynamic allocation method to balance the stratification factors. 5.2 Primary Endpoint The primary endpoint in this phase III trial is event-free survival (EFS) in those who achieve an induction response. Event-free survival will be defined as the time from induction response to the time of progressive-disease, secondary malignancy, or death. Those who have not experienced one of these defined events of interest at their last evaluation will be censored at that time point. All randomized patients meeting the eligibility criteria will be evaluable for the primary endpoint (EFS) analysis based on an intention to treat. The trial endpoint of EFS begins at the time of randomization, so patients that die during induction or fail to achieve an induction response are not randomized. We estimate that ~95% of patients who start induction will achieve an M2 marrow or better and will be randomized. Based on the transplant rates reported in C10403 (8 transplants overall reported out of the 296 evaluable patients), and the fact that we are using C10403 trial EFS estimates (not censored for transplant) as the basis for sample size calculations for this trial, we will perform the primary analysis without censoring patients at the time of transplant. Thus, our primary analysis will include all information regardless of transplant, assuming rates and timing of transplant will be similar across arms. This study has two separate components: an upfront tolerability assessment portion (run-in phase) followed by a full phase III evaluation of the two treatment regimens. The primary component of this trial will include patients who achieve a response to the induction therapy (estimated to be about 95% of the patients).



Based on the C10403 study, we expect an accrual of about 8 patients/month with induction response AYA B-cell ALL patients. With 140 induction response patients per treatment arm (280 total number of randomized patients), we will have 90% power to detect a significant improvement in EFS with the addition of inotuzumab assuming that the true EFS distributions correspond to 3-year EFS rates of 65% vs. 80% using a one-sided log-rank test to specifically test an significance level of 0.025. Assuming that at least 95% of patients will achieve some response to induction therapy in this protocol, and another 5% of patients otherwise non-evaluable (ineligible, drop out etc.), 310 total patients (155 per arm) will need to be enrolled to this trial. The final analysis will be conducted after 100 events have been observed without censoring for transplant. 5.3 Target Accrual The target accrual for this study is 324 patients, 162 per arm, using a 1:1 randomization. The target accrual rate is 8 patients per month. 6.0 CURRENT ACCRUAL

Study Activation Date 06/01/2017 Target Accrual (n) 324 Patients Screened or Pre-registered (n) 93 Current Accrual (n) 70 Expected Accrual Rate 8/month Accrual Rate – Safety Run-In .67/month Accrual Rate – Phase III 4.00/month

Safety-Run In

Phase III

0 0 01 0 0

1 0

31

Jun17 Jul17 Aug17 Sep17 Oct17 Nov17 Dec17 Jan18 Feb18 Mar18

Month

0

5

10

15

20

25

30

35

40

Total

Num

ber o

f Pati

ents

Expected Accrual 324 PatientsActual Accrual

A041501 Cumulative Accrual: Actual Versus ExpectedNumbers on the Accrual Line are M onthly Accrual



7.0 CURRENT STUDY STATUS This study opened on 06/01/2017 and has accrued 93 patients to pre-registration. A total of 70 patients were fully enrolled (Safety Run-in: 6, Phase III cohort: 64) with twenty-two screen failures and one patient who has not been fully registered yet. Study temporarily closed for the safety run-in for the first 6 evaluable patients, no patients received a Dose-Limiting Toxicity (DLT). The study reopened on 06/15/2018 for the Phase III portion of the trial. There are currently 64 patients on study. Of these, 46 achieved an M0/M1 marrow after Course I and were randomized, 7 went off treatment, 8 are waiting to be randomized and 3 failed to achieve an M0/M1/M2 and hence were not randomized. 8.0 PATIENT CHARACTERISTICS Table 8a. Demographics

Phase III Patients Randomized

(N=46)

Phase III Patients Not Randomized

(N=18) Safety Run-in

(N=6) Total

(N=70) Age

N 46 18 6 70 Mean (SD) 26.7 (6.36) 26.2 (5.26) 21.8 (2.79) 26.2 (5.97) Median 27.0 25.0 22.5 25.0 Q1, Q3 21.0, 32.0 22.0, 29.0 19.0, 24.0 21.0, 31.0 Range 18.0, 39.0 19.0, 37.0 18.0, 25.0 18.0, 39.0

Race

White 31 (67.4%) 12 (66.7%) 5 (83.3%) 48 (68.6%) Black or African American 2 (4.3%) 1 (5.6%) 0 (0.0%) 3 (4.3%) Asian 2 (4.3%) 0 (0.0%) 0 (0.0%) 2 (2.9%) Not reported: patient refused or

not available 6 (13.0%) 2 (11.1%) 1 (16.7%) 9 (12.9%)

02

53

33

54

2

5

5

54

8

73

Jun18 Aug18 Oct18 Dec18 Feb19 Apr19 Jun19 Aug19

Month

05

101520253035404550556065707580

Tota

l Num

ber o

f Pat

ients

Expected Accrual 324 PatientsActual Accrual




Phase III Patients Randomized

(N=46)

Phase III Patients Not Randomized

(N=18) Safety Run-in

(N=6) Total

(N=70) Unknown: Patient unsure 5 (10.9%) 3 (16.7%) 0 (0.0%) 8 (11.4%)

Gender

f 16 (34.8%) 8 (44.4%) 3 (50.0%) 27 (38.6%) m 30 (65.2%) 10 (55.6%) 3 (50.0%) 43 (61.4%)

Table 8b. Stratification Factors

Patients Randomized

(N=46) Total

(N=46) Age Group <=25 23 (50.0%) 23 (50.0%) >25 23 (50.0%) 23 (50.0%) CD20 status CD20+ 22 (47.8%) 22 (47.8%) Not CD20+ 24 (52.2%) 24 (52.2%) BM Response M0/M1 43 (93.5%) 43 (93.5%) M2 3 (6.5%) 3 (6.5%)

9.0 ADVERSE EVENTS

Adverse events (AEs) are reported using CTCAE version 5.0. 57 patients are evaluable for adverse events (AE) analyses (Arm 1: 38.60%, Arm 2: 35.09%, Arm 3: 15.79%, Arm 4: 10.53%). Commonly occurring grade 3+ AE include Lymphopenia (18%, Arm 1; 25%, Arm2; 22%, Arm 3; 51%, Arm 4), Neutrophils (96%, Arm 1; 90%, Arm 2; 100%, Arm 3; 100%, Arm 4), Platelets (87%, Arm 1; 95%, Arm 2; 89%, Arm 3; 100%, Arm 4), Anemia (32%, Arm 1; 50%, Arm 2; 11%, Arm 3; 50%, Arm 4), and White blood cell decreased (27%, Arm 1; 35%, Arm 2; 55%, Arm 3; 67%, Arm 4). There have been 2 deaths on treatment (one death (Prior to randomization) was due to a probably related Stroke, and one death (Arm 2: Initial agents with Ino (exp)) due to an unlikely related lung infection.) and two deaths off treatment (one patient (Arm 1: Initial agents w/o Ino (control)) from ALL (Disease) after withdrawing from protocol therapy, and one patient (Prior to Randomization) from HHV6 after going off treatment for other complicating disease). See below for a summary of adverse events by arm regardless of attribution.



Summary of Grade 3+ Adverse Events Regardless of Attribution

Number of Evaluable Patients: Initial agents w/o Ino (control) (Arm 1)=22

Initial agents with Ino (exp) (Arm 2)=20 Prior to Randomization (Arm 3)=9

Safety Run-in (Arm 4)=6 Patients with a maximum: Arm n (%) Total

Grade 3 Event 1 0 (0.0%)

2 2 (10.0%)

3 1 (11.1%)

4 0 (0.0%)

Grade 4 Event 1 22 (100.0%)

2 17 (85.0%)

3 7 (77.8%)

4 6 (100.0%)


2 1 (5.0%)

3 1 (11.1%)

4 0 (0.0%)

Hematologic Adverse Events


2 1 (5.0%)

3 1 (11.1%)

4 0 (0.0%)

Grade 4 Event 1 22 (100.0%)

2 18 (90.0%)

3 8 (88.9%)

4 6 (100.0%)


2 0 (0.0%)

3 0 (0.0%)

4 0 (0.0%)

Non-Hematologic Adverse Events

Grade 3 Event 1 12 (54.5%)

2 10 (50.0%)

3 3 (33.3%)




Number of Evaluable Patients: Initial agents w/o Ino (control) (Arm 1)=22

Initial agents with Ino (exp) (Arm 2)=20 Prior to Randomization (Arm 3)=9

Safety Run-in (Arm 4)=6 Patients with a maximum: Arm n (%)

4 3 (50.0%)


2 5 (25.0%)

3 5 (55.6%)

4 3 (50.0%)


2 1 (5.0%)

3 1 (11.1%)

4 0 (0.0%)

Note: Summaries are based on available patient data

Listing of Grade 3+ Adverse Events Max Grade Per Patient Per Event

Regardless of Attribution Number of Evaluable Patients:

Initial agents w/o Ino (control) (Arm 1)=22 Initial agents with Ino (exp) (Arm 2)=20

Prior to Randomization (Arm 3)=9 Safety Run-in (Arm 4)=6

Grade of AdverseEvent Arm 3-Severe 4-LifeThr 5-Lethal

n (%) n (%) n (%) Hematologic Adverse Events Blood/Bone Marrow Anemia 1 6 ( 27%) 1 ( 5%) 0 ( 0%) 2 10 ( 50%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%) 4 3 ( 50%) 0 ( 0%) 0 ( 0%) Hemoglobin increased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 2 ( 22%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Lymphopenia 1 2 ( 9%) 2 ( 9%) 0 ( 0%) 2 2 ( 10%) 3 ( 15%) 0 ( 0%)








n (%) n (%) n (%) 3 0 ( 0%) 2 ( 22%) 0 ( 0%) 4 2 ( 33%) 1 ( 17%) 0 ( 0%) Neutrophils/granulocytes (ANC/AGC) 1 1 ( 5%) 20 ( 91%) 0 ( 0%) 2 1 ( 5%) 17 ( 85%) 0 ( 0%) 3 3 ( 33%) 6 ( 67%) 0 ( 0%) 4 0 ( 0%) 6 (100%) 0 ( 0%) Platelets 1 5 ( 23%) 14 ( 64%) 0 ( 0%) 2 3 ( 15%) 16 ( 80%) 0 ( 0%) 3 3 ( 33%) 5 ( 56%) 0 ( 0%) 4 0 ( 0%) 6 (100%) 0 ( 0%) White blood cell decreased 1 0 ( 0%) 6 ( 27%) 0 ( 0%) 2 1 ( 5%) 6 ( 30%) 0 ( 0%) 3 2 ( 22%) 3 ( 33%) 0 ( 0%) 4 0 ( 0%) 4 ( 67%) 0 ( 0%) Non-Hematologic Adverse Events ** Acute kidney injury 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 2 ( 10%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Dyspareunia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Hepatobiliary disorders - Other, specify 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 10%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Infections and infestations - Oth spec 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 10%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 2 ( 33%) 0 ( 0%) 0 ( 0%)








n (%) n (%) n (%) Infusion related reaction 1 0 ( 0%) 1 ( 5%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Lung infection 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 1 ( 5%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Nervous system disorders - Oth spec 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Pulmonary edema 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 10%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Respiratory failure 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 11%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Stroke 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 1 ( 11%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Thromboembolic event 1 0 ( 0%) 1 ( 5%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Urine output decreased 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 1 ( 5%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%)








n (%) n (%) n (%) Vasovagal reaction 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 5%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Cardiovascular Hypertension 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypotension 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 3 ( 15%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Coagulation Disseminated intravascular coagulation 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 1 ( 11%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Fibrinogen 1 7 ( 32%) 0 ( 0%) 0 ( 0%) 2 5 ( 25%) 3 ( 15%) 0 ( 0%) 3 4 ( 44%) 1 ( 11%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) PTT (Partial Thromboplastin Time) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Gastrointestinal Colitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Diarrhea 1 0 ( 0%) 0 ( 0%) 0 ( 0%)








n (%) n (%) n (%) 2 3 ( 15%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Dysphagia (difficulty swallowing) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Mucositis/stomatitis (func/symp) 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Nausea 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Pancreatitis 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Typhlitis (cecal inflammation) 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Vomiting 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Hemorrhage Hematoma 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%)








n (%) n (%) n (%) Hepatic ALT, SGPT 1 4 ( 18%) 0 ( 0%) 0 ( 0%) 2 3 ( 15%) 0 ( 0%) 0 ( 0%) 3 3 ( 33%) 0 ( 0%) 0 ( 0%) 4 4 ( 67%) 0 ( 0%) 0 ( 0%) AST, SGOT 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 5 ( 25%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Albumin, serum-low (hypoalbuminemia) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 2 ( 10%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Alkaline phosphatase 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 1 ( 17%) 0 ( 0%) Bilirubin (hyperbilirubinemia) 1 2 ( 9%) 1 ( 5%) 0 ( 0%) 2 2 ( 10%) 1 ( 5%) 0 ( 0%) 3 3 ( 33%) 1 ( 11%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Infection/Febrile Neutropenia Febrile neutropenia 1 4 ( 18%) 0 ( 0%) 0 ( 0%) 2 11 ( 55%) 0 ( 0%) 0 ( 0%) 3 2 ( 22%) 0 ( 0%) 0 ( 0%) 4 4 ( 67%) 1 ( 17%) 0 ( 0%) Infection w/ normal or Grade 1/2 ANC 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Infection with unknown ANC 1 0 ( 0%) 1 ( 5%) 0 ( 0%) 2 5 ( 25%) 2 ( 10%) 0 ( 0%)








n (%) n (%) n (%) 3 0 ( 0%) 2 ( 22%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Lymphatics Edema:limb 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Metabolic/Laboratory Calcium, serum-low (hypocalcemia) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Glucose, serum-high (hyperglycemia) 1 6 ( 27%) 1 ( 5%) 0 ( 0%) 2 3 ( 15%) 1 ( 5%) 0 ( 0%) 3 2 ( 22%) 0 ( 0%) 0 ( 0%) 4 2 ( 33%) 0 ( 0%) 0 ( 0%) Lipase 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Phosphate, serum-low (hypophosphatemia)

1 0 ( 0%) 0 ( 0%) 0 ( 0%)

2 2 ( 10%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Potassium, serum-low (hypokalemia) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Sodium, serum-low (hyponatremia) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%)








n (%) n (%) n (%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Triglyceride, serum-high 1 2 ( 9%) 3 ( 14%) 0 ( 0%) 2 1 ( 5%) 2 ( 10%) 0 ( 0%) 3 2 ( 22%) 1 ( 11%) 0 ( 0%) 4 4 ( 67%) 1 ( 17%) 0 ( 0%) Neurology Depressed level of consciousness 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 1 ( 5%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Encephalopathy 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 1 ( 11%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Mood alteration 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Neuropathy: sensory 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Syncope (fainting) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 1 ( 17%) 0 ( 0%) 0 ( 0%) Pain Pain 1 4 ( 18%) 0 ( 0%) 0 ( 0%) 2 2 ( 10%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 2 ( 33%) 0 ( 0%) 0 ( 0%) Pulmonary








n (%) n (%) n (%) Adult Respiratory Distress Syndrome 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 2 ( 10%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Dyspnea (shortness of breath) 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Hypoxia 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 2 ( 10%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Renal /Genitourinary Creatinine 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%) Syndromes Tumor lysis syndrome 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 1 ( 5%) 0 ( 0%) 0 ( 0%) 3 0 ( 0%) 0 ( 0%) 0 ( 0%) 4 0 ( 0%) 0 ( 0%) 0 ( 0%)

10.0 IMBEDDED CORRELATIVES A041501: Low Density Array (LDA) Assay and EFS Participation to imbedded correlative A041501 was required for all patient registered to A041501. There are currently 93 patients enrolled on this study. A041501: Minimal Residual Disease (MRD) Detection and EFS Participation to imbedded correlative A041501 was required for all patient registered to A041501. There are currently 93 patients enrolled on this study. A041501-LC1: Molecular Genetics of AYA ALL



Participation to imbedded correlative A041501-LC1 was optional for all patient registered to A041501. There are currently 79 patients enrolled on this study. A041501-PP1: Pharmacogenomic Determinants of toxicity Participation to imbedded correlative A041501-PP1 was optional for all patient registered to A041501. There are currently 79 patients enrolled on this study. A041501-PP2: Asparaginase Pharmacokinetics in AYA Participation to imbedded correlative A041501-PP2 was optional for all patient registered to A041501. There are currently 78 patients enrolled on this study. A041501-HO1: Health Outcomes: Adherence to Oral Chemotherapy and Outcomes in Adolescents and Young Adults (AYAs) with Acute Lymphoblastic Leukemia (ALL) Participation to imbedded correlative A041501-HO1 was optional for all patient registered to A041501. There are currently 74 patients enrolled on this study.



Alliance Study A041701 – A Randomized Phase II/III Study of Conventional Chemotherapy +/- Uproleselan (GMI-1271) in Older Adults with Acute Myeloid Leukemia Receiving Intensive Induction

Chemotherapy

Data as of 09/10/2019 Committee: Leukemia Study Statisticians: Jun (Vivien) Yin, Ph.D. Study Chair: Geoffrey L. Uy, MD Luke Huebner, M.S. 1.0 OBJECTIVES Primary: Phase II

Compare the event-free survival (EFS) of daunorubicin, cytarabine plus uproleselan versus daunorubicin and cytarabine in subjects ≥ age 60 with previously untreated acute myeloid leukemia

Primary: Phase III Compare the overall survival (OS) of the daunorubicin, cytarabine plus uproleselan to daunorubicin and cytarabine in this patient population.

Secondary

1. Determine the rates of complete remission (CR), complete remission with incomplete count recovery (CRi), complete remission with incomplete hematopoietic recovery (CRh) and cytogenetic complete remission (CCyR) for each chemotherapy regimen.

2. Determine the overall survival (OS), and remission duration of patients for each chemotherapy regimen.

3. Describe the frequency and severity of adverse events for patients for each chemotherapy regimen

4. Describe the interaction of pretreatment disease and patient characteristics including morphology, cytogenetics, molecular genetic features, WBC count and hemogram, and performance status on clinical outcomes.

2.0 CURRENT SCHEMA



3.0 ELIGIBILITY CRITERIA

• Diagnosis of AML based on 2017 WHO criteria excluding acute promyelocytic leukemia with PMLRARA

• No activating mutation in Fms-like tyrosine kinase-3 (FLT3) • No evidence of CNS involvement of AML • No prior chemotherapy for MDS or AML including hypomethylating agents or lenalidomide (see

section 3.3.2 for exceptions) • Age ≥ 60 years • Total Bilirubin ≤ 3 x upper limit of normal (ULN) • Creatinine ≤ 3 x upper limit of normal (ULN) or Creatinine Clearance ≥ 30 mL/min/1.73m2

4.0 TREATMENT SCHEDULE

Arm 1 Treatment Remission Induction Second Remission

Induction (if required) Consolidation (up to 3 cycles)

Daunorubicin 60 mg m2/day IV Days 1-3 (total dose 180 mg/m2)

60 mg/m2/day IV Days 1-2 (total dose 120 mg/m2)

Cytarabine 100 mg/m2/day CIVI Days 1-7 (168 hour infusion, total dose 700 mg/m2)

100 mg/m2/day CIVI Days 1-5 (120 hour infusion, total dose 500 mg/m2)

2 g/m2/day by IV infusion over 3 hours on Days 1-5 (total dose 10 gms/m2)

Bone marrow Day 14 (+3 days)



examination (aspirate and biopsy)

Arm 2 Treatment Remission Induction Second Remission

Induction (if required) Consolidation (up to 3 cycles)

Uproleselan 800 mg IV, once a day on Day 1, and q12 hours on Days 2-10

800 mg IV, once on Day 1, and q12 hours on Days 2-8

Daunorubicin 60 mg m2/day IV Days 2-4 (total dose 180 mg/m2)

60 mg/m2/day IV Days 2-3 (total dose 120 mg/m2)

800 mg IV, once on Day 1, and q12 hours on Days 2-8

Cytarabine 100 mg/m2/day CIVI Days 2-8 (168 hour infusion, total dose 700 mg/m2)

100 mg/m2/day CIVI Days 2-6 (120 hour infusion, total dose 500 mg/m2)

2 g/m2/day by IV infusion over 3 hours on Days 2-6 (total dose 10 gms/m2)

Bone marrow examination (aspirate and biopsy)

Day 14 (+3 days)

5.0 STUDY DESIGN

5.1 Study Phase/Type of Design/Stratification Factors This is an open-label, randomized phase II/III study. The primary objective of the Phase II study is to determine based on the event-free survival (EFS) whether the combination of uproleselan plus daunorubicin/cytarabine should be tested further against standard of care: daunorubicin/cytarabine in the phase III component of this trial. The primary objective of the Phase III study is to compare the OS between uproleselan plus daunorubicin/cytarabine versus the control arm (daunorubicin/cytarabine). Patients accrued during the Phase II portion of the trial will be used in the Phase III analysis. Randomization will be stratified on the following stratification factors: age (60-69 vs. 70 and older), performance status (0-1 vs. 2-3), de novo vs. secondary/therapy related AML. Patients will be randomized to receive one of the two treatment regimens with equal allocation using a permutated block method to balance the stratification factors. 5.2 Primary Endpoint Phase II component: Event-free survival (EFS). EFS is defined as the time from the date of registration/randomization to the first of failure to achieve a CR during induction, relapse, or death due to any cause, with patients last known to be alive and event-free censored at the date of last contact. Patients who are removed from protocol treatment for allogeneic HCT will not be censored for EFS. Patients who receive other non-protocol therapy without relapse or CR during induction will be censored at the time they discontinue the treatment. All randomized patients meeting the eligibility criteria will be evaluable for the primary endpoint (EFS) analysis based on an intention to treat.

Patients will be randomized to receive daunorubicin and cytarabine or the novel regimen with equal allocation using a dynamic allocation method. E2906 study6 reported a 1-year EFS of 29%. Therefore, we estimate that the 1-year EFS in the daunorubicin and cytarabine arm will be 30%. We are interested in testing the alternative hypothesis that the 1-year EFS in the novel experimental arm will be at least 47% (a 17% improvement in the 1-year EFS). This translates to an improvement



in the median EFS from 7 to 11 months (HR = 0.64), assuming exponential distributions of EFS in both control and experimental arm. A sample size of 131 evaluable patients per arm (262 total) provides 96% power to detect an improvement in median EFS from 7 months to 11 months (a hazard ratio of 0.64), using a one-sided log-rank test at a significance level of 10%. Phase III component: Overall survival (OS) – measured from the date of registration/randomization to death from any cause, with patients last known to be alive censored at the date of last contact. All randomized patients will be evaluable for this endpoint. A median OS of 12 months is anticipated on the control arm.6 We are interested in testing the alternative hypothesis that the median OS in the novel experimental arm will be at least 16 months (a 33% improvement in the median OS, for a HR of 0.75). This translates into an improvement in the 1-year OS from 50% to 60%, assuming exponential survival. A randomized trial comparing the novel agents passing the Phase II component against the standard arm (daunorubicin and cytarabine) will be conducted using a 1:1 randomization scheme. A sample size of 335 evaluable patients per arm (670 total) provides 90% power to detect an improvement in median OS from 12 months to 16 months (a hazard ratio of 0.75), using a one-sided log-rank test at a significance level of 2.5%. The overall power for the phase II/III design is 81% (=0.9*0.9). The total sample size for the Phase III component will include the patients rolled over from the Phase II component.

5.3 Target Accrual The anticipated accrual rate is approximately 5 pts/month in the first year, 10 pts/month second year, and 14 patients per month afterwards. The phase II component is expected to accrue in 30 months after trial activation. Accrual will be suspended between the phase II and phase III component for primary endpoint analysis from phase II; the suspension between the Phase II and Phase III is expected to be 12 months to allow for follow-up on the last phase II patients and completion of the primary analysis for phase II. The phase III component is expected to accrue in approximately 59 months. Including the suspension between Phase II and III, the total study duration is expected to be approximately 83 months, or until the last Phase III patient accrued has been observed for at least 12 months.

6.0 CURRENT ACCRUAL

Study Activation Date 01/15/2019 Target Accrual (n) 670 Patients Screened/Pre-registered (n) 52/43 Current Accrual (n) 32 Expected Accrual Rate, 1st year 5/month Accrual Rate – Since activation 3.5/month Accrual Rate – Past 6 months 5.3/month



7.0 CURRENT STUDY STATUS

The study opened on 01/15/2019 and has screened 52 patients, pre-registered 43 patients (the study protocol was amended to add pre-registration step post activation) and accrued 32 patients as of the beginning of September. There have been four deaths; two on treatment (Both were due to Tumor) and two off treatment (one was due to Tumor and one was due to disease progression). One patient went off treatment due to an adverse event of ejection fraction decreased.

8.0 PATIENT CHARACTERISTICS Table 8a. Demographics

Active Treatment (Daunorubicin +

Cytarabine) (N=15)

Active Treatment (Uproleselan + Daunorubicin +

Cytarabine) (N=17)

Total (N=32)

Age N 15 17 32 Mean (SD) 67.6 (4.3) 68.5 (6.1) 68.0 (5.3) Median 67.5 67.6 67.6

0 0

3

62

6

5

9 1

Jan19 Feb19 Mar19 Apr19 May19 Jun19 Jul19 Aug19 Sep19

Month

0

5

10

15

20

25

30

35

40

45

50To

tal N

umbe

r of P

atien

tsExpected Accrual 670 PatientsActual Accrual




Active Treatment (Daunorubicin +

Cytarabine) (N=15)


Cytarabine) (N=17)

Total (N=32)

Q1, Q3 63.4, 69.9 63.3, 73.9 63.4, 71.1 Range (61.6-75.6) (61.5-77.9) (61.5-77.9) Race White 2 (13.3%) 1 (5.9%) 3 (9.4%) Black or African American 0 (0.0%) 3 (17.6%) 3 (9.4%) 13 (86.7%) 13 (76.5%) 26 (81.3%) Gender Male 6 (40.0%) 6 (35.3%) 12 (37.5%) Female 9 (60.0%) 11 (64.7%) 20 (62.5%)

Table 8b. Stratification Factors

Active Treatment (Daunorubicin + Cytarabine)

(N=15)


Cytarabine) (N=17)

Total (N=32)

Age Group

60-69 12 (80.0%) 12 (70.6%) 24 (75.0%)

70 and older 3 (20.0%) 5 (29.4%) 8 (25.0%)

ECOG Performance status

0-1 13 (86.7%) 13 (76.5%) 26 (81.3%)

2-3 2 (13.3%) 4 (23.5%) 6 (18.8%)

ONSET AML

de novo 14 (93.3%) 17 (100.0%) 31 (96.9%)

Secondary/therapy related

1 (6.7%) 0 (0.0%) 1 (3.1%)

9.0 ADVERSE EVENTS

9.1 Adverse Event Summary Eighteen patients were evaluable for adverse events; fourteen patients have no AE data submitted. All 18 have reported a grade 3 or higher adverse event. Commonly occurring grade 4+ AE include Neutrophils/granulocytes (Arm A: 5 (56%); Arm B: 2 (22%)), Platelets (Arm A: 6



(67%); Arm B: 4 (44%)), and White blood cell decreased (Arm A: 6 (67%); Arm B: 4 (44%)). There have been four deaths; two on treatment (Both were due to Tumor) and two off treatment (one was due to Tumor and one was due to disease progression). One patient went off treatment due to an adverse event of grade 4 ejection fraction decreased. See Appendix F for a detailed list of adverse events by arm regardless of attribution. Note: Arm A = Daunorubicin + Cytarabine, Arm B = Uproleselan + Daunorubicin + Cytarabine.


Number of Evaluable Patients: Arm A =9 Arm B =9

Patients with a maximum: Arm n (%) Total

Grade 3 Event A 1 (11.1%)

B 3 (33.3%)


B 4 (44.4%)


B 2 (22.2%)



B 0 (0.0%)


B 0 (0.0%)


B 0 (0.0%)



B 3 (33.3%)


B 4 (44.4%)


B 2 (22.2%)






Arm A=9 Arm B=9 Grade of AdverseEvent

Arm 3-Severe 4-LifeThr 5-Lethal n (%) n (%) n (%)


ALT, SGPT A 2 ( 22%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 11%) 0 ( 0%) AST, SGOT A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 11%) 0 ( 0%) Albumin, serum-low (hypoalbuminemia)

A 3 ( 33%) 0 ( 0%) 0 ( 0%)

B 0 ( 0%) 0 ( 0%) 0 ( 0%) Anemia A 6 ( 67%) 1 ( 11%) 0 ( 0%) B 4 ( 44%) 0 ( 0%) 0 ( 0%) Anorexia A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 1 ( 11%) 0 ( 0%) 0 ( 0%) Bilirubin (hyperbilirubinemia) A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 1 ( 11%) 0 ( 0%) 0 ( 0%) Death not associated with CTCAE term

A 0 ( 0%) 0 ( 0%) 0 ( 0%)

B 0 ( 0%) 0 ( 0%) 1 ( 11%) Dyspnea (shortness of breath) A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 11%) 0 ( 0%) Ejection fraction decreased A 0 ( 0%) 1 ( 11%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Febrile neutropenia A 6 ( 67%) 0 ( 0%) 0 ( 0%) B 3 ( 33%) 0 ( 0%) 0 ( 0%) Glucose, serum-high (hyperglycemia)

A 1 ( 11%) 0 ( 0%) 0 ( 0%)

B 1 ( 11%) 0 ( 0%) 0 ( 0%) Heart failure A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Infection w/ normal or Grade 1/2 ANC

A 1 ( 11%) 0 ( 0%) 0 ( 0%)

B 0 ( 0%) 0 ( 0%) 0 ( 0%) Infection with unknown ANC A 3 ( 33%) 0 ( 0%) 0 ( 0%) B 1 ( 11%) 1 ( 11%) 1 ( 11%) Infections and infestations - Oth spec

A 0 ( 0%) 0 ( 0%) 0 ( 0%)







B 1 ( 11%) 0 ( 0%) 0 ( 0%) Lung infection A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 1 ( 11%) 0 ( 0%) 0 ( 0%) Lymphopenia A 2 ( 22%) 2 ( 22%) 0 ( 0%) B 1 ( 11%) 2 ( 22%) 0 ( 0%) Magnesium, serum-high (hypermagnesemia)

A 1 ( 11%) 0 ( 0%) 0 ( 0%)

B 0 ( 0%) 0 ( 0%) 0 ( 0%) Mucositis/stomatitis (func/symp) A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 1 ( 11%) 0 ( 0%) 0 ( 0%) Neutrophils/granulocytes (ANC/AGC)

A 0 ( 0%) 5 ( 56%) 0 ( 0%)

B 1 ( 11%) 2 ( 22%) 0 ( 0%) Pain A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Pericardial effusion (non-malignant)

A 0 ( 0%) 0 ( 0%) 0 ( 0%)

B 1 ( 11%) 0 ( 0%) 0 ( 0%) Pericarditis A 0 ( 0%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 1 ( 11%) 0 ( 0%) Phosphate, serum-low (hypophosphatemia)

A 1 ( 11%) 0 ( 0%) 0 ( 0%)

B 1 ( 11%) 0 ( 0%) 0 ( 0%) Platelets A 1 ( 11%) 6 ( 67%) 0 ( 0%) B 0 ( 0%) 4 ( 44%) 0 ( 0%) Potassium, serum-high (hyperkalemia)

A 0 ( 0%) 0 ( 0%) 0 ( 0%)

B 1 ( 11%) 0 ( 0%) 0 ( 0%) Potassium, serum-low (hypokalemia)

A 1 ( 11%) 0 ( 0%) 0 ( 0%)

B 0 ( 0%) 0 ( 0%) 0 ( 0%) Respiratory failure A 0 ( 0%) 1 ( 11%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%) Sodium, serum-low (hyponatremia) A 1 ( 11%) 0 ( 0%) 0 ( 0%) B 0 ( 0%) 0 ( 0%) 0 ( 0%)







Supraventricular and nodal arrhythmia

A 0 ( 0%) 0 ( 0%) 0 ( 0%)

B 1 ( 11%) 0 ( 0%) 0 ( 0%) White blood cell decreased A 1 ( 11%) 6 ( 67%) 0 ( 0%) B 0 ( 0%) 4 ( 44%) 0 ( 0%)

10.0 IMBEDDED CORRELATIVES Not Applicable



Alliance - A041702 – A Randomized Phase III Study of Ibrutinib Plus Obinutuzumab Versus Ibrutinib Plus Venetoclax and Obinutuzumab in Untreated Older Patients (≥ 70 Years of Age) with

Chronic Lymphocytic Leukemia (CLL)

Data as of 09/06/2019

Committee: Leukemia Study Statisticians: Amy Ruppert Stark, PhD Study Chair: Jennifer Woyach, MD Gabriela Perez, MS 1.0 OBJECTIVES Primary

To compare the progression-free survival (PFS) between control treatment and experimental treatment strategies: ibrutinib/obinutuzumab (IO) with ibrutinib maintenance (IM) versus ibrutinib/venetoclax/obinutuzumab (IVO) regardless of IM or observation.

Secondary

1. To compare BM MRD- CR rates, MRD rates, and depth of response at Cycle 15 Day 1 between patients treated with IO versus IVO.

2. To compare overall survival (OS) between the control and experimental treatment strategies: IO with IM versus IVO regardless of IM or observation.

3. To compare the 5-year PFS and OS for the control and experimental treatment strategies: IO with IM versus IVO regardless of IM or observation.

4. To describe the toxicity profile for each of the treatment strategies and by each treatment course.

5. To determine whether baseline cytogenetic abnormalities by FISH and stimulated karyotype or IGHV mutational status correlates with BM MRD- CR status and PFS of each treatment strategy.

6. To determine whether mutations in TP53, NOTCH1, SF3B1, XPO1, PLCG2, and BRAF correlate with BM MRD- CR status or PFS of each treatment strategy and determine how the frequency of these mutations change over time.

7. To determine how frequencies of DNA mutations change during the course of therapy and whether these changes are different between IO versus IVO treatment.

8. To compare MRD status between blood and bone marrow at the end of induction treatment/Cycle 15 Day 1 to determine whether blood MRD can be used as a surrogate to bone marrow MRD with these treatment regimens.



RE-REGISTRATION (Step 2)

2.0 CURRENT SCHEMA Schema

1 Cycle = 28 Days

Patients will be followed for 10 years from study registration (Step 1) or until death, whichever comes first.

PRE-REGISTRATION (STEP 0)

REGISTRATION/RANDOMIZATION (STEP 1)

Central specimen submission for FISH (see Sec 6.2), Local assessment of Rai Stage (see Sec 3.3), & confirmation of

eligibility (see Sec 3.3)

Arm 1 Ibrutinib 420 mg PO daily days 1-28 for 15 cycles Obinutuzumab 100 mg IV 100 mg on C1D1, 900 mg on C1D2, 1000 mg on Cycle1D8 & C1D15, C2-6D1

Arm 2 Ibrutinib 420 mg PO daily days 1-28 for 15 cycles Obinutuzumab 100 mg IV 100 mg on C1D1, 900 mg on C1D2, 1000 mg on C1D8 & C1D15, C2-6D1 Venetoclax 20 mg daily PO beginning C3D1, dose escalated weekly to a final dose of 400 mg on C4D1, then 400 mg daily PO C4D1-C14D28

Any response except BM MRD- CR

(BM MRD+ CR, PR, PRL, SD)

BM MRD - CR

Observation q3 cycles for 6 years from registration (step 1), then q6 cycles until progression

Ibrutinib 420 mg PO daily days 1-28 until progression or unacceptable adverse events

Ibrutinib 420 mg PO daily days 1-28 until progression or unacceptable adverse events

C15D1 Response Assessment Specimen submission for central BM MRD & local response assessment &

labs performed per Sec 5.0.,

At the same time, Continue Ibrutinib 420 mg PO daily C15D1-D28.

C15D1 Response Assessment Specimen submission for central BM MRD & local response assessment &

labs performed per Sec 5.0.

At the same time, Continue Ibrutinib 420 mg PO daily C15 D1-D28.



3.0 ELIGIBILITY CRITERIA -Diagnosis with CLL in accordance with 2018 IWCLL criteria

-Intermediate or high-risk Rai stage CLL -Criteria met for treatment as defined by 2018 IWCLL guidelines -No prior therapy for CLL (except palliative steroids or treatment of autoimmune complications per Section 3.3.3) -Age ≥ 70 years -ECOG performance status 0-2 -No comorbid conditions or other active diseases per Section 3.3.7 -Not taking concomitant medications as outlined in Section 3.3.8 -No known allergy to mannitol -No prior significant hypersensitivity to rituximab

-No major surgery within 10 days or minor surgery within 7 days 4.0 TREATMENT SCHEDULE Arm 1 Ibrutinib Obinutuzumab

Cycle 1 D1-28 C2

C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15

Day 1 D2 D8 D15 D1 D1 D1 D1 D1

Ibrutinib 420 mg daily

Obinutuzumab

100 mg

900 mg

1000 mg

1000 mg

1000 mg

1000 mg

1000 mg

1000 mg

1000 mg

Arm 2 Ibrutinib, Venetoclax, and Obinutuzumab Cycle 1 D1-28 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C13 C14 C15

Day 1 D2 D8 D15

Ibrutinib PO

420 mg daily

Obinutuzumab IV

100 mg

900 mg

1000 mg

1000mg

Day 1 1000 mg

D1 1000 mg

D1 1000 mg

D1 1000 mg

D1 1000 mg

Venetoclax PO

20 mg daily,

400 mg daily



dose escalated weekly*

* Arm 2 Venetoclax Dose Escalation

Cycle 3 Cycle 4 Day 1 – 7 D8 - 14 D15-21 D22 - 28 D1 - 7

20 mg 50 mg 100 mg 200 mg 400 mg



5.0 STUDY DESIGN

5.1 Study Phase/Type of Design/Stratification Factors Patients will be randomized using dynamic allocation procedures in a 1:1 manner to the two treatment arms: (Arm 1: Ibrutinib, Obinutuzumab vs. Arm 2: Ibrutinib, Venetoclax, and Obinutuzumab). Randomization will be stratified on Rai stage (intermediate vs. high) and high-risk FISH abnormality del(17p13.1) (present vs. absent).

5.2 Primary Endpoint The primary endpoint in this phase III trial is progression-free survival (PFS), which will be defined from randomization date until the earlier of disease progression or death from any cause, censoring patients alive and progression-free at the date of last known clinical assessment.

The primary goal of this phase III trial is to determine whether the experimental treatment strategy of IVO followed by IM for patients without BM MRD- CR and IM discontinuation for patients with BM MRD- CR has superior PFS compared to the control treatment strategy of IO followed by IM for all patients. We will test the null hypothesis that the hazard ratio is equal to 1.0 versus the alternative hypothesis that the hazard ratio is equal to 0.55 in favor of the experimental treatment strategy. Assuming exponential parameters for control and experimental treatment strategy groups are 0.071 and 0.039, respectively, this corresponds to a median PFS of 9.717 years vs. 17.667 years and is equivalent to 5-year PFS rates of 70% vs. 82.187%. Based on design assumptions, the 70% PFS rate at 5 years assumed for the control treatment strategy group corresponds with data available from a randomized phase III trial, in which previously untreated patients aged 65 years or older received ibrutinib until disease progression or unacceptable toxic effects and had a PFS estimate at 18 months of 90% (Burger et al, 2015).

There is 90% power for this one-sided log-rank test of superiority with the experimental treatment strategy versus the control treatment strategy using a group sequential design and constraining the one-sided type I error to 0.025 (i.e., two-sided error of 0.05). This design requires 128 events and translates to 431 total evaluable patients when assuming uniform accrual over 3 years and a minimum follow-up of 5 years.

5.3 Target Accrual The target accrual for this study is 454 patients using a 1:1 randomization. The target accrual rate is 13 patients per month.

6.0 CURRENT ACCRUAL

Study Activation Date 01/04/2019 Target Accrual (n) 454 Patients screened or pre-registered (n) 81 Current Accrual (n) 63 Expected Accrual Rate 13/month Accrual Rate – Since activation 8/month Accrual Rate – Past 6 months (if applicable) 10/month



0 2 7 8 8 810

18 2

Jan19 Feb19 Mar19 Apr19 May19 Jun19 Jul19 Aug19 Sep19

Month

0

50

100

150

200

250

300

350

400

450To

tal N

umbe

r of P

atien

tsExpected Accrual 454 PatientsActual Accrual


7.0 CURRENT STUDY STATUS

This study opened on January 4, 2019. As of September 6, 2019, 63 patients have been randomized. 60 patients (95%) are alive and remain on active treatment.

8.0 PATIENT CHARACTERISTICS

All randomized participants are included in the table.

Table 8a. Demographics

Arm 1 (IO) (N=32)

Arm 2 (IVO) (N=31)

Total (N=63)

Age N 32 31 63 Mean (SD) 74.5 (3.6) 75.2 (3.5) 74.8 (3.5) Median 74.0 75.0 74.0 Q1, Q3 71.0, 78.0 72.0, 78.0 72.0, 78.0 Range (70.0-83.0) (70.0-82.0) (70.0-83.0) Race White 31 (96.9%) 28 (90.3%) 59 (93.7%) Not reported 0 (0.0%) 2 (6.5%) 2 (3.2%) Unknown 1 (3.1%) 1 (3.2%) 2 (3.2%) Gender Female 12 (37.5%) 7 (22.6%) 19 (30.2%) Male 20 (62.5%) 24 (77.4%) 44 (69.8%)



Table 8b. Stratification Factors Arm 1 (IO)

(N=32) Arm 2 (IVO) (N=31)

Total (N=63)

Rai stage classification category Intermediate (Stage I/II) 13 (40.6%) 12 (38.7%) 25 (39.7%) High (Stage III/IV) 19 (59.4%) 19 (61.3%) 38 (60.3%) High-risk FISH abnormality del(17p13.1)

Absent 27 (84.4%) 27 (87.1%) 54 (85.7%) Present 5 (15.6%) 4 (12.9%) 9 (14.3%)

9.0 ADVERSE EVENTS

9.1 Adverse Event Summary 37 patients are evaluable for adverse events (AE) analyses (Arm 1: 19, Arm 2: 18). Commonly occurring grade 3+ AE include anemia (16% Arm 1), leukocytosis (11% Arm 1), Lymphocyte count increased (16% Arm 1, 11% Arm 2), Neutrophils/granulocytes (ANC/AGC) (26% Arm 1, 28% Arm 2), platelets (22% Arm 1, 11% Arm 2), and hypertension (11% Arm 1, 11% Arm 2). There have been 0 deaths on treatment. See below for a summary of adverse events by arm regardless of attribution.

Summary of Grade 3+ Adverse Events


Arm 1=19 Arm 2=18 Patients with a maximum: Arm n (%) Total


2 13 (72.2%)


2 0 (0.0%)


2 0 (0.0%)



2 10 (55.6%)


2 0 (0.0%)


2 0 (0.0%)






Number of Evaluable Patients: Arm 1=19 Arm 2=18

Patients with a maximum: Arm n (%)

2 4 (22.2%)


2 0 (0.0%)


2 0 (0.0%)




Arm 1=19 Arm 2=18 Grade of AdverseEvent


Hematologic Adverse Events Blood/Bone Marrow

Anemia 1 3 ( 16%) 0 ( 0%) 0 ( 0%) 2 1 ( 6%) 0 ( 0%) 0 ( 0%) Leukocytosis 1 2 ( 11%) 0 ( 0%) 0 ( 0%) 2 1 ( 6%) 0 ( 0%) 0 ( 0%) Lymphocyte count increased 1 3 ( 16%) 0 ( 0%) 0 ( 0%) 2 2 ( 11%) 0 ( 0%) 0 ( 0%) Lymphopenia 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%) Neutrophils/granulocytes (ANC/AGC)

1 4 ( 21%) 1 ( 5%) 0 ( 0%)

2 5 ( 28%) 0 ( 0%) 0 ( 0%) Platelets 1 2 ( 11%) 2 ( 11%) 0 ( 0%) 2 2 ( 11%) 0 ( 0%) 0 ( 0%)

Non-Hematologic Adverse Events **

Infections and infestations - Oth spec

1 1 ( 5%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Pulmonary edema 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 6%) 0 ( 0%) 0 ( 0%)

Cardiovascular





Arm 1=19 Arm 2=18 Grade of AdverseEvent


Hypertension 1 2 ( 11%) 0 ( 0%) 0 ( 0%) 2 2 ( 11%) 0 ( 0%) 0 ( 0%) Supraventricular and nodal arrhythmia

1 1 ( 5%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Gastrointestinal

Diarrhea 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Hepatic Albumin, serum-low (hypoalbuminemia)

1 1 ( 5%) 0 ( 0%) 0 ( 0%)

2 0 ( 0%) 0 ( 0%) 0 ( 0%) Infection/Febrile Neutropenia

Infection with unknown ANC 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Lymphatics Edema:limb 1 0 ( 0%) 0 ( 0%) 0 ( 0%) 2 1 ( 6%) 0 ( 0%) 0 ( 0%)

Metabolic/Laboratory Sodium, serum-low (hyponatremia) 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

Pulmonary Pneumonitis/pulmonary infiltrates 1 1 ( 5%) 0 ( 0%) 0 ( 0%) 2 0 ( 0%) 0 ( 0%) 0 ( 0%)

10.0 IMBEDDED CORRELATIVES Laboratory Correlative Studies: There will be one sub-study and all patients are required to

participate. The correlative science objectives are to compare MRD status between blood and bone marrow at the end of induction treatment/Cycle 15 Day 1 to determine whether blood MRD can be used as a surrogate to bone marrow MRD with these treatment regimens.

ECOG-ACRIN Cancer Research Group E1910 Study Progress and Safety Report Fall 2019

Page 1

E1910 A PHASE III RANDOMIZED TRIAL OF BLINATUMOMAB FOR NEWLY DIAGNOSED BCR-ABL NEGATIVE B ACUTE LYMPHOBLASTIC LEUKEMIA IN ADULTS

Sponsor(s) Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Mark Litzow Statistician Dr. Zhuoxin Sun Data Specialist Henry Baptista Phase of Study III Type of Study Therapeutic Committee Leukemia Accrual Objective 488 Patients Participating Groups ECOG-ACRIN, CTSU NSC# 740, 3590, 10023, 14575, 26271, 34521, 63878,

67574, 141540, 624239, 697732, 765986 Clinicaltrials.gov Study ID NCT02003222 Study Status Open to Accrual Date Proposed June 26, 2012 Date Activated December 17, 2013 Schema


Page 2


Page 3


Page 4

Table 1a. Accrual by ECOG-ACRIN Institution

Institution Name Step 1 Step 2 Step 3 Step 4 Beaumont NCORP 0 0 0 0 Beth Israel Deaconess Medical Center 3 3 3 1 Cancer Research Consortium of West Michigan NCORP 1 2 2 0 Dartmouth Hitchcock Medical Center 2 0 0 0 Dayton NCORP 1 1 0 0 Emory University/Winship Cancer Institute 2 1 1 1 Froedtert and the Medical College of Wisconsin 17 11 9 3 Geisinger Cancer Institute NCORP 0 0 0 0 Georgia NCORP 7 2 2 0 Gulf South MU NCORP 1 0 0 0 Heartland Cancer Research NCORP 1 0 0 0 Johns Hopkins Univ/Sidney Kimmel Cancer Center 33 27 23 9 Loyola University Medical Center 1 1 1 0 Mayo Clinic 10 5 2 0 Memorial Sloan Kettering Cancer Center 1 0 0 0 Montana Cancer Consortium NCORP 2 1 0 0 NorthShore Univ HealthSystem-Evanston Hospital 2 1 1 0 Northwestern University 24 12 11 3 Ochsner NCORP 2 1 1 1 Pacific Cancer Research Consortium NCORP 0 1 0 1 Penn State Milton S Hershey Medical Center 1 0 0 0 Rutgers Cancer Institute of New Jersey 7 3 3 1 Stanford Cancer Institute Palo Alto 1 0 0 0 Stony Brook University Medical Center 0 0 0 0 Thomas Jefferson University Hospital 4 2 2 0 UT Southwestern/Simmons Cancer Center-Dallas 5 3 3 1 University of Alabama at Birmingham Cancer Center 1 1 1 1 University of Kansas Cancer Center 4 1 1 0 University of North Carolina at Chapel Hill 1 0 0 0 University of Pennsylvania/Abramson Cancer Center 25 15 10 5 University of Wisconsin Hospital and Clinics 10 5 5 3 VCU Massey Cancer Center MU NCORP 13 9 6 2 Washington University School of Medicine 4 1 1 0 Wichita NCORP 5 3 3 1 Wisconsin NCORP 3 1 1 0 Yale University 0 1 0 0 Total 194 114 92 33

Table 1b. Accrual by Group

Step 1 Step 2 Step 3 Step 4

ECOG-ACRIN 194 114 92 33 CCTG 16 7 6 2 SWOG 115 74 61 24 ALLIANCE 111 66 56 26 NRG 18 16 14 6 Total 454 277 229 91


Page 5

Table 1c. Projected Accrual

Step 1 Step 2 Step 3 Step 4

Accrual goal 488 Planned accrual rate 72/yr Accrual to date 454 277 229 91 Annual accrual rate Overall 81/yr 50/yr 41/yr 16/yr Last 6 months 124/yr 66/yr 68/yr 38/yr Projected date of closure October 2019


Page 6

Table 2. Patient Status as of July 17, 2019

Step 1 Step 2 Step 3 Step 4 Cases Entered 454 277 229 91 Ineligible 6 6 5 0 Never Started Assigned Therapy 7 2 8 0

Reason for ineligibility Step 1:

Patient was BCR/ABL+ (19004, 19063, 19193, 19259). Bone Marrow pathology report was not done (19155). Pre-study bone marrow biopsy not obtained within 1 week of registration (19392).

Reason for not starting assigned therapy Step 1: Patient withdrawal/refusal (19066, 19260). Patient ineligible (19155, 19193, 19322, 19547); medical

decision (19523). Reason for ineligibility Step 2:

CR/CRi not confirmed (19037, 19053, 19139). ECOG Performance Status reported as 3, and also neurological complications (19194). Lab values not obtained <= 48 hours prior to registration (19120, 19239)

Reason for not starting assigned therapy Step 2: Neurological complications (19194). Decrease blood counts (19392).

Reason for ineligibility Step 3: Baseline labs (bilirubin, creatinine, anc, blasts, platelets) not done before randomization (19040). Serum Creatinine and Bilirubin were not obtained within 48 of step 3 registration in order to confirm eligibility (19051, 19053, 19504), Blast % in Blood not reported at Baseline (19218)

Reason for not starting assigned therapy Step 3:

Patient withdrawal/refusal (19093, 19221). Disease progression (19223, 19044, 19352, 19370, 19424). PI discretion (19156)


Page 7

Table 3a. Demographics --Step 1

Variable Level Arm A

(n=454) Sex Male 236 (52.0)

Female 218 (48.0) Race White 372 (90.7)

African-American 20 (4.9) Asian 8 (2.0) Native Hawaiian 1 (0.2) Native American 7 (1.7) Multirace 2 (0.5) Unknown/Unreported 44

Ethnicity Hispanic 65 (15.3) Non-Hispanic 361 (84.7) Unknown/Missing 28

Age Median 51 Minimum 30 Maximum 70

Table 3b. Demographics --Step 2

Variable Level Arm B

(n=277) Sex Male 137 (49.5)

Female 140 (50.5) Race White 228 (90.8)

African-American 12 (4.8) Asian 6 (2.4) Native Hawaiian 1 (0.4) Native American 3 (1.2) Multirace 1 (0.4) Unknown/Unreported 26




Page 8

Table 3c. Demographics --Step 3

Variable Level Arm C

(n=118) Arm D

(n=111) Total

(n=229) Sex Male 53 (44.9) 58 (52.3) 111 (48.5)

Female 65 (55.1) 53 (47.7) 118 (51.5) Race White 94 (88.7) 94 (94.0) 188 (91.3)

African-American 9 (8.5) 3 (3.0) 12 (5.8) Asian 1 (0.9) 2 (2.0) 3 (1.5) Native Hawaiian 1 (0.9) 0 (0.0) 1 (0.5) Native American 1 (0.9) 1 (1.0) 2 (1.0) Unknown/Unreported 12 11 23

Ethnicity Hispanic 18 (15.7) 13 (12.7) 31 (14.3) Non-Hispanic 97 (84.3) 89 (87.3) 186 (85.7) Unknown/Missing 3 9 12

Age Median 52 52 52 Minimum 30 30 30 Maximum 70 70 70

Table 3d. Demographics --Step 4

Variable Level Arm E (n=91)

Sex Male 45 (49.5) Female 46 (50.5)

Race White 74 (92.5) African-American 2 (2.5) Asian 1 (1.3) Native Hawaiian 1 (1.3) Native American 2 (2.5) Unknown/Unreported 11




Page 9

Table 4. Record Status

Form Name Forms Due

Forms Received %

Adverse Event Form 2156 2105 97.6% Baseline Hematology/Chemistry 1028 1022 99.4% Disease Follow-up Status 3088 3062 99.2% Follow-Up Hematology/Chemistry 19724 19686 99.8% Late Adverse Event Form 47 47 100.0% Off Treatment 94 91 96.8% Off-Treatment with Intent to Reg Next Step 775 774 99.9% Other Adverse Event Form 1082 1075 99.4% Patient Characteristics 3182 3156 99.2% Report Period and Vital Status Form 3351 3304 98.6% Treatment Agent: 6 Mercaptopurine 790 780 98.7% Treatment Agent: Blinatumomab 292 288 98.6% Treatment Agent: Cyclophosphamide (1d) 109 108 99.1% Treatment Agent: Cyclophosphamide (2d) 358 357 99.7% Treatment Agent: Cytarabine (16d) 357 356 99.7% Treatment Agent: Cytarabine (1d) 432 424 98.1% Treatment Agent: Cytarabine (5d) 361 355 98.3% Treatment Agent: Cytarabine (8d) 108 107 99.1% Treatment Agent: Daunorubicin (4d) 538 529 98.3% Treatment Agent: Dexamethasone 536 527 98.3% Treatment Agent: Etoposide (5d) 362 356 98.3% Treatment Agent: Leucovorin 265 265 100.0% Treatment Agent: Methotrexate (13d) 331 322 97.3% Treatment Agent: Methotrexate (1d) 901 887 98.4% Treatment Agent: Methotrexate (2d) 266 266 100.0% Treatment Agent: Methotrexate (4d) 357 356 99.7% Treatment Agent: Methotrexate IT (1d) 268 264 98.5% Treatment Agent: Pegaspargase 1196 1181 98.7% Treatment Agent: Prednisone 331 323 97.6% Treatment Agent: Rituximab (1d) 198 194 98.0% Treatment Agent: Rituximab (2d) 327 327 100.0% Treatment Agent: Vincristine (1d) 337 334 99.1% Treatment Agent: Vincristine (4d) 538 529 98.3%


Page 10

Table 5a. Reasons Off Treatment - Step 1 For Patients Not Registered To Subsequent Steps (Includes all patients who

started treatment and for whom off-treatment data have been received)

Reasons N % Adverse event/side effects/complications 9 7.0 Alternative therapy 11 8.6 Death on study 12 9.4 Disease progression- relapse during active treatment 26 20.3 Other 37 28.9 Patient off-treatment for other complicating disease 2 1.6 Patient withdrawal/refusal after beginning protocol therapy 13 10.2 Treatment completed per protocol criteria 18 14.1 Total off treatment 128 100.0

Table 5b. Reasons Off Treatment - Step 2 For Patients Not Registered To Subsequent Steps (Includes all patients who


Reasons N % Adverse event/side effects/complications 1 2.5 Alternative therapy 1 2.5 Disease progression- relapse during active treatment 11 27.5 Other 5 12.5 Patient withdrawal/refusal after beginning protocol therapy 2 5.0 Treatment completed per protocol criteria 20 50.0 Total off treatment 40 100.0

Table 5c. Reasons Off Treatment - Step 3 For Patients Not Registered To Subsequent Steps (Includes all patients who


Reasons N % Adverse event/side effects/complications 5 5.3 Alternative therapy 7 7.4 Death on study 3 3.2 Disease progression- relapse during active treatment 16 17.0 Other 8 8.5 Patient withdrawal/refusal after beginning protocol therapy 8 8.5 Treatment completed per protocol criteria 47 50.0 Total off treatment 94 100.0


Page 11

Table 5d. Reasons Off Treatment - Step 4

(Includes all patients who started treatment and for whom off-treatment data have been received)

Reasons N %

Adverse event/side effects/complications 2 3.8 Alternative therapy 1 1.9 Death on study 1 1.9 Disease progression- relapse during active treatment 8 15.1 Other 4 7.5 Patient withdrawal/refusal after beginning protocol therapy 7 13.2 Treatment completed per protocol criteria 29 54.7 Total off treatment 52 98.1

Table 6. Toxicity Incidence (Treatment-Related)

Step 1 (Arm A)

Toxicity Type

Treatment Arm A (n=404)

Grade 3 4 5

(n) (n) (n) Anemia 184 24 - Blood and lymphatic system disorders - Other, specify 2 4 - Disseminated intravascular coagulation 1 - - Febrile neutropenia 95 3 - Leukocytosis 1 - - Cardiac disorders - Other, specify - 1 - Chest pain - cardiac 1 - - Myocardial infarction - - 1 Pericarditis 1 - - Sinus bradycardia 1 - - Sinus tachycardia 1 - - Retinopathy 1 - - Abdominal pain 11 - - Colitis 1 - - Constipation 2 - - Diarrhea 7 - - Gastric hemorrhage 1 - - Gastritis 1 - - Gastrointestinal disorders - Other, specify 3 - - Mucositis oral 5 - - Nausea 15 - - Oral hemorrhage 1 - - Pancreatitis 6 1 - Proctitis 1 - - Rectal pain 2 - - Small intestinal obstruction - 1 -


Page 12

Toxicity Type


Grade 3 4 5

(n) (n) (n) Typhlitis 2 - - Vomiting 15 1 - Fatigue 26 - - Fever 3 - - General disorders and administration site conditions - Other, specify 1 - - Pain 1 - - Edema limbs 1 - - Infusion related reaction 2 1 - Hepatic failure - 2 1 Hepatobiliary disorders - Other, specify - 1 - Allergic reaction 2 - - Anaphylaxis 1 - - Catheter related infection 8 - - Eye infection 1 - - Infections and infestations - Other, specify 13 1 - Otitis externa 1 - - Sepsis - 14 1 Sinusitis 3 - - Skin infection 5 - - Upper respiratory infection 1 - - Urinary tract infection 9 - - Pancreas infection 1 - - Abdominal infection 1 - - Enterocolitis infectious 3 - - Bone infection 1 - - Lung infection 10 1 - Vascular access complication 1 - - Activated partial thromboplastin time prolonged 2 - - Alanine aminotransferase increased 35 5 - Alkaline phosphatase increased 11 1 - Aspartate aminotransferase increased 21 1 - Blood bilirubin increased 23 12 - Cholesterol high - 1 - Fibrinogen decreased 10 5 - Investigations - Other, specify 1 1 - Lipase increased 1 3 - Lymphocyte count decreased 16 92 - Lymphocyte count increased 1 - - Neutrophil count decreased 14 300 - Platelet count decreased 26 257 - Weight loss 1 - - White blood cell decreased 6 196 - GGT increased 3 2 - Anorexia 7 - - Dehydration 7 - - Hypercalcemia 1 - -


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Toxicity Type


Grade 3 4 5

(n) (n) (n) Hyperglycemia 28 1 - Hyperkalemia 2 - - Hypertriglyceridemia 2 13 - Hyperuricemia - 1 - Hypoalbuminemia 8 - - Hypocalcemia 3 - - Hypokalemia 1 - - Hyponatremia 17 1 - Hypophosphatemia 7 - - Tumor lysis syndrome 21 - - Glucose intolerance 3 - - Arthralgia 2 - - Back pain 1 - - Generalized muscle weakness 6 - - Muscle weakness lower limb 1 - - Cerebrospinal fluid leakage 1 - - Cognitive disturbance 1 - - Dizziness 2 - - Encephalopathy 2 1 - Headache 19 - - Intracranial hemorrhage 1 1 - Paresthesia 1 - - Peripheral motor neuropathy 2 - - Seizure 1 - - Somnolence 1 - - Stroke 1 1 1 Syncope 3 - - Vasovagal reaction 2 - - Confusion 3 - - Delirium 1 - - Insomnia 1 - - Personality change 1 - - Restlessness 1 - - Acute kidney injury 2 2 - Adult respiratory distress syndrome - - 1 Dyspnea 3 - - Epistaxis 2 - - Hiccups 1 - - Hypoxia 2 - - Pneumonitis 3 - - Respiratory, thoracic and mediastinal disorders - Other, specify 1 - - Sore throat 1 - - Wheezing 1 - - Bronchopulmonary hemorrhage - 1 - Rash maculo-papular 1 - - Urticaria 1 - -


Page 14

Toxicity Type


Grade 3 4 5

(n) (n) (n) Hematoma 1 - - Hypertension 15 - - Hypotension 7 1 - Thromboembolic event 8 6 - WORST DEGREE (NON-HEMATOLOGIC) 180 67 5

Step 2 (Arm B)

Toxicity Type

Treatment Arm B (n=252)

Grade 3 4 5

(n) (n) (n) Anemia 44 1 - Febrile neutropenia 1 - - Abdominal pain 3 - - Colitis 1 - - Diarrhea 3 - - Gastrointestinal disorders - Other, specify 1 - - Mucositis oral 1 - - Nausea 3 - - Pancreatitis 3 - - Fatigue 4 - - Hepatic failure 1 - - Anaphylaxis - 1 - Catheter related infection 2 - - Sepsis - 3 - Skin infection 1 - - Lung infection 1 - - Activated partial thromboplastin time prolonged 1 - - Alanine aminotransferase increased 12 - - Alkaline phosphatase increased 3 - - Aspartate aminotransferase increased 9 - - Blood bilirubin increased 3 1 - Creatinine increased 1 - - Fibrinogen decreased 2 - - Investigations - Other, specify 1 - - Lipase increased 3 1 - Lymphocyte count decreased 16 16 - Neutrophil count decreased 38 29 - Platelet count decreased 15 14 - Weight loss 1 - - White blood cell decreased 11 7 - GGT increased 1 - - Alkalosis 1 - -


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Toxicity Type

Treatment Arm B (n=252)

Grade 3 4 5

(n) (n) (n) Dehydration 1 - - Hyperglycemia 9 2 - Hypertriglyceridemia - 3 - Hypocalcemia 1 - - Hypokalemia 3 - - Hyponatremia 1 - - Hypophosphatemia 1 - - Tumor lysis syndrome 1 - - Glucose intolerance 1 - - Myalgia 1 - - Pain in extremity 1 - - Generalized muscle weakness 1 - - Headache 1 - - Hyperhidrosis 1 - - Rash maculo-papular 1 - - Hypertension 3 - - Hypotension 1 - - Thromboembolic event 1 - - WORST DEGREE (NON-HEMATOLOGIC) 50 11 -


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Step 3 Arm C

Toxicity Type

Treatment Arm Treatment Arm C (n=107) C (n=107)

Blinitumomab Consolidation Cycle 1 Cycle 2 Cycles 1-2 Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycles 1-6 Grade Grade Grade Grade Grade Grade Grade Grade Grade Grade

3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)

Anemia 6 - - - - - 6 - - 4 - - 16 1 - 11 - - 2 - - 5 - - 1 - - 17 1 - Blood and lymphatic system disorders - Other, specify - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - Febrile neutropenia - - - 1 - - 1 - - 4 2 - 2 - - 5 - - 1 - - 2 - - - - - 11 2 - Chest pain - cardiac - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Sinus tachycardia 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Ear pain 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Abdominal pain - - - - - - - - - 1 - - - - - 1 - - - - - - - - - - - 2 - - Diarrhea - - - - - - - - - - - - - - - 1 - - - - - 1 - - - - - 2 - - Nausea - - - - - - - - - 2 - - - - - - - - - - - 1 - - - - - 3 - - Vomiting - - - - - - - - - - - - 1 - - 1 - - - - - 1 - - - - - 3 - - Fatigue - - - 1 - - 1 - - - - - - - - - - - - - - 1 - - - - - 1 - - Fever - - - - - - - - - - - - - - - 1 - - - - - 1 - - - - - 2 - - Gait disturbance 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Hepatobiliary disorders - Other, specify 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Cytokine release syndrome 2 1 - - - - 2 1 - - - - - - - - - - - - - - - - - - - - - - Appendicitis perforated - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Catheter related infection 2 - - 1 - - 3 - - - - - - - - 1 - - - - - - - - - - - 1 - - Device related infection - - - - - - - - - - - - - - - - - - - - - 1 - - - - - 1 - - Enterocolitis infectious - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Infections and infestations - Other, specify 2 - - - - - 2 - - - - - - - - - - - 1 - - - - - - - - 1 - - Lung infection - - - - - - - - - - 1 - - - - 1 - - - - - - - - - - - 1 1 - Sepsis - - - - 1 - - 1 - - 3 - - - - - - - - - 1 - 2 - - - - - 5 1 Sinusitis - - - 1 - - 1 - - - - - - - - - - - - - - - - - - - - - - - Urinary tract infection - - - 1 - - 1 - - - - - - - - 1 - - - - - - - - - - - 1 - -


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Toxicity Type




Activated partial thromboplastin time prolonged - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Alanine aminotransferase increased 1 1 - - - - 1 1 - 1 - - 1 - - - - - - - - - - - - - - 1 - - Alkaline phosphatase increased - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Aspartate aminotransferase increased 1 1 - - - - 1 1 - - - - 1 - - - - - - - - - - - - - - 1 - - Blood bilirubin increased - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Cholesterol high - - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1 - Fibrinogen decreased - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Investigations - Other, specify 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Lymphocyte count decreased 2 13 - 1 2 - 2 14 - 2 1 - 2 1 - 3 3 - 2 1 - 1 - - 2 - - 3 6 - Neutrophil count decreased 12 10 - 6 5 - 13 14 - - 37 - 3 25 - 3 33 - 3 3 - - 27 - 2 2 - 1 46 - Platelet count decreased 2 2 - - 1 - 2 3 - 4 19 - 4 12 - 4 26 - - 1 - 3 17 - - - - 5 34 - Weight gain - - - - - - - - - - - - - - - - - - 1 - - - - - 1 - - 2 - - White blood cell decreased - 1 - 1 - - 1 1 - 3 9 - 2 3 - 3 10 - - 1 - - 4 - - - - 5 18 - Dehydration 1 - - - - - 1 - - - - - - - - 1 - - - - - - - - - - - 1 - - Hyperglycemia 1 - - - - - 1 - - 1 1 - 1 - - 5 - - - - - - - - 1 - - 4 1 - Hypertriglyceridemia - - - - - - - - - - 2 - - 2 - - 2 - 1 - - 1 - - - - - - 4 - Hypocalcemia - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - Hyponatremia 1 - - - - - 1 - - 1 - - - - - 1 - - - - - - - - - - - 1 - - Hypophosphatemia - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Avascular necrosis 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Bone pain - - - - - - - - - - - - 1 - - - - - - - - - - - - - - 1 - - Ataxia 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Cognitive disturbance 2 - - - - - 2 - - - - - - - - - - - - - - - - - - - - - - - Concentration impairment 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Depressed level of consciousness 2 - - - - - 2 - - - - - - - - - - - - - - - - - - - - - - - Dysarthria 1 - - 1 - - 2 - - - - - - - - - - - - - - - - - - - - - - -


Page 18

Toxicity Type




Dysphasia 3 - - 1 - - 4 - - - - - - - - - - - - - - - - - - - - - - - Encephalopathy 1 1 - - - - 1 1 - - - - - - - - - - - - - - - - - - - - - - Headache - - - - - - - - - 1 - - 1 - - 1 - - - - - - - - - - - 3 - - Intracranial hemorrhage - - 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - Seizure 1 1 - - - - 1 1 - - - - - - - - - - - - - - - - - - - - - - Syncope - - - - - - - - - 1 - - - - - 1 - - - - - 1 - - - - - 3 - - Tremor 3 - - - - - 3 - - - - - - - - - - - - - - - - - - - - - - - Confusion 3 - - - - - 3 - - - - - - - - - - - 1 - - - - - - - - 1 - - Acute kidney injury - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Epistaxis - - - - - - - - - - - - - - - 1 - - - - - - - - - - - 1 - - Capillary leak syndrome 1 - - - - - 1 - - - - - - - - - - - - - - - - - - - - - - - Hypertension - 1 - - - - - 1 - - - - - - - 1 - - - - - - - - - - - 1 - - Hypotension - - - - - - - - - 1 - - - - - - - - - - - - - - - - - 1 - - Thromboembolic event - - - - - - - - - 2 - - 1 - - 1 - - 1 - - 1 - - 1 - - 2 - - WORST DEGREE (NON-HEMATOLO - - - 4 1 - - - - - - - - - - 15 2 - - - - 4 2 - 3 - - - - - WORST DEGREE (NON-HEMATOLOGIC) 23 2 1 - - - 25 3 1 9 8 - 7 2 - - - - 5 - 1 - - - - - - 23 10 1


Page 19

Step 3 Arm D

Toxicity Type

Treatment Arm D (n=96)

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycles

1-4 Grade Grade Grade Grade Grade

3 4 5 3 4 5 3 4 5 3 4 5 3 4 5 (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n) (n)

Anemia 16 1 - 15 1 - 13 - - 7 1 - 35 2 - Febrile neutropenia 7 1 - 6 - - 4 - - 2 - - 16 1 - Abdominal pain - - - - - - 1 - - - - - 1 - - Nausea 1 - - - - - - - - - - - 1 - - Vomiting 3 - - - - - - - - - - - 3 - - Fatigue 3 - - 1 - - - - - - - - 4 - - General disorders and administration site conditions - Other, specify 1 - - - - - - - - - - - 1 - - Allergic reaction 1 - - - - - - - - - - - 1 - - Catheter related infection 3 1 - - 1 - 1 - - - - - 4 1 - Infections and infestations - Other, specify 2 - - - - - 1 - - - - - 3 - - Lung infection - 1 - - - - - - - - - - - 1 - Meningitis - - - - - - 1 - - - - - 1 - - Sepsis - 5 - - 2 - - - - - - - - 6 - Sinusitis - - - - - - 1 - - - - - 1 - - Upper respiratory infection 1 - - - - - - - - - - - 1 - - Urinary tract infection - - - - - - 1 - - - - - 1 - - Alanine aminotransferase increased 2 - - 1 - - 3 1 - 1 - - 6 1 - Alkaline phosphatase increased 1 - - - - - - - - - - - 1 - - Aspartate aminotransferase increased - - - - - - - 1 - 1 - - 1 1 - Lymphocyte count decreased 3 4 - 1 5 - 2 9 - 3 2 - 5 12 - Neutrophil count decreased 5 58 - 1 38 - 2 25 - 2 22 - 4 66 - Platelet count decreased 9 30 - 4 19 - 3 21 - 2 8 - 8 46 - Weight loss - - - 1 - - - - - - - - 1 - - White blood cell decreased 3 21 - 1 11 - 2 13 - 2 6 - 2 32 - Hyperglycemia - - - - - - 3 2 - - - - 3 2 - Hypertriglyceridemia 1 2 - - - - - - - - - - 1 2 - Hyponatremia 1 - - - - - - - - - - - 1 - - Hypophosphatemia 2 - - 1 - - 1 - - - - - 3 - - Iron overload 1 - - 1 - - - - - - - - 1 - - Myalgia - - - - - - 1 - - - - - 1 - - Neck pain - - - - - - 1 - - - - - 1 - - Headache 2 - - 3 - - 2 - - 1 - - 5 - - Peripheral sensory neuropathy 1 - - 1 - - 1 - - - - - 1 - - Depression 1 - - - - - - - - - - - 1 - - Pneumonitis 1 - - - - - - - - - - - 1 - - Hypertension 1 - - - - - - - - - - - 1 - - WORST DEGREE (NON-HEMATOLOGIC) 14 8 - 11 2 - 14 3 - 4 - - 25 12 -


Page 20

Step 3 Transplant

Toxicity Type

Treatment Arm C (n=19) D (n=19)

Grade Grade 3 4 5 3 4 5

(n) (n) (n) (n) (n) (n) Anemia 6 - - 6 - - Febrile neutropenia 4 1 - 5 - - Atrial fibrillation 1 - - - - - Anal mucositis - - - 1 - - Colitis 2 - - - - - Diarrhea 3 - - 1 - - Dry mouth - - - 1 - - Dysphagia - - - 1 - - Esophagitis 1 - - - - - Gastrointestinal disorders - Other, specify 1 - - - - - Mucositis oral 2 - - 3 1 - Nausea 1 - - 1 - - Oral pain - - - 1 - - Rectal mucositis 1 - - - - - Small intestinal mucositis 1 - - - - - Typhlitis - - - 1 - - Chills - - - 1 - - Fatigue 1 - - 1 - - Pain - - - 1 - - Infections and infestations - Other, specify 2 - - - - - Lung infection 1 - - 1 - - Lymphocyte count decreased - 4 - - 7 - Neutrophil count decreased - 9 - 1 11 - Platelet count decreased 1 10 - - 10 - White blood cell decreased - 9 - - 7 - Anorexia 2 - - 3 - - Hyperglycemia 1 - - - - - Hypokalemia 1 - - - - - Iron overload - - - 1 - - Back pain - - - 1 - - Trismus - - - 1 - - Headache 1 - - - - - Hematuria - - - 1 - - Dyspnea - - - 1 - - Epistaxis - - - 1 - - Pulmonary edema - - - 1 - - Sore throat - - - 1 - - Dry skin - - - 1 - - Rash acneiform 1 - - - - - WORST DEGREE (NON-HEMATOLOGIC) 6 1 - 6 1 -


Page 21

Step 4 Maintenance

Toxicity Type

Treatment Arm C (n=37) D (n=38)


(n) (n) (n) (n) (n) (n) Anemia 4 - - 2 - - Febrile neutropenia 2 - - - - - Abdominal pain 1 - - - - - Mucositis oral 2 - - 1 - - Nausea 1 - - - - - Pancreatitis - 1 - - - - Vomiting 2 - - - - - Fatigue 1 - - - - - Hepatic failure - - - 1 - - Infections and infestations - Other, specify 1 - - - - - Upper respiratory infection 1 - - - - - Urinary tract infection 1 - - - - - Lung infection 1 - - - - - Alanine aminotransferase increased 5 - - 9 - - Aspartate aminotransferase increased 1 - - 3 - - Blood bilirubin increased 2 - - 3 4 - Investigations - Other, specify 1 - - - - - Lipase increased - 1 - - - - Lymphocyte count decreased - 3 - 4 2 - Neutrophil count decreased 1 19 - 3 10 - Platelet count decreased 3 8 - 2 4 - Serum amylase increased - 1 - - - - White blood cell decreased 1 7 - 1 6 - Dehydration 1 - - - - - Hyperglycemia 1 - - 1 - - Hypertriglyceridemia - 1 - - - - Hyponatremia 1 - - - - - Metabolism and nutrition disorders - Other, specify - 1 - - - - Back pain - - - 1 - - Avascular necrosis 2 - - - - - Treatment related secondary malignancy - - 1 - - - Headache - - - 1 - - Peripheral sensory neuropathy - - - 2 - - Psychiatric disorders - Other, specify 1 - - - - - Hypertension - - - 1 - - Thromboembolic event 1 - - - - - WORST DEGREE (NON-HEMATOLOGIC) 13 1 1 14 4 -


Page 22

Table 7. Lethal Adverse Events

Case Arm Description of Event 19001 A Death NOS 19126 A Intracranial hemorrhage 19215 A Sudden death NOS 19220 A Febrile neutropenia 19243 A Sepsis 19299 A Sepsis 19305 A Infections and infestations - Other 19345 A Adult respiratory distress syndrome 19378 A Hepatic failure 19452 A Sepsis 19456 A Myocardial infarction 19514 A Stroke 19521 A Cardiac arrest 19540 A Hepatic failure 19685 A Intracranial hemorrhage 19119 C Intracranial hemorrhage 19327 C Sepsis 19088 D Cardiac arrest 19047 E Cardiac arrest

Table 8. Second Primary Cancers (By arm during which event was reported)

Site Arm A Arm B Arm E

Acute Non-Lymphocytic Leukemia - ANLL, AML 1 - - Leukemia, Type Not Specified - - 1 Melanoma 1 - - Non-Small Cell Lung 1 - - Pancreas 1 - - Skin Cancer Not Melanoma - 1 -

ECOG-ACRIN Cancer Research Group EA9161 Study Progress and Safety Report Fall 2019

Page 1

EA9161 A RANDOMIZED PHASE III STUDY OF THE ADDITION OF VENETOCLAX TO IBRUTINIB AND OBINUTUZUMAB VERSUS IBRUTINIB AND OBINUTUZUMAB IN UNTREATED YOUNGER PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Sponsor(s)

Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Tait Shanafelt Statistician Dr. Xin Victoria Wang Data Specialist Elene Assefa Phase of Study III Type of Study Therapeutic Committee Leukemia Accrual Objective 720 Patients Participating Groups ECOG-ACRIN, SWOG, ALLIANCE, NRG NSC# 748645, 766270, 793436 Clinicaltrials.gov Study ID NCT03701282 Study Status Open to Accrual Date Activated January 3, 2019 Schema


Page 2

Purpose of Study EA9161 Primary Objective: To compare the progression free survival (PFS) of the time limited administration of the three-drug combination Ibrutinib-Obinutuzumab-Venetoclax (IOV) to Ibrutinib-Obinutuzumab (IO) in CLL patients younger than 70 years of age. Secondary Objectives: (1) Evaluate overall survival (OS) of patients based on treatment arm. (2) Monitor and assess toxicity of treatment based on treatment arm. (3) Compare minimal residual disease (MRD) status as assessed by flow cytometry after 12, 18, 24, and 30 months of treatment of the two treatment arms. (4) To compare quality of life (QOL) in CLL patients during the first 12 months of treatment among patients on each treatment arm. (5) To compare QOL over the long-term in CLL patients receiving continuous therapy using Ibrutinib to that of CLL patients who completed time limited therapy. (6) Determine the effect of pretreatment clinical and biological characteristics (e.g. disease stage, IGHV mutation status, FISH) on clinical outcomes (e.g. complete response, PFS) of the different arms. (7) Compare the genetic abnormalities and dynamics of intra-clonal architecture of CLL patients before and after treatment on each treatment arm and explore relationships with treatment resistance. (8) Explore the effects of each treatment arm on T-cell immune function. (9) Evaluate the ability of prognostic model that incorporates clinical and biologic characters to predict a response to therapy and clinical outcome (PFS, OS). (10) Evaluate signaling networks downstream of the B-cell receptor in patients receiving Ibrutinib-based therapy. Collect relapse samples to study mechanisms of resistance for patients on both treatment arms. (11) Conduct cost effectiveness analysis of treatment for patients in each treatment arm. Study Population Previously untreated CLL patients between 18 and 70 years of age requiring therapy. ECOG PS 0-2. Excludes patients with deletion 17p13. Summary of Study Design Because we expect the IOV arm to have moderate improvement in PFS and, at the same time, the duration of therapy for the IOV arm is 19 cycles whereas patients on IO need to be on therapy indefinitely, a hybrid non-inferiority design is used. We assume the median PFS for the IO arm to be 78 months. The null hypothesis is that the hazard ratio of IOV over IO is 1.18 or larger, corresponding to a 12-month reduction in median PFS to 66 months for the IOV arm. The alternative hypothesis is that this hazard ratio is less than 1.18, meaning that the IOV arm is non-inferior to the IO arm. We design the study to have 80% power to detect an improvement in hazard ratio to 0.83 or less, corresponding to median of 94 months or more for the IOV arm, with one-sided alpha of 0.025. Assuming an accrual rate of 20 patients per month, with one interim analysis and one final analysis, this design requires 720 patients accrued over 36 months and an additional follow-up of 37.2 months to reach the full information of 258 events. Progress to Date This study was activated on January 3, 2019. As of July 17, 2019, 120 patients have been accrued. Accruals by ECOG-ACRIN institutions and by group are shown in Table 1a and 1b. Projected accruals are shown in Table 1c and Figure 1. Table 2 summarizes patient status. Table 3 shows patient demographic information by treatment arm. Record status by form is presented in Table 4. Treatment-related toxicity data are available for 69 patients and are summarized in Table 5. A summary of the collection of quality of life data is presented in Table 6. There have been no report of patients not starting assigned protocol therapy or off treatment. No treatment-related lethal adverse events or second primary cancers have been reported.


Page 3

Table 1a. Accrual by ECOG-ACRIN Institution

Institution Name Step 1 Catholic Health Initiatives NCORP 5 Colorado Cancer Research Program NCORP 2 Heartland Cancer Research NCORP 5 Holy Cross Hospital 1 Mayo Clinic 22 Metro Minnesota Community Oncology Res Consortium 4 Michigan Ca Res Consortium NCORP 2 Montana Cancer Consortium NCORP 3 Ochsner NCORP 2 Pacific Cancer Research Consortium NCORP 4 Penn State Milton S Hershey Medical Center 1 Rutgers Cancer Institute of New Jersey 1 UT Southwestern/Simmons Cancer Center-Dallas 3 University of Kansas Cancer Center 1 University of Oklahoma Health Sciences Center 1 University of Wisconsin Hospital and Clinics 1 Wichita NCORP 2 Wisconsin NCORP 2 Yale University 2 Total 64

Table 1b. Accrual by Group ECOG-ACRIN 64 SWOG 30 ALLIANCE 21 NRG 5 Total 120

Table 1c. Projected Accrual Accrual goal 720 Planned accrual rate 240/yr Accrual to date 120 Annual accrual rate Overall 225/yr

Projected date of closure January 2022


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Figure 1. EA9161 Cumulative Accrual

Table 2. Patient Status as of July 17, 2019

Cases Entered 120 Ineligible 0 Never Started Assigned Therapy 0

020

4060

8010

012

0

Num

ber o

f Pat

ient

s

Jan 2019 Mar 2019 May 2019 Jul 2019

TargetActual


Page 5

Table 3. Demographics

Variable Level Arm A (n=60)

Arm B (n=60)

Total (n=120)

Sex Male 41 (68.3) 41 (68.3) 82 (68.3) Female 19 (31.7) 19 (31.7) 38 (31.7)

Race White 53 (94.6) 52 (98.1) 105 (96.3) African-American 2 (3.6) 1 (1.9) 3 (2.8) Asian 1 (1.8) 0 (0.0) 1 (0.9) Unknown/Unreported 4 7 11

Ethnicity Hispanic 3 (5.1) 1 (1.8) 4 (3.4) Non-Hispanic 56 (94.9) 56 (98.2) 112 (96.6) Unknown/Missing 1 3 4

Age Median 61 60 60 Minimum 40 31 31 Maximum 69 69 69

Table 4. Record Status

Form Name Forms Due

Forms Received %

Adverse Events 156 148 94.9% Disease Description at Study Entry 113 112 99.1% Disease Follow-Up Status 174 160 92.0% Follow-Up Hematology/Chemistry 495 479 96.8% Hematology/Chemistry 112 109 97.3% Patient Characteristics 293 282 96.2% Report Period and Vital Status Form 181 170 93.9% Treatment Agent: Ibrutinib 168 150 89.3% Treatment Agent: Obinituzumab 161 158 98.1% Treatment Agent: Venetoclax 16 15 93.8%


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Table 5. Grade 3 and Above Treatment-related Toxicity Incidence

Toxicity Type

Treatment Arm A (n=33) B (n=36)


(n) (n) (n) (n) (n) (n) Anemia 1 - - - - - Blood and lymphatic system disorders - Other, specify - - - 1 - - Leukocytosis 2 - - 1 - - Atrial fibrillation - - - 1 - - Diarrhea - - - 1 - - Chills 1 - - - - - Allergic reaction 1 - - - - - Infusion related reaction 5 1 - 3 - - Lymphocyte count decreased 2 - - 2 - - Lymphocyte count increased 2 - - 2 - - Neutrophil count decreased 2 3 - 2 3 - Platelet count decreased 1 - - 3 1 - White blood cell decreased 1 - - 1 - - Hyperkalemia - 1 - - - - Hypoxia 1 - - - - - Rash maculo-papular - - - 1 - - Flushing 1 - - - - - Hypotension 1 - - - - - WORST DEGREE 12 5 - 8 4 -

Table 6. QOL Table

QOL Timepoint

Patients Reaching

Timepoint % Forms

Completed Baseline 78 92.3 Cycle 3 13 100.0 Cycle 7 0 Cycle 15 0 End of Cycle 19 0 6 months after treatment 0 12 months after treatment 0 18 months after treatment 0 24 months after treatment 0 48 months after registration 0

Documents

LEUKEMIA COMMITTEE 2020/ROS... · 2020. 3. 19. · leukemia in their peripheral blood or bone marrow. Patients must have ≥ 5% blasts in the peripheral blood or bone marrow. At least