Leukemia - swogstat.org 2011/Leukemia.pdf · Title: Microsoft Word - Leukemia.doc Author: markb Created Date: 3/3/2011 1:58:45 PM

APRIL 14 - 16, 2011 SOUTHWEST ONCOLOGY GROUP LEUKEMIA 1

LEUKEMIA COMMITTEE


CONTENTS

Initial Registrations to Therapeutic Studies . . . . . . . . . . . . . . . . . . . . . 3

Patient Registration by Study and Arm . . . . . . . . . . . . . . . . . . . . . . . 4

S9007 Biologic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

S9910 Biologic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

S0325 Phase IIb Intergroup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

S0521 Phase III . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

S0535 Phase II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30

S0703 Phase II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34

S0805 Phase II Intergroup . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

S0910 Phase II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41

S0919 Phase II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

C10403 Phase II Intergroup . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

C10404 Phase II Intergroup . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

C10603 Phase III SWOG Endorsed CTSU Study . . . . . . . . . . . . . . . . 51

C10701 Phase II SWOG Endorsed CTSU Study . . . . . . . . . . . . . . . . . 53

E1905 Phase II Intergroup . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

E1908 Phase II SWOG Endorsed CTSU Study . . . . . . . . . . . . . . . . . . 57

E2905 Phase III SWOG Endorsed CTSU Study . . . . . . . . . . . . . . . . . 59


Initial Registrations to Therapeutic Studies

by 12 Month Intervals

LEUKEMIA COMMITTEE

0

50

100

150

200

250

300

350

400

450

Time of registration

JAN 2005DEC 2005

160

16

70

161

JAN 2006DEC 2006

99

14

50

125

JAN 2007DEC 2007

140

9

50

142

JAN 2008DEC 2008

164

8

49

199

JAN 2009DEC 2009

125

12

55

131

JAN 2010DEC 2010

88

825

28

MEMBER AFFILIATE CCOP NON-SWOG


Patient Registration by Study and Arm

LEUKEMIA COMMITTEE

July-Dec

2010

Jan-June

2010

July-Dec

2009

All

Patients

S9007 Cytogenetic Studies in Leukemia Patients

Cytogenetics Samples 2 33 70 3,315 S9910 Leukemia Central Lab/Tissue Repository

Specimen Submission 1 33 71 1,265 S0106 AML, Mylotarg/Ara-C/Daunomycin

ARA-C + Daunomycin + Mylotarg 0 0 13 317

ARA-C + Daunomycin 0 0 11 320

0 0 24 637 S0333 Non-L3 ALL, Double Induction DNR + VCR + Pred + PEG-L-Asp 0 0 3 79 S0521 APL, Low/Int Risk, Maint vs Obs

ATRA + ARA-C + Daunorubicin 0 23 31 105 S0535 APL, High Risk, ATRA/arsenic/G.O.

ATRA + G.O. + Arsenic 0 17 9 34 S0605 AML, del5q, Age 60+, Revlimid

Revlimid 0 2 6 41 S0703 AML, age 60+, Azacitidine G.O.

Hydroxyurea/Azacitidine/G.O. 0 38 37 90 S0805 Ph+ ALL, Dasatinib/CVAD +/- BMT

Induction/Consolidation 1 0 0 1 S0910 Rel Ph-,B-ALL, Epratuzumab+Cy+Clo

ARA-C+Clofarabine+Epratruzumab 3 0 0 3 S0919 Rel AML: Pravastatin+Ida+Ara-C

Pravastatin+Idarubicin+Ara-C 5 4 1 10 C10403 Adolescent/Young Adult ALL *

Sequential Chemotherapy 11 14 5 35 C10404 CLL, Flu/Rituxan combinations *

Flu/Rituximab 1 1 1 3 Flu/Rituximab/Lenalidomide 2 0 1 3

Flu/Cy/Rituximab 2 1 1 4

5 2 3 10 C10501 CLL, Early Intervention vs Obs * Total Registrations 0 0 2 8 C10603 AML PKC 412, blinded, FLT3 *

Total Registrations 12 5 1 20 E1905 MDS/CMMoL/AML-TLD, Aza +/- MS-275 *

Azacitidine 0 0 0 8

Azacitidine + MS-275 0 2 0 14

0 2 0 22 E2905 MDS, Len vs Len + Epo * Total Registrations 2 3 7 12

* For non-SWOG coordinated studies only SWOG registrations are shown.


S9007/BIOLOGIC

S9007 Biologic

Coordinating Group: SWOG

Cytogenetic Studies in Leukemia Patients

Participants: SWOG, CTSU

Study Coordinator: D Roulston

Statisticians: H Gundacker, K Kopecky

Data Coordinator: T Maher

Date Activated: 7/15/1991

Objectives To estimate the frequencies and prognostic signi-

ficance of cytogenetic abnormalities in marrow or

blood cells of leukemia patients prior to treatment

on SWOG protocols and at various times in the

course of their treatment.

To estimate correlations between the presence of

cytogenetic features and of clinical, pathophysio-

logical, cellular, or molecular characteristics in these patients.

To provide quality control for all SWOG cytoge-

netic data.

Patient Population Patients must be registered to any SWOG leuke-

mia protocol approved after January 1, 1990, in-

cluding ECOG patients registered to S9300.

Summary Statement As of December 31, 2010, a total of 3,315 pa-

tients were registered on this study.


S9007/BIOLOGIC

Registration by Institution

Registrations ending December 31, 2010

Institutions Total

Reg Institutions Total

Reg

Wichita CCOP

201 Oregon Hlth Sci Univ

28Loyola University 161 LSU-New Orleans CCOP 27Puget Sound 128 Southeast CCC CCOP 27Michigan, U of 124 South Alabama CCOP 25City of Hope Med Ctr 119 Stanford University/City of Hope Med Ctr 25LSU-Shreveport 107 Cincinnati MC, U of 24Columbus CCOP 97 Scott & White/TX A&M 24Wayne State Univ 93 Mississippi, Univ of 23Cleveland Clinic OH 88 Virginia Mason CCOP 22Utah, U of 79 Oklahoma, Univ of 21Ohio State U 76 Breslin Cancer Ctr/Henry Ford Hosp 20Rochester, Univ of 72 Kaiser, Sacramento/Davis, U of CA 19Kansas City CCOP 66 BAMC/WHMC 18Davis, U of CA 61 H Lee Moffitt CC 17Henry Ford Hosp 58 Riverside Methodist/Ohio State U 17St Louis CCOP 55 Sutter Hlth Western/Davis, U of CA 17Dayton CCOP 54 Akron Gen Med Ctr/Cleveland Clinic OH 16St Louis University 52 CALGB 14Stanford University 52 Carilion Medical Ctr/Temple University 13Upstate Carolina 49 Scott & White CCOP 13Central IL CCOP 48 Temple University 13San Antonio, U of TX 48 Allegheny CCOP 12MUSC, Hollings CC 45 Michael Reese Hosp/Oklahoma, Univ of 12Arkansas, U of 44 Michigan CRC CCOP 12Montana CCOP 42 Northwest CCOP 12Arizona, U of 39 Tulane Univ/San Antonio, U of TX 11Atlanta Reg CCOP 39 Aultman Hospital/Ohio State U 10Stormont-Vail Health/Kansas, U of 38 Hawaii MBCCOP, U of 10So Calif, U of 36 LSU-Shreveport CCOP 10Boston Univ Med Ctr 33 Tulane University 10ECOG 33 NCCTG 9Grand Rapids CCOP 32 Salem Hospital/Oregon Hlth Sci Univ 9Providence Hosp 32 SW Cancer & Res Ctr/San Antonio, U of TX 9New Mexico, U of 30 Thompson Ca Surv Ctr/San Antonio, U of TX 9Colorado, U of 29 Hawaii, U of 8New Mexico MBCCOP 29 Santa Rosa Mem Hosp/Davis, U of CA 8

Columbia River CCOP 28 All Other Institutions 296

Kentucky, U of 28 Total (196 Institutions) 3,315


S9910/BIOLOGIC

S9910 Biologic


Leukemia Centralized Reference Laboratories and Tissue Repositories,

Ancillary

Participants: SWOG, CTSU

Study Coordinators: C Willman, J Radich




Objectives To develop and apply laboratory assays for the

rapid and precise diagnosis of leukemia patients

and identify biologic, genetic, and molecular pa-

rameters that distinguish different subtypes of

human leukemia with differing responses to ther-

apy.

To develop "risk-adapted" therapeutic approaches

in which biologic, genetic, and molecular para-meters are used to target individual patients to tai-

lored therapeutic regimens, or, to randomize and

stratify patients to different treatment arms of a

therapeutic trial.

To develop new automated and standardized la-

boratory methods for the detection and monitor-

ing of therapeutic responsiveness and minimal re-

sidual disease in leukemia patients and develop

new clinical approaches to employ such data in therapeutic decision making and clinical trial de-

sign.

To maintain and expand tissue repositories of

highly characterized leukemia samples from un-

iformly treated SWOG patients to promote inter-

group and external fundamental scientific colla-

borations and to perform continued critical pros-

pective and retrospective correlative biologic stu-

dies.

To utilize scientific information generated from

intergroup and collaborative studies to assist the Leukemia Committee in the development of new

and more effective treatment regimens.

Patient Population Patients must be registered on a SWOG treatment

study for lymphoid leukemia (ALL or CLL),

myeloid leukemia (AML or CML) or myelodys-

plasia on or after the date of activation of this

study.

Summary Statement As of December 31, 2010, 1,265 patients were

registered to this study.


S9910/BIOLOGIC



Institutions Total


Reg

Michigan, U of

108 Providence Hosp

19 Wichita CCOP 95 Kansas City CCOP 18 Loyola University 93 H Lee Moffitt CC 17 Rochester, Univ of 72 Dayton CCOP 15 Puget Sound 55 Oregon Hlth Sci Univ 15 Stanford University 50 Kentucky, U of 14 Columbus CCOP 48 St Louis CCOP 14 MUSC, Hollings CC 45 CALGB 13 Utah, U of 43 Davis, U of CA 13 Cleveland Clinic OH 39 Arizona, U of 12 Wayne State Univ 38 San Antonio, U of TX 12 City of Hope Med Ctr 32 LSU-Shreveport CCOP 10 New Mexico MBCCOP 32 Stanford University/City of Hope Med Ctr 10 LSU-Shreveport 28 Arkansas, U of 9 Southeast CCC CCOP 25 Atlanta Reg CCOP 9 Grand Rapids CCOP 22 Henry Ford Hosp 9 Upstate Carolina 22 NCCTG 9 Montana CCOP 21 So Calif, U of 9 Central IL CCOP 20 Sutter Hlth Western/Davis, U of CA 8 ECOG 20 All Other Institutions 102 Stormont-Vail Health/Kansas, U of 20 Total (78 Institutions) 1,265


S0325/IIB

S0325 Phase IIb Intergroup


A Phase IIb Study of Molecular Responses to Imatinib at Standard or

Increased Doses, or Dasatinib (BMS-354825)(NSC-732517) for Previously

Untreated Patients with Chronic Myelogenous Leukemia (CML) in Chronic

Phase

Intergroup Participants: SWOG, CALGB (10303), ECOG, NCIC CTG (CM.1)

Study Coordinators: B Druker, M Slovak, J Radich, P Emanuel (ECOG),

M Wadleigh (CALGB), J Lipton (NCIC CTG)

Statisticians: K Kopecky, H Gundacker



Date Closed: 2/28/2009

Schema

R

A

N

D

O

M I

Z

E

Chronic phase

CML within 6

months of diagnosis

Imatinib 400 mg/day

Dasatinib 100 mg/day*

E

V

A

L

U A

T

E

Level of molecular

response at 1 year Imatinib 800 mg/day*

* Accrual to the dasatinib arm began on November 29, 2006.

Accrual to the imatinib 800 mg/day arm was closed on February 1, 2007.

Objectives To compare the molecular response, as measured

by the decrease in BCR-ABL transcripts after 12

months of treatment, in patients with previously

untreated CML in chronic phase who are treated with either dasatinib 100 mg/day or imatinib

(STI-571, Gleevec®) 400 mg/day.

To test whether increasing the dose of imatinib

(STI-571, Gleevec®) from 400 mg/day to 800

mg/day increases the rate of molecular response,

as measured by the decrease in BCR-ABL tran-

scripts after 12 months of treatment, in patients

with previously untreated CML in chronic phase.

To estimate rates of cytogenetic and hematologic

responses to imatinib 400 mg/day, imatinib 800

mg/day, and dasatinib 100 mg/day.

To evaluate in a preliminary manner the prognos-

tic effects of der(9) and der(22) chromosomal de-

letions for response in CML patients treated with

imatinib and dasatinib.

To investigate in a preliminary manner changes

in gene expression at relapse or progression com-

pared to pre-treatment.

To estimate the frequency and severity of toxici-ties of the three treatment regimens.


S0325/IIB

To evaluate, in a preliminary manner, the overall

survival and relapse-free survival of patients

treated with these regimens.

Patient Population Patients must have a diagnosis of CML in chronic

phase based on bone marrow aspiration and biop-

sy and peripheral blood counts obtained within 28

days before registration. Patients must be regis-

tered on this study within 180 days after the date

of first being diagnosed with CML, based on a

cytogenetic or molecular analysis demonstrating

the presence of the Philadelphia chromosome or

variants of the (9;22) translocation or testing

positive for BCR-ABL by RT-PCR. Patients may

have secondary chromosomal abnormalities in

addition to the Philadelphia chromosome and re-main eligible.

Patients must not have received prior treatment

for CML with the exception of hydroxyurea

and/or anagrelide. Patients must not have re-

ceived any prior chemotherapy regimen for peri-

pheral blood stem cell mobilization. Patients must

not have undergone major surgery within 28 days

before registration, and must have fully recovered

from any other prior major surgery.

Patients must have reached their 18th birthdays,

have a Zubrod performance status of 0, 1, or 2,

and have adequate hepatic function. Patients must

not have the following cardiac symptoms prior to

entry on study: uncontrolled angina, congestive

heart failure or MI within six months of study en-

try, diagnosed or suspected congenital long QT

syndrome, any history of clinically significant

ventricular arrhythmias (such as ventricular ta-

chycardia, ventricular fibrillation, or Torsades de pointes), prolonged QTc interval on pre-entry

electrocardiogram (> 45 msec), or uncontrolled

hypertension. Patients must not have a history of

significant bleeding disorder unrelated to cancer,

including congenital bleeding disorders (e.g., von

Willebrand's disease) and acquired bleeding dis-

order within one year (e.g., acquired anti-factor

VII antibodies).

Stratification/Descriptive Factors Patient randomization will be stratified by Has-

ford risk category: low vs intermediate vs high.

Accrual Goals The total accrual goal for this study is 400 eligi-

ble patients with 240 randomized between dasati-

nib and low dose imatinib. One interim analysis

will be conducted during the course of this study,

when the 12-month molecular response can be

evaluated for 120 eligible post-amendment pa-

tients (approximately 60 patients for each of the imatinib 400 mg/day and dasatinib arms).

Summary Statement Effective November 29, 2006, this study was

modified to add a third study arm of dasatinib

100 mg/day. The imatinib 800 mg/day arm was

closed to accrual on February 1, 2007. Accrual to

the two remaining arms was closed on February 28, 2009 because the accrual goal was met.

A total of 403 patients were registered to this

study. The following summary is presented in

two parts corresponding to the first two study ob-

jectives. The first part is based on the 153 patients

who were concurrently randomized between the

two imatinib arms, and the second part on the 253

patients who were concurrently randomized be-

tween imatinib 400 mg/day and dasatinib. Note

that the three patients who were registered when all three arms were open are included in both

parts.

1. Imatinib 400 mg/day (standard dose) versus

Imatinib 800 mg/day (high dose):

Seven of the 153 patients on these arms did not

have CML in chronic phase and are ineligible and

excluded from the analysis. One patient who did not receive protocol therapy due to lack of insur-

ance coverage is also excluded from the analysis.

Five major protocol deviations were reported

among the 145 analyzable patients. Two patients

had a prolonged discontinuation of protocol ther-

apy and two others continued to receive protocol

therapy after treatment failure. These four pa-

tients are included in the analysis. A fifth patient

randomized to the high dose arm received the

standard dose regimen. This patient is excluded from the toxicity analysis but is included in all

other analyses.

Six patients were removed from each regimen

due to various toxicities. All 34 patients who

were removed from protocol therapy for reasons

other than progression or death have been eva-

luated for hematologic response, and 28 (82%)

achieved complete hematologic responses.

No fatal toxicities have been reported on either

imatinib arm. Various Grade 4 toxicities, most

commonly hematologic, were reported for nine

(13%) of 72 patients evaluated for toxicities on

the standard dose regimen, and for ten (14%) of

72 patients on the high dose arm. Grade 3 fatigue

was reported for 11 (15%) patients in the high

dose arm, but none in the standard dose arm.

Sixty-three (88%) of the 72 patients evaluated for hematologic response in the standard dose arm

achieved a complete hematologic remission (CR)

or unconfirmed hematologic CR (95% confidence

interval, 78% to 94%). On the high dose arm, 66

(90%) of the 73 patients evaluated for hematolog-


S0325/IIB

ic response achieved a confirmed or unconfirmed

hematologic CR (95% confidence interval, 81%

to 96%).

Five (10%) of 49 patients with 12-month follow-up specimens assayed by RT-PCR achieved mo-

lecular response (4-log reduction of BCR-

ABL/BCR ratio) in the standard dose arm (95%

confidence interval 3% to 22%), compared to 14

(25%) of 55 on the high dose arm (95% confi-

dence interval 15% to 39%, p=0.073).

Five patients on the standard dose arm have died

for a two-year survival rate of 89%. Two patients

on the high dose arm have died for a two-year

survival rate of 95%. There is no statistically sig-nificant difference in overall survival between the

two doses of imatinib (log rank p-value=0.29). Of

the 63 patients who achieved a hematologic re-

mission with the standard dose, six patients re-

lapsed and three died without a report of relapse

for a two-year relapse-free survival rate of 83%.

Of the 66 patients who achieved a hematologic

remission with the high dose, two patients re-

lapsed and a third died without a report of relapse

for a two-year relapse-free survival rate of 97%.

There is no statistically significant difference in relapse-free survival between the two doses of

imatinib (log rank p-value=0.074).

2. Imatinib 400 mg/day versus Dasatinib:

Two hundred fifty-three patients were rando-

mized between these arms. Five were ineligible

and excluded from this analysis: two with Ph-

negative disease, two who did not have CML in

chronic phase, and one with prolonged QTc in-terval. Two patients on the imatinib arm are not

evaluable and excluded from the analysis: one did

not receive protocol therapy due to lack of insur-

ance coverage and the other withdrew consent af-

ter four days of protocol treatment.

Three major protocol deviations were reported,

all for patients randomized to dasatinib. Two pa-

tients received only half of the protocol dose: one

due to patient error and one due to non-compliance. A third patient randomized to the da-

satinib arm received the imatinib standard dose

regimen and is also a major protocol deviation.

This patient is excluded from the toxicity analysis

but is included in all other analyses.

Fifteen patients were removed from the imatinib

arm and 19 from the dasatinib arm due to various

toxicities. All 79 patients who were removed

from protocol therapy for reasons other than pro-

gression or death have been evaluated for hema-

tologic response, and 62 (78%) achieved com-

plete hematologic responses.

No fatal toxicities have been reported for either the imatinib or dasatinib arm. Of the 123 imatinib

patients evaluated for toxicities, Grade 4 toxici-

ties were reported for two patients (2%): one with

thrombocytopenia and one with neutropenia and

thrombocytopenia. Grade 4 toxicities were re-

ported for 17 (14%) of 122 patients evaluated for

dasatinib toxicity, most commonly hematologic.

Grade 4 non-hematologic toxicities were reported

for seven patients on the dasatinib arm: febrile

neutropenia in two patients, and elevated LDH

(coded as Metabolic/Lab-other), cardiac ische-

mia/infarction, conduction abnormality asystole, pericardial effusion, and sensory neuropathy in

one patient each.

One hundred twelve (91%) of the 123 patients

evaluated for hematologic response in the imati-

nib arm achieved a complete hematologic remis-

sion (CR) or unconfirmed hematologic CR (95%

confidence interval, 85% to 95%). On the dasati-

nib arm, 107 (87%) of the 123 patients evaluated

for hematologic response achieved a confirmed or unconfirmed hematologic CR (95% confidence

interval, 80% to 92%).

Among patients with follow-up specimens as-

sayed by RT-PCR, the rate of molecular response

(4-log reduction of BCR-ABL/BCR ratio) at 12

months was 18/90 (20%, 95% confidence interval

12% to 30%) on the imatinib arm and 27/99

(27%, 95% confidence interval 19% to 37%) on

the dasatinib arm, which is not a significant dif-

ference (p=0.31).

Four patients on the imatinib arm have died for a

two-year survival rate of 98%. Three patients on

the dasatinib arm have died for a two-year sur-

vival rate of 97%. There is no statistically signifi-

cant difference in overall survival between the

imatinib and dasatinib arms (log rank p-

value=0.55). Of the 112 patients who achieved a

hematologic remission on the imatinib arm, five

patients relapsed and two died without a report of relapse for a two-year relapse-free survival rate of

95%. Of the 107 patients who achieved a hemato-

logic remission on the dasatinib arm, three pa-

tients relapsed and another died without a report

of relapse for a two-year relapse-free survival rate

of 96%. There is no statistically significant dif-

ference in relapse-free survival between these two

arms (log rank p-value=0.29).


S0325/IIB

Initial Registrations By 3 Month Intervals

0

10

20

30

40

50

Time of Registration

OCTDEC2004

3

3

JANMAR2005

21

APRJUN2005

4

4

JULSEP2005

8

13

OCTDEC2005

10

5

JANMAR2006

9

13

APRJUN2006

7

12

JULSEP2006

15

11

OCTDEC2006

15

14

JANMAR2007

6

5

2

APRJUN2007

18

11

JULSEP2007

13

11

OCTDEC2007

12

18

JANMAR2008

21

27

APRJUN2008

15

15

JULSEP2008

15

14

OCTDEC2008

16

16

JANMAR2009

10

9

Dasatinib Imatinib 400 mg/day Imatinib 800 mg/day


Institutions

Total

Reg

Institutions

Total

Reg

ECOG

108 Kansas City CCOP

4

NCIC-CTG 87 Rochester, Univ of 4CALGB 74 Loyola University 3Columbus CCOP 16 St Louis CCOP 3Michigan, U of 13 Puget Sound 2Wichita CCOP 13 St Louis University 2Utah, U of 10 Upstate Carolina 2City of Hope Med Ctr 8 Dayton CCOP 1Montana CCOP 8 Mansfield Gen Hosp/Cleveland Clinic OH 1Southeast CCC CCOP 8 MD Anderson, Florida/Arkansas, U of 1Central IL CCOP 7 Michigan CRC CCOP 1Oregon Hlth Sci Univ 7 San Antonio, U of TX 1So Calif, U of 7 Singing River Hosp/Mississippi, Univ of 1

Providence Hosp 5 St Joseph Hospital/Puget Sound 1

Stormont-Vail Health/Kansas, U of 5 Total (29 Institutions) 403


S0325/IIB

Registration, Eligibility, and Evaluability

Imatinib 400 mg/day versus Imatinib 800 mg/day

Data as of February 9, 2011

TOTAL

Imatinib

400 mg/day

Imatinib

800 mg/day

NUMBER REGISTERED

153 75 78

INELIGIBLE 7 2 5 ELIGIBLE 146 73 73 Not Analyzable 1 1 0 RESPONSE ASSESSMENT Determinable 136 67 69 Not Determinable 9 5 4 ADVERSE EVENT ASSESSMENT Evaluable 144 72 72 Not Evaluable 1 0 1

Patient Characteristics



Imatinib 400 mg/day Imatinib 800 mg/day

(n=72) (n=73)

AGE Median

50.8

52.1

Minimum 23.9 20.0 Maximum 80.4 82.4 SEX Males

46

64% 47

64%

Females 26 36% 26 36% HISPANIC Yes

0

0% 1

1%

No 47 65% 48 66% Unknown 25 35% 24 33% RACE White

44

61% 55

75%

Black 5 7% 3 4% Asian 1 1% 2 3% Unknown 22 31% 13 18% HASFORD RISK CATEGORY Low

15

21% 15

21%

Intermediate 22 31% 22 30% High 35 49% 36 49%


S0325/IIB

Treatment Summary



TOTAL

Imatinib

400 mg/day

Imatinib

800 mg/day

NUMBER ON PROTOCOL TREATMENT

14 10 4

NUMBER OFF PROTOCOL TREATMENT 131 62 69 REASON OFF TREATMENT Treatment completed as planned 89 37 52 Adverse Events or side effects 12 6 6 Refusal unrelated to adverse events 12 7 5 Progression/relapse 6 4 2 Death 2 1 1 Other - not protocol specified 10 7 3 Reason under review 0 0 0MAJOR PROTOCOL DEVIATIONS 5 2 3


S0325/IIB

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


Adverse Events Unlikely or Not Related to Treatment Excluded

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


Imatinib

400 mg/day

Imatinib

800 mg/day

(n=72) (n=72)

Grade

Grade

ADVERSE EVENT ≤ 2 3 4 5 ≤ 2 3 4 5

ALT

71 1 0 0 69 2 1 0

AST 71 1 0 0 71 0 1 0Bilirubin 71 1 0 0 72 0 0 0Blurred vision 71 1 0 0 71 1 0 0CPK 69 2 1 0 72 0 0 0Diarrhea 71 1 0 0 66 6 0 0Distension 72 0 0 0 71 1 0 0Dizziness 71 1 0 0 72 0 0 0Dyspnea 72 0 0 0 70 2 0 0Edema-head and neck 70 1 1 0 72 0 0 0Edema-limb 72 0 0 0 70 2 0 0Edema-trunk/genital 72 0 0 0 71 1 0 0Edema-viscera 71 1 0 0 72 0 0 0Fatigue 72 0 0 0 61 11 0 0Febrile neutropenia 71 1 0 0 71 1 0 0GGT 72 0 0 0 71 1 0 0GI Inf, 0-2 ANC: colon 72 0 0 0 71 1 0 0GI Pain: abdomen 71 1 0 0 68 4 0 0GU Inf, 0-2 ANC: UTI 71 0 1 0 72 0 0 0Hemoglobin 67 4 1 0 64 7 1 0Hepatobiliary-other 72 0 0 0 71 1 0 0Hypoxia 72 0 0 0 71 1 0 0Leukocytes 71 1 0 0 70 2 0 0Lung Inf, 0-2 ANC: lung 72 0 0 0 71 1 0 0Lung Pain: chest/thorax 72 0 0 0 71 1 0 0Lymphopenia 71 0 1 0 71 1 0 0Mood alteration: depression 71 0 1 0 72 0 0 0Muscle weakness: whole body 72 0 0 0 71 1 0 0Musculo. Pain: back 72 0 0 0 71 1 0 0Musculo. Pain: bone 71 0 1 0 69 3 0 0Musculo. Pain: joint 72 0 0 0 71 1 0 0Musculo. Pain: limb 72 0 0 0 71 1 0 0Musculo. Pain: muscle 71 1 0 0 69 3 0 0Nausea 70 2 0 0 70 2 0 0Neuro Pain: head/headache 71 1 0 0 71 1 0 0Neutrophils 64 5 3 0 60 8 4 0Platelets 66 5 1 0 58 8 6 0Pruritus 72 0 0 0 71 1 0 0Rash 71 1 0 0 68 3 1 0Restrictive cardiomyopathy 72 0 0 0 71 1 0 0Vomiting 71 1 0 0 72 0 0 0Weight gain 72 0 0 0 71 1 0 0 MAXIMUM GRADE ANY ADVERSE EVENT Number

50 13 9 0 30 32 10 0

Hematologic Response



Imatinib

400 mg/day

Imatinib

800 mg/day

Complete Response

59 82% 62 85%

Unconfirmed Complete Response 4 6% 4 5%Stable/No Response 4 6% 2 3%Increasing Disease 0 0% 1 1%Assessment Inadequate 5 7% 4 5% Total

72 100% 73 100%


S0325/IIB

Overall Survival by Treatment Arm



0%

20%

40%

60%

80%

100%

0 24 48 72

Months since Complete Remission

Imatinib 800 mg/day

Imatinib 400 mg/day

At Risk

73

72

Deaths

2

5

2-Year

Estimate

95%

89%

Relapse-Free Survival by Treatment Arm



0%

20%

40%

60%

80%

100%

0 24 48 72


Imatinib 800 mg/day

Imatinib 400 mg/day

At Risk

66

63

Failed

3

9

2-Year

Estimate

97%

83%


S0325/IIB


Imatinib 400 mg/day versus Dasatinib


TOTAL

Imatinib

400 mg/day Dasatinib

NUMBER REGISTERED

253 127 126

INELIGIBLE 5 2 3 ELIGIBLE 248 125 123 Not Analyzable 2 2 0 RESPONSE ASSESSMENT Determinable 231 118 113 Not Determinable 15 5 10 ADVERSE EVENT ASSESSMENT Evaluable 245 123 122 Not Evaluable 1 0 1




Imatinib 400 mg/day Dasatinib

(n=123) (n=123)

AGE Median

50.7

47.7


72

59% 75

61%


1

1% 6

5%


85

69% 75

61%

Black 3 2% 2 2% Asian 3 2% 2 2% Pacific Islander 0 0% 1 1% Native American 1 1% 0 0% Multi-Racial 1 1% 3 2% Unknown 30 24% 40 33% HASFORD RISK CATEGORY Low

44

36% 44

36%

Intermediate 45 37% 40 33% High 34 28% 39 32%


S0325/IIB

Treatment Summary



TOTAL

Imatinib



136 57 79



S0325/IIB






Imatinib

400 mg/day

Dasatinib

(n=123) (n=122)

Grade

Grade

ADVERSE EVENT ≤ 2 3 4 5 ≤ 2 3 4 5

ALT

120 3 0 0 121 1 0 0

AST 121 2 0 0 121 1 0 0Blurred vision 123 0 0 0 121 1 0 0Bronchospasm 122 1 0 0 122 0 0 0CNS ischemia 123 0 0 0 121 1 0 0CPK 123 0 0 0 121 1 0 0Cardiac ischemia/infarction 123 0 0 0 120 1 1 0Colitis 123 0 0 0 120 2 0 0Cond. Abn.: Asystole 123 0 0 0 121 0 1 0Constipation 123 0 0 0 121 1 0 0Dehydration 123 0 0 0 121 1 0 0Diarrhea 121 2 0 0 116 6 0 0Dizziness 122 1 0 0 122 0 0 0Dyspnea 121 2 0 0 115 7 0 0Edema-head and neck 121 2 0 0 122 0 0 0Edema-limb 122 1 0 0 121 1 0 0Fatigue 122 1 0 0 121 1 0 0Febrile neutropenia 123 0 0 0 119 1 2 0GI Pain: abdomen 122 1 0 0 120 2 0 0Hemoglobin 118 5 0 0 110 11 1 0Hot flashes 123 0 0 0 121 1 0 0Hyperglycemia 123 0 0 0 119 3 0 0Hyperkalemia 123 0 0 0 121 1 0 0Hypernatremia 123 0 0 0 121 1 0 0Hypertension 123 0 0 0 121 1 0 0Hypokalemia 121 2 0 0 121 1 0 0Hypophosphatemia 122 1 0 0 121 1 0 0Inf, 3-4 ANC: blood 123 0 0 0 121 1 0 0Left vent. diastolic dysfunct. 123 0 0 0 121 1 0 0Leukocytes 120 3 0 0 119 2 1 0Lung Inf, 0-2 ANC: lung 123 0 0 0 120 2 0 0Lung Inf, 0-2 ANC: sinus 123 0 0 0 121 1 0 0Lung Inf, 3-4 ANC: lung 123 0 0 0 120 2 0 0Lung Inf, Unk ANC: sinus 123 0 0 0 121 1 0 0Lung Pain: chest/thorax 122 1 0 0 121 1 0 0Lymphopenia 122 1 0 0 119 3 0 0Metabolic/Lab-other 123 0 0 0 121 0 1 0Mucositis, clin: oral cavity 121 2 0 0 122 0 0 0Musculo. Pain: back 122 1 0 0 122 0 0 0Musculo. Pain: bone 123 0 0 0 121 1 0 0Musculo. Pain: joint 121 2 0 0 121 1 0 0Musculo. Pain: muscle 122 1 0 0 122 0 0 0Nausea 122 1 0 0 122 0 0 0Neuro Pain: head/headache 120 3 0 0 119 3 0 0Neuropathy-motor 123 0 0 0 121 1 0 0Neuropathy-sensory 123 0 0 0 121 0 1 0Neutrophils 108 14 1 0 104 13 5 0Pain-other 122 1 0 0 122 0 0 0Pericardial effusion 123 0 0 0 119 2 1 0Platelets 113 8 2 0 100 13 9 0Pleural effusion 122 1 0 0 119 3 0 0Prolonged QTc 123 0 0 0 121 1 0 0Pruritus 121 2 0 0 122 0 0 0Pulmonary-other 123 0 0 0 121 1 0 0Rash 121 2 0 0 122 0 0 0Retinal detachment 122 1 0 0 122 0 0 0Sex/Rep Inf, 0-2 ANC: scrotum

123 0 0 0 121 1 0 0

Vaginal mucositis 123 0 0 0 121 1 0 0Vomiting 123 0 0 0 121 1 0 0Watery eye 123 0 0 0 121 1 0 0Weight gain 123 0 0 0 120 2 0 0 MAXIMUM GRADE ANY ADVERSE EVENT Number

80 41 2 0 54 51 17 0


S0325/IIB

Hematologic Response



Imatinib


Complete Response

100 81% 100 81%

Unconfirmed Complete Response 12 10% 7 6%Stable/No Response 6 5% 6 5%Increasing Disease 0 0% 0 0%Assessment Inadequate 5 4% 10 8% Total

123 100% 123 100%




0%

20%

40%

60%

80%

100%

0 12 24 36 48


Imatinib 400 mg/day

Dasatinib

At Risk

123

123

Deaths

4

3

2-Year

Estimate

98%

97%


S0325/IIB

Relapse-Free Survival by Treatment Arm



0%

20%

40%

60%

80%

100%

0 12 24 36 48


Dasatinib

Imatinib 400 mg/day

At Risk

107

112

Failed

4

7

2-Year

Estimate

96%

95%


S0521/III

S0521 Phase III


A Randomized Trial of Maintenance Versus Observation for Patients with

Previously Untreated Low and Intermediate Risk Acute Promyelocytic

Leukemia (APL), Phase III

Participants: SWOG, CTSU (endorsed by ECOG and CALGB)

Study Coordinators: S Coutre, D Persons, C Willman

Statisticians: K Kopecky, H Gundacker



Date Closed: 5/27/2010

Schema

R E G I S T R A T I O N

Observation: No therapy


ATRA, Dauno- rubicin, Ara-C

Arsenic Trioxide (2 cycles)

Induction

Gemtuzumab

Ozogamicin

CR, CRi or PR

ATRA, Dauno- rubicin, (2 cycles)

CR or CRi R

E G I S T

R A T I O N

not CRm

CRm

Consolidation #1 and #2

Consolidation #3 and #4

R A N

D O M I Z E

Post-Consolidation

Maintenance: ATRA, 6-MP, MTX

- The study design was revised on August 15, 2010: See the Summary Statement for details.

Objectives To compare disease-free survival (DFS) among

patients with previously untreated low and inter-mediate risk APL who are PCR-negative for

PML-RARα after consolidation therapy and re-

ceive maintenance therapy versus patients who

receive no maintenance therapy.


S0521/III

To assess toxicities of induction, consolidation

and maintenance therapies.

To test whether gene expression profiles assessed

prior to treatment are predictive of resistance to remission induction chemotherapy, correlate with

detectable minimal residual disease post-

consolidation, and predict relapse-free survival in

patients who respond to induction chemotherapy.

To investigate in a preliminary manner the out-

comes of patients who fail to achieve or maintain

PCR-negativity after consolidation therapy, when

treated with gemtuzumab ozogamicin.

Patient Population Patients must have a morphologically confirmed

diagnosis of low or intermediate risk acute pro-

myelocytic leukemia (APL), or the variant form

of APL, based on bone marrow or peripheral

blood examination performed within 14 days be-

fore registration. The WBC and platelet count

confirming low or intermediate risk must be ob-

tained within 48 hours before registration, with

the following exception: if the patient received

ATRA before registration, this WBC and platelet count must be obtained within 48 hours before

ATRA was started. Patients who are known to be

PML-RARα-negative by the RT-PCR assay are

not eligible. Patients with recurrent disease are

not eligible.

Patients must not have received systemic chemo-

therapy, hydroxyurea, or leukapheresis for acute

leukemia, with the exception of ATRA at a dose

of ≤ 45 mg/m2/day for ≤ 5 days before registra-

tion. Patients must not have received more than one dose of intrathecal chemotherapy for acute

leukemia. Since patients must have low or inter-

mediate risk APL to be eligible for the study, the

use of hydroxyurea or leukapheresis will not be

necessary and is prohibited.

Patients must be 18 years old or older, and must

have a Zubrod performance status of 0, 1, 2, or 3.

Patients with unstable cardiac arrhythmias or un-

stable angina are not eligible.

Stratification/Descriptive Factors At the post-consolidation randomization, patients

who are in CRm will be stratified by (1) age: 18-

60 vs > 60 years, (2) APL risk group: low vs in-

termediate, and (3) Did the patient receive con-

solidation cycle 3 or 4 (ATRA plus daunorubi-

cin): Yes vs No.

Accrual Goals The accrual goal of this study is 400 eligible pa-

tients (200 per arm) randomized to step 3 (post-

consolidation). If 80% of patients registered to

the first step are randomized, the total accrual to

the study will be 500 patients.

Summary Statement The study was closed to entry of new patients on

May 27, 2010 due to inadequate accrual. Effec-

tive August 15, 2010 patients proceeding to post-

consolidation therapy were no longer registered

to gemtuzumab therapy and all eligible patients, regardless of molecular response, were non-

randomly assigned to receive post-consolidation

chemotherapy.

A total of 105 patients were accrued to the induc-

tion registration. None are known to be ineligible.

Four patients were taken off protocol induction

therapy due to the following toxicities: unre-

solved renal failure, pneumonia with Grade 4

neutropenia, pseudotumor cerebri, and ATRA

syndrome. One patient withdrew consent on Day 30 of induction.

All 105 patients were evaluated for induction tox-

icities. One patient suffered a fatal toxicity (typh-

litis). Grade 4 non-hematologic toxicities were

reported for another 22 patients including three

with retinoic acid syndrome or APL differentia-

tion syndrome, one with DIC, and one with both

retinoic acid syndrome or APL differentiation

syndrome and DIC.

One hundred four patients have been evaluated

for response and 79 patients achieved complete

response (76%, 95% CI 67%-84%), one of whom

was with incomplete blood count recovery. Only

one patient had resistant disease. Seven of the

105 patients have died for a one-year survival rate

of 93% (95% CI 88%-98%). One patient relapsed

from CR after completing consolidation therapy

but before registration to post-consolidation. No

other patients have had reports of clinical relapse.

Ninety-two patients were registered for consoli-

dation therapy. One major protocol deviation was

reported for a patient who received extra ATRA

and daunorubicin in error for the third consolida-

tion cycle. This patient came off protocol consol-

idation treatment for that reason. Another patient

was taken off consolidation therapy by the treat-

ing physician before starting daunorubicin due to

HIV-related frailty. Six additional patients came off consolidation therapy due to toxicity: one for

pericardial effusion with pericarditis during the

first consolidation cycle, one for sepsis after the

first cycle, one each for thrombocytopenia and

reduced ejection fraction after the second cycle,

one for severe headache during the third cycle,

and one for neuropathy after the third cycle. One

death (cardiac dysfunction) was reported during

consolidation therapy and was reported as possi-

bly attributable to protocol treatment. Grade 4

non-hematologic toxicities were reported for five

additional patients during consolidation: one each with infection and pericardial effusion during the


S0521/III

first consolidation cycle, one with infection and

elevated LFTs during the second cycle, one with

infection during the third cycle, and one with car-

diac dysfunction during the fourth cycle.

Sixty-five patients were registered to post-

consolidation therapy, 55 were randomized and

ten were non-randomly assigned to post-

consolidation chemotherapy after the study de-

sign revision. Three major protocol deviations

were reported for patients who were randomized

to receive post-consolidation therapy but refused

treatment. A fourth patient refused after starting

post-consolidation therapy. Two patients came

off post-consolidation therapy due to toxicity: one

due to severe headache and fatigue and one due

to headache, fever, nausea, vomiting and dysp-

nea.

Of the 27 patients evaluated for post-

consolidation toxicities, no fatal toxicities have been reported. Grade 4 non-hematologic toxici-

ties (elevated LFTs) were reported for one patient

during post-consolidation therapy.

One patient was registered to post-consolidation

gemtuzumab therapy before the registration was

closed to accrual due to the study design revision.

There have been no reports of fatal or Grade 4

non-hematologic toxicities for this patient. No pa-

tients registered to post-consolidation therapy

have relapsed and one patient died without a re-port of relapse.

Initial Registrations By 3 Month Intervals

0

10

20

Time of Registration

OCTDEC2007

3

JANMAR2008

4

APRJUN2008

8

JULSEP2008

2

OCTDEC2008

9

JANMAR2009

14

APRJUN2009

11

JULSEP2009

13

OCTDEC2009

18

JANMAR2010

13

APRJUN2010

10

ATRA + ARA-C + Daunorubicin


Institutions Total


Reg

CALGB

47 MUSC, Hollings CC

1ECOG 28 New Mexico MBCCOP 1Stanford University 9 Puget Sound 1Michigan, U of 4 Southeast CCC CCOP 1Loyola University 3 Tulane University 1Rochester, Univ of 3 Utah, U of 1

Wichita CCOP 3 Wayne State Univ 1

Central IL CCOP 1 Total (15 Institutions) 105


S0521/III



ATRA

+ ARA-C +

Daunorubicin

ATRA

+ ARA-C +

Daunorubicin

NUMBER REGISTERED

105 ADVERSE EVENT ASSESSMENT

ELIGIBLE 105 Evaluable 105 RESPONSE ASSESSMENT Determinable 95 Not Determinable 9 Too Early 1



ATRA + ARA-C +

Daunorubicin

ATRA + ARA-C +

Daunorubicin

(n=105) (n=105)

AGE RACE

Median 49.1 White 87 83% Minimum 20.5 Black 8 8% Maximum 82.4 Asian 7 7% Native American 1 1%SEX Unknown 2 2% Males 61 58% Females 44 42% HISPANIC Yes 6 6% No 87 83% Unknown 12 11%

Treatment Summary

Induction


ATRA

+ ARA-C +

Daunorubicin


0

NUMBER OFF PROTOCOL TREATMENT 105 REASON OFF TREATMENT Treatment completed as planned 96 Adverse Events or side effects 4 Refusal unrelated to adverse events 1 Progression/relapse 0 Death 3 Other - not protocol specified 0 Reason under review 1MAJOR PROTOCOL DEVIATIONS 0


S0521/III


Induction


Non-Hematologic Adverse Events Only



ATRA + ARA-C +

Daunorubicin

ATRA + ARA-C +

Daunorubicin

(n=105) (n=105)

Grade

Grade

ADVERSE EVENT ≤ 2 3 4 5 ADVERSE EVENT ≤ 2 3 4 5

ALT

100 5 0 0

Inf, 0-2 ANC: blood

104 0 1 0

AST 103 2 0 0 Inf, 3-4 ANC: blood 95 10 0 0Acidosis 104 0 1 0 Infection-other 103 2 0 0Alkaline phosphatase 104 1 0 0 Lung Hemorrhage: lung 104 0 1 0Alkalosis 103 1 1 0 Lung Hemorrhage: nose 103 2 0 0Anorexia 101 4 0 0 Lung Inf, 3-4 ANC: lung 97 8 0 0Bilirubin 98 7 0 0 Lung Inf, 3-4 ANC: up. aero. 104 1 0 0CNS hemorrhage 104 1 0 0 Lung Inf, Unk ANC: lung 104 1 0 0CPK 103 1 1 0 Metabolic/Lab-other 104 1 0 0Cardiac Arrhythmia-other 104 1 0 0 Mood alteration: agitation 104 1 0 0Cardiac troponin T 103 1 1 0 Mood alteration: depression 104 1 0 0Cholesterol 104 0 1 0 Mucositis, clin: oral cavity 102 3 0 0Coagulation-other 103 2 0 0 Mucositis, clin: rectum 104 1 0 0Confusion 101 4 0 0 Muscle weakness: low. extrem. 104 1 0 0Creatinine 103 1 1 0 Muscle weakness: up. extrem. 104 1 0 0DIC 94 9 2 0 Muscle weakness: whole body 103 1 1 0Diarrhea 94 11 0 0 Musculo. Pain: back 103 2 0 0Distension 103 2 0 0 Musculo. Pain: limb 104 1 0 0Dizziness 104 1 0 0 Musculo. Pain: muscle 102 1 2 0Dry skin 104 1 0 0 Musculo. Pain: neck 104 1 0 0Dyspnea 94 9 2 0 Myositis 103 1 1 0Enteritis 104 1 0 0 Nausea 99 6 0 0Fatigue 97 8 0 0 Neuro Pain: head/headache 95 10 0 0Febrile neutropenia 47 52 6 0 Neuropathy-motor 104 1 0 0Fever 104 1 0 0 Pericardial effusion 104 0 1 0GI Hemorrhage: rectum 104 1 0 0 Petechiae 103 2 0 0GI Inf, 3-4 ANC: cecum 104 1 0 0 Photosensitivity 104 1 0 0GI Inf, 3-4 ANC: colon 102 3 0 0 Pleural effusion 104 0 1 0GI Inf, 3-4 ANC: gums 104 1 0 0 Prolonged QTc 102 3 0 0GI Inf, 3-4 ANC: tooth 104 1 0 0 Rash 102 3 0 0GI Inf, Unk ANC: gums 104 1 0 0 Renal failure 99 5 1 0GI Inf, Unk ANC: rectum 104 1 0 0 Renal-other 104 0 1 0GI Pain: abdomen 102 3 0 0 Retinal detachment 104 0 1 0GU Hemorrhage: vagina 104 1 0 0 Retinoic acid syndrome 92 9 4 0GU Inf, 3-4 ANC: UTI 104 1 0 0 Sexual/Repro. Pain: scrotum 104 1 0 0GU Inf, Unk ANC: bladder 104 1 0 0 Skin Inf, 0-2 ANC: skin 102 3 0 0Gait/walking 104 0 1 0 Skin Inf, 3-4 ANC: skin 102 3 0 0Hep Inf, 0-2 ANC: gallbladder 104 1 0 0 Skin Inf, Unk ANC: skin 104 1 0 0Hyperglycemia 101 4 0 0 Syncope 102 3 0 0Hypertension 102 3 0 0 Thrombosis/embolism 104 1 0 0Hypertriglyceridemia 100 4 1 0 Typhlitis 102 1 1 1Hypoalbuminemia 101 4 0 0 Vasovagal episode 104 1 0 0Hypocalcemia 102 2 1 0 Vent Arrhyth: Vent Tachy. 104 0 1 0Hypokalemia 101 4 0 0 Vomiting 104 1 0 0Hyponatremia 101 4 0 0 Weight gain 104 1 0 0Hypophosphatemia 98 7 0 0 Hypotension 104 1 0 0 MAXIMUM GRADE ANY ADVERSE EVENT Hypoxia 99 5 1 0 Number 14 68 22 1


S0521/III

Response

Initial Registration


ATRA + ARA-C

+ Daunorubicin

Complete Response

78 75%

CR w/Incomplete Hem. Recovery 1 1%Partial Response 15 14%Assessment Inadequate 7 7%Resistant Disease 1 1%Died <7 Days After 1st Course 2 2% Total

104 100%


Initial Registration


0%

20%

40%

60%

80%

100%

0 12 24 36

Months After Registration

ATRA + ARA-C + Daunorubicin

At Risk

105

Deaths

7

1-Year

Estimate

93%


Consolidation


Consolidation Consolidation

NUMBER REGISTERED


ELIGIBLE 92 Evaluable 88 Too Early 4


S0521/III

Treatment Summary

Consolidation


Consolidation


5



Consolidation





Consolidation Consolidation

(n=88) (n=88)

Grade

Grade


ALT

85 2 1 0

Mood alteration: anxiety

87 1 0 0

AST 86 1 1 0 Mucositis, funct: oral cav. 87 1 0 0Anorexia 87 1 0 0 Musculo. Pain: joint 84 4 0 0Dehydration 87 1 0 0 Musculo. Pain: limb 87 1 0 0Dysphagia 87 1 0 0 Musculo. Pain: muscle 86 2 0 0Fatigue 83 5 0 0 Nausea 84 4 0 0Febrile neutropenia 80 7 1 0 Neuro Pain: head/headache 85 3 0 0Fever 87 1 0 0 Neuropathy-sensory 86 2 0 0Flu-like syndrome 87 1 0 0 Opportunistic infection 87 1 0 0GI Pain: abdomen 87 1 0 0 Pericardial effusion 87 0 1 0GI Pain: rectum 87 1 0 0 Pericarditis 87 1 0 0Hyperglycemia 84 4 0 0 Pneumonitis 87 0 1 0Hypertension 87 1 0 0 Prolonged QTc 82 6 0 0Hypertriglyceridemia 87 1 0 0 Rash 87 1 0 0Hyperuricemia 87 1 0 0 Renal failure 87 1 0 0Hypocalcemia 87 1 0 0 Restrictive cardiomyopathy 87 1 0 0Hypophosphatemia 87 1 0 0 Skin Inf, 0-2 ANC: skin 87 1 0 0Hypotension 86 1 1 0 Vasovagal episode 87 1 0 0Inf, 0-2 ANC: blood 83 3 2 0 Vent Arrhyth: Vent Tachy. 87 1 0 0Inf, 0-2 ANC: cath.-related 87 1 0 0 Vomiting 87 1 0 0Inf, 3-4 ANC: blood 87 1 0 0 Left vent. systolic dysfunct. 85 1 1 1 MAXIMUM GRADE ANY ADVERSE EVENT Lung Pain: chest/thorax 86 2 0 0 Number 51 31 5 1Lung Pain: throat/phar/lar 87 1 0 0


S0521/III


Post-Consolidation: Chemotherapy or Observation


TOTAL

ATRA

+ 6MP +

MTX Observation

NUMBER REGISTERED

65 38 27

ELIGIBLE 65 38 27 ADVERSE EVENT ASSESSMENT Evaluable 27 27 0 Not Evaluable 3 3 0 Too Early 8 8 0 Not Applicable 27 0 27

Treatment Summary



ATRA

+ 6MP +

MTX


21








ATRA + 6MP +

MTX

ATRA + 6MP +

MTX

(n=27) (n=27)

Grade

Grade


ALT

26 0 1 0

Nausea

26 1 0 0

AST 26 0 1 0 Neuro Pain: head/headache 23 4 0 0Fatigue 26 1 0 0 Pruritus 26 1 0 0Hypertriglyceridemia 26 1 0 0 Left vent. systolic dysfunct. 26 1 0 0 MAXIMUM GRADE ANY ADVERSE EVENT Mucositis, clin: oral cavity 26 1 0 0 Number 19 7 1 0


S0535/II

S0535 Phase II


A Phase II Study of ATRA, Arsenic Trioxide and Gemtuzumab Ozogamicin

in Patients with Previously Untreated High-Risk Acute Promyelocytic

Leukemia

Participants: SWOG, CTSU (endorsed by ECOG and CALGB)

Study Coordinators: J Lancet, R Komrokji, C Willman, M Slovak




Schema

R

E G I S T R A T I O

N

Induction Consolidation 1 and 2

ATRA + Gemtuzumab ozogamicin + Arsenic trioxide

CR Arsenic trioxide (2 cycles)

if remain in CR

Consolidation 3 and 4

ATRA + Daunomycin (2 cycles)

if remain in CR

Gemtuzumab ozogamicin (1 dose/month for 2 months)

Consolidation 5 and 6

if remain in CR

ATRA + 6-MP + Methotrexate (for 1 year)

Maintenance

Objectives To assess the event-free survival and death during

the first six weeks in patients with previously un-

treated high-risk acute promyelocytic leukemia

treated with a combined regimen of all trans reti-noic acid (ATRA), arsenic trioxide, and gemtu-

zumab ozogamicin.

To estimate the frequency and severity of toxici-

ties of this regimen in this group of patients.

To investigate the molecular response rate utiliz-ing this regimen in high-risk patients.


diagnosis of high-risk acute promyelocytic leu-

kemia (APL), based on bone marrow examination


S0535/II

performed within 14 days before registration. The

WBC confirming high-risk status must be ob-

tained within 24 days of registration. Patients

who are known to be PML-RARα negative by

RT-PCR assay are not eligible.

Patients must not have received prior systemic

chemotherapy for acute leukemia, with the excep-

tion of ATRA, which may be administered for up

to three days prior to registration. Administration

of hydroxyurea, corticosteroids, or leukapheresis

to control high cell counts prior to registration is

permitted.

Patients must have reached their 18th birthday.

Patients with prolonged QTc > 0.47 seconds are not eligible.

Accrual Goals Initially, 32 eligible patients will be accrued. If

more than seven of these patients die within the

first six weeks, the study will be closed. Other-

wise, 38 additional eligible patients will be ac-

crued for a total of 70 eligible patients. Patients

enrolled before RT-PCR results are known and

who are subsequently found to be negative for PML-RARα will not be counted towards these

goals.

Summary Statement The study was temporarily closed to accrual on

June 22, 2010 and re-activated on January 4,

2011 when an alternative gemtuzumab supply be-

came available. In addition, the criteria have been

met for continuation to complete accrual.

As of December 31, 2010, a total of 34 patients have been accrued. Two patients are ineligible

and excluded from the following analysis: one

patient was PML-RARα negative by FISH and

one patient did not have high-risk APL. Two pa-

tients who did not receive protocol therapy after

registration are also excluded: one patient was

found to be PML-RARα negative by cytogenetics

and FISH and another who was hospitalized for

transfusions after registration. One patient was

removed from protocol therapy after one month

due to lack of insurance coverage.

No fatal toxicities have been reported for the 27

patients evaluated for induction toxicities. Grade

4 non-hematologic induction toxicities were re-

ported for two patients: one with sensory neuro-

pathy and one with prolonged QTc, dyspnea, and

elevated creatinine.

Grade 4 febrile neutropenia was reported for one

patient during consolidation therapy. There have been no other reports of Grade 4 or higher non-

hematologic toxicities during consolidation. In

addition, no fatal or Grade 4 non-hematologic

toxicities have been reported for patients on

maintenance therapy.



Institutions Total

Reg

CALGB

15

ECOG 8Stanford University 3MUSC, Hollings CC 2Wichita CCOP 2Grand Rapids CCOP 1Loyola University 1Puget Sound 1

Utah, U of 1

Total (9 Institutions) 34


Registrations ending December 31, 2010; Data as of March 2, 2011

ATRA + G.O.

+ Arsenic

ATRA + G.O.

+ Arsenic

NUMBER REGISTERED


INELIGIBLE 2 Evaluable 27 ELIGIBLE 32 Too Early 3 Not Analyzable 2


S0535/II



ATRA + G.O. + Arsenic ATRA + G.O. + Arsenic

(n=30) (n=30)

AGE HISPANIC

Median 45.3 Yes 1 3% Minimum 21.2 No 25 83% Maximum 69.6 Unknown 4 13% SEX RACE Males 10 33% White 27 90% Females 20 67% Black 2 7% Pacific Islander 1 3%

Treatment Summary

Induction


ATRA + G.O.

+ Arsenic


2



S0535/II


Induction





ATRA

+ G.O. + Arsenic

ATRA

+ G.O. + Arsenic

(n=27) (n=27)

Grade

Grade


ALT

23 4 0 0

Hypocalcemia

26 1 0 0

ARDS 26 1 0 0 Hypokalemia 22 5 0 0AST 24 3 0 0 Hyponatremia 26 1 0 0Anorexia 25 2 0 0 Hypophosphatemia 23 4 0 0Bilirubin 26 1 0 0 Hypoxia 25 2 0 0Confusion 26 1 0 0 Left vent. systolic dysfunct. 26 1 0 0Constipation 25 2 0 0 Lung Inf, 3-4 ANC: lung 26 1 0 0Creatinine 26 0 1 0 Muscle weakness: whole body 25 2 0 0DIC 25 2 0 0 Musculo. Pain: muscle 26 1 0 0Diarrhea 26 1 0 0 Nausea 25 2 0 0Dyspnea 25 1 1 0 Neuro Pain: head/headache 24 3 0 0Fatigue 24 3 0 0 Neuropathy-sensory 26 0 1 0Febrile neutropenia 17 10 0 0 PTT 26 1 0 0Fever 26 1 0 0 Prolonged QTc 22 4 1 0Fibrinogen 26 1 0 0 Rash 26 1 0 0GFR 26 1 0 0 Somnolence 26 1 0 0GU Inf, 0-2 ANC: UTI 26 1 0 0 Syncope 26 1 0 0Hyperglycemia 22 5 0 0 Syndromes-other 26 1 0 0Hypermagnesemia 25 2 0 0 Weight Loss 26 1 0 0Hypertension 24 3 0 0 Hyperuricemia 26 1 0 0 MAXIMUM GRADE ANY ADVERSE EVENT Hypoalbuminemia 26 1 0 0 Number 8 17 2 0


S0703/II

S0703 Phase II

A Phase II Trial of Azacitidine (NSC-102816) Plus Gemtuzumab

Ozogamicin as Induction and Post-Remission Therapy in Patients of Age 60

and Older with Previously Untreated Non-M3 Acute Myeloid Leukemia

Study Coordinators: S Nand, J Godwin, C Willman, T Norwood


Data Coordinator: C White


Schema

R E G I S T E R

Induction Consolidation

Azacitidine + Gemtuzumab (1 or 2 cycles)

CR or CRi*

Azacitidine + Gemtuzumab (1 cycle)

Azacitidine (4 cycles)

*CRi: Morphologic complete remission with incomplete blood count recovery

Maintenance

CR or CRi*

Objectives To test whether outcomes of patients of age 60 or

older with previously untreated non-M3 acute

myeloid leukemia treated with azacitidine plus

gemtuzumab ozogamicin are sufficient to warrant

Phase III investigation. This will be tested inde-pendently in two groups of patients: (1) good risk

patients, defined as those of age 60-69 years or

with a Zubrod performance status 0-1, and (2)

poor risk patients, defined as those who are at

least 70 years old and have a Zubrod performance

status 2-3.


ties of this regimen in the good and poor risk

groups of patients.

To investigate in a preliminary manner the dis-

ease-free survival of patients who achieve com-

plete remission and receive post-remission thera-

py on this study.

To investigate in a preliminary manner the cyto-

genetic response rates of patients treated with this

regimen.

To investigate in a preliminary manner the effects

of cytogenetic abnormalities, promoter and global methylation changes and multidrug resistance on

overall survival and response to azacitidine plus

gemtuzumab ozogamicin therapy.


diagnosis of acute myeloid leukemia (AML) with

classification other than WHO acute promyelo-

cytic leukemia (FAB M3), based on bone marrow

examination performed within 14 days prior to registration. Patients with blastic transformation

of chronic myelogenous leukemia are not eligi-

ble.

Patients must not have received prior systemic

chemotherapy for acute leukemia. Administration

of hydroxyurea to control high WBC count prior

to registration is permitted. Patients with a history


S0703/II

of prior myelodysplastic syndrome (MDS) are el-

igible. However prior treatment of MDS with

AML induction-type chemotherapy or high dose

chemotherapy with hematopoietic stem cell sup-

port is not allowed. Patients may have received

hematopoietic growth factors, thalidomide, lena-lidomide, arsenic trioxide, signal transduction in-

hibitors and low dose cytarabine (< 100

mg/m2/day) for treatment of myelodysplastic

syndrome. Patients with previous therapy with

azacitidine, decitabine and gemtuzumab ozoga-

micin are not eligible. Patients must be off prior

therapy for MDS at least 30 days prior to study

registration and all toxicities must have resolved.

Patient must have a Zubrod performance status of

0, 1, 2, or 3 and have reached their 60th birthday. Patients with known hypersensitivity to azaciti-

dine, mannitol, hydroxyurea or gemtuzumab ozo-

gamicin are not eligible. Patients must have ade-

quate hepatic and renal function. Patients must

have an adequate cardiac function with left ven-

tricular ejection fraction of 40% or higher and no

clinical evidence of congestive heart failure. Pa-

tients with central nervous involvement are ex-

cluded. If central nervous involvement is clinical-

ly suspected, it must be ruled out by performing a

lumbar puncture. Patients not known to be HIV+ must be tested for HIV infection within 14 days

prior to registration. Patients who are HIV+ may

be eligible providing they meet all of the follow-

ing additional criteria: Patient must have no histo-

ry of AIDS defining events; CD4 cells ≥ 500

mm³; viral load of < 50 copies HIV mRNA/mm³

if on cART (combination antiviral therapy) or

<25,000 copies HIV mRNA if not on cART; no

zidovudine or stavudine as part of cART. Patients

who are HIV+ and do not meet all of these crite-

ria will not be eligible for this study. Patients with

other prior malignancies are not allowed except for the following: (a) adequately treated basal cell

or squamous cell skin cancer; or (b) any diagnosis

of malignancy made at least two years earlier, of

which there is no clinically evident cancer, and

for which the patient has completed all chemothe-

rapy and radiotherapy at least six months prior to

study registration.

Stratification/Descriptive Factors In order to allow outcomes to be investigated in-dependently between the good and poor risk

groups, patients will be stratified according to

risk status defined as follows: good risk patients

of age 60-69 or Zubrod performance status 0 or 1

vs poor risk patients of age 70 or older and Zu-

brod performance status 2 or 3.

Accrual Goals For the good risk group, initially, 30 eligible pa-

tients will be accrued. If fewer than twelve of

these patients achieve CR or CRi (complete re-

mission with incomplete blood count recovery) or

fewer than 23 survive more than 30 days, then the

study will be closed. Otherwise, 43 additional el-

igible good risk patients will be accrued for a to-

tal of 73 eligible good risk patients.

For the poor risk group, initially, 15 eligible pa-

tients will be accrued. If fewer than two of these

patients achieve CR or CRi (complete remission

with incomplete blood count recovery) or fewer

than eight patients survive more than 30 days,

then the study will be closed. Otherwise, 51 addi-

tional eligible poor risk patients will be accrued

for a total of 66 eligible poor risk patients.

Summary Statement The study was temporarily closed to accrual on

June 22, 2010 and re-activated on February 23,

2011 when an alternative gemtuzumab supply

was obtained. For both risk groups, the criteria

have been met for continuation to complete ac-

crual. As of December 31, 2010, a total of 90 pa-

tients have been accrued with 67 patients in the

good risk group and 23 patients in the poor risk

group.

Investigators are reminded to pay careful atten-

tion to the protocol definitions of good and poor

risk to ensure patients are correctly stratified.

1. Good Risk:

One patient, who did not start protocol treatment

because of an elevated WBC count, is not analyz-

able and is excluded from the analysis. Therefore, 66 good risk patients are included in this analysis.

One patient was taken off induction therapy after

two doses due to declining health status. One pa-

tient received the first induction cycle but not the

re-induction cycle due to elevated WBC count.

An additional patient who received the first cycle

of induction did not receive re-induction protocol

therapy due to toxicity (elevated LFTs).

Of the 62 patients evaluated for induction toxici-

ty, three deaths have been reported as possibly at-tributable to treatment: one due to infection and

two (disease progression and secondary malig-

nancy) are under review. Eight additional patients

had reports of Grade 4 non-hematologic toxici-

ties; two with infection, two with thrombo-

sis/embolism, and one each with atrial fibrilation

(coded as Cardiac Arrhythmia-other), cardiac

ischemia/infarction, hypocalcemia, anorexia and

muscle weakness, infection and increased biliru-

bin, and infection and dyspnea.

One good risk patient came off protocol mainten-

ance therapy after one cycle due to renal toxicity.

No Grade 4 or higher toxicities have been re-


S0703/II

ported for patients on consolidation or mainten-

ance therapy.

2. Poor Risk:

One poor risk patient who died before receiving

any protocol treatment is not analyzable and is

excluded from the analysis. Therefore, 22 poor

risk patients are included in this analysis. One pa-

tient was taken off protocol therapy due to toxici-

ty (COPD exacerbation) during the first induction

cycle. Another patient received the first induction

cycle but was not given re-induction due to pro-

gression not defined per protocol.

No fatal toxicities have been reported for the poor

risk patients. Four of the 22 patients evaluated for

induction toxicity had reports of Grade 4 non-

hematologic toxicities; three with infection and

one with hypotension and arrhythmia.

One poor risk patient came off protocol mainten-

ance therapy after two cycles due to neutropenia.

No Grade 4 or higher toxicities have been re-

ported for patients on consolidation or mainten-

ance therapy.



Institutions Total


Reg

Loyola University

17 Wichita CCOP

4Michigan, U of 12 Kansas City CCOP 3Stanford University 11 Southeast CCC CCOP 3Kentucky, U of 9 Grand Rapids CCOP 2Central IL CCOP 5 Michigan CRC CCOP 2Columbia River CCOP 5 Mississippi, Univ of 1New Mexico MBCCOP 5 Montana CCOP 1

Wayne State Univ 5 St Joseph Med Ctr/So Calif, U of 1

Stormont-Vail Health/Kansas, U of 4 Total (17 Institutions) 90


Classified by Risk Group

Registrations ending December 31, 2010; Data as of February 15, 2011

TOTAL Good risk Poor risk

NUMBER REGISTERED

90 67 23

ELIGIBLE 90 67 23 Not Analyzable 2 1 1 ADVERSE EVENT ASSESSMENT Evaluable 84 62 22 Too Early 4 4 0


S0703/II




Good risk Poor risk

(n=66) (n=22)

AGE Median

70.6

75.2


37

56% 18

82%


3

5% 0

0%


64

97% 22

100%

Black 1 2% 0 0% Asian 1 2% 0 0%

Treatment Summary


Induction


TOTAL Good risk Poor risk


0 0 0



S0703/II



Induction





Good risk Poor risk

(n=62) (n=22)

Grade

Grade

ADVERSE EVENT ≤ 2 3 4 5 ≤ 2 3 4 5

ALT

60 2 0 0 21 1 0 0

AST 60 2 0 0 22 0 0 0Anorexia 59 2 1 0 21 1 0 0Bilirubin 60 1 1 0 22 0 0 0CNS hemorrhage 61 1 0 0 22 0 0 0Cardiac Arrhythmia-other 61 0 1 0 22 0 0 0Cardiac ischemia/infarction 61 0 1 0 22 0 0 0Cardio. Pain: cardiac/heart 62 0 0 0 21 1 0 0Confusion 61 1 0 0 22 0 0 0Constipation 61 1 0 0 22 0 0 0Diarrhea 60 2 0 0 22 0 0 0Disease progression, NOS 60 0 0 2 22 0 0 0Dyspnea 61 0 1 0 21 1 0 0Edema-limb 61 1 0 0 22 0 0 0Eye Inf, 3-4 ANC: conjunct. 61 1 0 0 22 0 0 0Fatigue 56 6 0 0 18 4 0 0Febrile neutropenia 39 20 3 0 14 7 1 0GI Hemorrhage: upper GI 61 1 0 0 22 0 0 0GI Inf, 3-4 ANC: colon 62 0 0 0 21 1 0 0GI Inf, 3-4 ANC: tooth 59 3 0 0 22 0 0 0GU Inf, 3-4 ANC: UTI 60 2 0 0 21 1 0 0GU Inf, 3-4 ANC: kidney 62 0 0 0 21 0 1 0Hepatobiliary-other 61 1 0 0 22 0 0 0Hyperglycemia 58 4 0 0 19 3 0 0Hypertension 61 1 0 0 22 0 0 0Hypoalbuminemia 59 3 0 0 21 1 0 0Hypocalcemia 59 2 1 0 20 2 0 0Hypokalemia 57 5 0 0 22 0 0 0Hyponatremia 58 4 0 0 22 0 0 0Hypophosphatemia 58 4 0 0 22 0 0 0Hypotension 61 1 0 0 21 0 1 0Hypoxia 60 2 0 0 22 0 0 0Inf, 0-2 ANC: blood 61 1 0 0 22 0 0 0Inf, 3-4 ANC: blood 54 8 0 0 21 0 1 0Inf, 3-4 ANC: cath-related 61 1 0 0 21 1 0 0Infection-other 62 0 0 0 21 1 0 0Lung Inf, 3-4 ANC: lung 58 3 1 0 21 1 0 0Lung Inf, 3-4 ANC: sinus 60 1 0 1 22 0 0 0Mood alteration: depression 62 0 0 0 20 2 0 0Mucositis, funct: oral cav. 61 1 0 0 22 0 0 0Muscle weakness: whole body 60 1 1 0 21 1 0 0Petechiae 61 1 0 0 22 0 0 0Pleural effusion 62 0 0 0 21 1 0 0Pneumonitis 62 0 0 0 21 1 0 0Pulmonary-other 61 1 0 0 22 0 0 0Rash 61 1 0 0 22 0 0 0Secondary malignancy 61 0 0 1 22 0 0 0Skin Inf, 0-2 ANC: skin 61 1 0 0 22 0 0 0Skin Inf, 3-4 ANC: skin 58 4 0 0 22 0 0 0Skin Inf, Unk ANC: skin 61 1 0 0 22 0 0 0Supra Arrhyth: Atrial Fib. 61 1 0 0 21 0 1 0Thrombosis/embolism 60 0 2 0 22 0 0 0 MAXIMUM GRADE ANY ADVERSE EVENT Number

18 33 8 3 8 10 4 0


S0805/II

S0805 Phase II Intergroup


Phase II Study of Combination of Hyper-CVAD and Dasatinib (NSC-

732517) With or Without Allogeneic Stem Cell Transplant in Patients with

Philadelphia (Ph) Chromosome Positive and/or BCR-ABL Positive Acute

Lymphoblastic Leukemia (ALL)(A BMT Study)

Participants: SWOG, BMT CTN, CTSU (endorsed by ECOG and

CALGB)

Study Coordinators: F Ravandi, S O'Brien, S Forman, C Ha, J Wong, J Radich,

D Porter (BMT CTN)

Statisticians: H Gundacker, K Kopecky, M Othus



Schema


1

Single agent dasatinib


3

Hyper-CVAD + dasatinib alternating

cycles with

High dose methotrexate, cytarabine + dasatinib

(total of 8 cycles)

Transplant ready?

CR


2

Transplant

Yes

Induction/ consolidation:

Transplant ready?


4

Maintenance: vincristine, prednisone + dasatinib interrupted on cycles 6 and 13 by Hyper-CVAD + dasatinib

No Yes

No


S0805/II

Objectives To test whether the relapse-free survival after al-

logeneic stem cell transplantation among Phila-

delphia chromosome positive and/or BCR/ABL

positive acute lymphoblastic leukemia (ALL) pa-

tients given an intensive short-term chemotherapy regimen of Hyper-CVAD in combination with the

tyrosine kinase inhibitor dasatinib is sufficiently

high to warrant further investigation.

To test whether the continuous complete remis-

sion rate for previously untreated Philadelphia

chromosome positive and/or BCR/ABL positive

acute lymphoblastic leukemia (ALL) patients

given an intensive short-term chemotherapy re-

gimen of Hyper-CVAD given in combination

with the tyrosine kinase inhibitor dasatinib is suf-ficiently high to warrant Phase III investigation.

To investigate in a preliminary manner the rela-

tive effectiveness of MRD detection using real-

time quantitative PCR for BCR/ABL versus flow

cytometry to predict the outcome of patients

treated by the hyper-CVAD + dasatinib regimen

and/or allogeneic stem cell transplant.


ties of the intensive short-term chemotherapy re-

gimen in these patients.

To estimate the overall survival of all patients on

this study.

Patient Population Patients must have a morphologic diagnosis of

acute lymphoblastic leukemia (ALL), as defined in the protocol, with evidence of ALL involve-

ment in bone marrow and/or blood. Patients with

only extramedullary disease in the absence of

bone marrow or blood involvement are not eligi-

ble. Patients with M0 AML, mixed lineage leu-

kemia, or L3 (Burkitts) are not eligible for this

study. For ALL in marrow or peripheral blood,

immunophenotyping of the blood or marrow

lymphoblasts must be performed to determine li-

neage. Patients must be Philadelphia (Ph) chro-

mosome positive and/or BCR/ABL positive as confirmed by standard cytogenetics, FISH, and/or

polymerase chain reaction (PCR) testing per-

formed by a local laboratory.

Patients may have received no more than one

course of remission induction therapy for ALL,

providing this induction course was given prior to

the results of the cytogenetics testing for Ph

chromosome or BCR/ABL status being known.

Patients who have received any post-remission

therapy for ALL or who have relapsed from com-

plete remission are not eligible. Any prior induc-

tion chemotherapy must have been completed within 28 days prior to registration. For patients

who have received any prior therapy that was not

remission induction therapy, one of the following

must be true: at least six weeks must have elapsed

since any monoclonal antibodies were given, at

least seven days must have elapsed since any oth-

er treatment was given, and all toxicities of the

remission induction therapy must have resolved

to Grade ≤ 2; or the patient must have rapidly

progressive disease. For previously treated pa-

tients, the Study Coordinator must be contacted

before registration, in order to determine the re-gimen to be given in the first course of induc-

tion/consolidation therapy, based on prior thera-

py.

Patients must be at least 18 but no more than 50

years of age and must have Zubrod performance

status of 0, 1, or 2. Patients must not have active

pericardial effusion, ascites, or pleural effusion of

any grade, or prolonged QTc interval (QTc > 480

msec). Patients must not have prior history of known Type I hypersensitivity or anaphylactic

reactions to doxorubicin and must have adequate

renal and hepatic function.

Stratification/Descriptive Factors The patients will be stratified as follows: pre-

viously untreated vs achieved remission (CR or

CRi) vs refractory.

Accrual Goals Accrual will continue until 34 eligible patients

have received an allogeneic stem cell transplant.

It is anticipated that 85 eligible patients will need

to be registered to reach the accrual goal for the

transplanted patients.

Summary Statement This study was activated as of September 1, 2009.

On August 1, 2010, an amendment was activated

adding participation of BMT CTN and CTSU (endorsed by ECOG and CALGB) on this study.

As of December 31, 2010, one patient has been

accrued (through the CTSU from a CALGB insti-

tution).


S0910/II

S0910 Phase II

A Phase II Study of Epratuzumab (NSC-716711) in Combination with

Cytarabine and Clofarabine for Patients with Relapsed or Refractory Ph-

Negative Precursor B-Cell Acute Lymphoblastic Leukemia (ALL)

Study Coordinators: A Advani, S Coutre, J Radich

Statisticians: M Othus, H Gundacker



Objectives To test whether the complete remission rate (CR

+ CRi) in patients with relapsed or refractory pre-

cursor B-cell acute lymphoblastic leukemia (ALL) is sufficiently high following treatment

with cytarabine, clofarabine, and epratuzumab to

warrant further investigation.


ties associated with the dosing schedule of cyta-

rabine, clofarabine, and epratuzumab outlined by

this protocol.

To investigate in a preliminary manner the effect of minimal residual disease laboratory correlates

and cytogenetic factors on prognosis in this pa-

tient population.

Patient Population Patients must have a prior morphologic diagnosis

of precursor B-cell acute lymphoblastic leukemia

(ALL) (non T-cell) as defined in the protocol and

be either refractory to a standard induction regi-

men or have relapsed following successful prior induction therapy. Patients with M0 AML, mixed

lineage leukemia, or L3 (Burkitt's) are not eligi-

ble. Patients must have evidence of ALL in their

marrow or peripheral blood. At least 20% of mar-

row and/or peripheral blood lymphoblasts must

be CD22+ by flow cytometry from a sample col-

lected within 14 days prior to registration. Pa-

tients must have at least 5% lymphoblasts present

in the blood or bone marrow within 14 days prior

to registration. Patients must have a diagnosis of

Philadelphia chromosome-negative ALL. Patients

with unknown Ph status by cytogenetics or FISH and unknown BCR/ABL status by PCR are eligi-

ble for registration, but must be removed from

protocol therapy if found to be Ph+ or

BCR/ABL+ after registration.

Patients may have had any number or prior thera-

pies. Patients may have received prior allogeneic

or autologous bone marrow transplant. However,

patients who have received prior transplant (allo-geneic or autologous) will not be eligible if they

are still receiving immunosuppression therapy for

the treatment of graft versus host disease

(GvHD). Patients with prior allogeneic bone mar-

row transplant will be eligible only if both of the

following conditions are met: the transplant must

have been performed more than 90 days before

registration to this study, and the patient must not

have ≥ Grade 2 acute GvHD or either moderate or

severe limited chronic GvHD, or extensive chron-

ic GvHD of any severity. Patients must not have

received prior chemotherapy, any other investiga-tional agents, or have undergone any major sur-

gery within 14 days prior to registration, with the

following exceptions: hydroxyurea, which may

be administered concurrently with study drug un-

til the white blood count has come down to a rea-

sonable level as deemed by the treating physician,

maintenance therapy with steroids, vincristine,

and/or anti-metabolite agents, such as but not li-

mited to, mercaptopurine, thioguanine and me-

thotrexate. All drug-related toxicities must have

resolved to ≤ Grade 2. Patients less than 22 years of age must be willing to receive prophylactic in-

trathecal chemotherapy as defined in the protocol

while on study. Patients must not have received

previous treatment with clofarabine or epratuzu-

mab.

Patients must be at least 16 years of age and have

a Zubrod performance status of 0, 1, or 2. Patients

must not have active CNS involvement by clini-

cal evaluation. Patients with previous docu-

mented history of CNS involvement of ALL, or


S0910/II

with clinical signs or symptoms consistent with

CNS involvement of ALL must have a lumbar

puncture which is negative for CNS involvement

of ALL. Patients must undergo triplicate EKG

within 14 days prior to registration. Electrolytes

(K and Mg) should be corrected prior to the first EKG. For QTc > 500, the Study Coordinator

must be contacted to determine whether the pa-

tient will be eligible. Patients must not have a

systemic fungal, bacterial, viral, or other infection

that is not controlled. Patients must have adequate

renal and hepatic function. Patients must not have

≥ Grade 2 neuropathy (cranial, motor or sensory).

Patients known to be positive for HIV may be el-

igible but must be discussed with and approved

by the Study Coordinator prior to registration. Pa-

tients must not be pregnant or nursing because of

the teratogenic potential of the drug used in this

study.

Accrual Goals Initially, 20 eligible patients will be accrued. If

fewer than two patients achieve CR, the study

will be closed. Otherwise, 15 additional eligible

patients will be accrued for a total of 35 eligible

patients.

Summary Statement The study opened to accrual on August 15, 2010.

As of December 31, 2010, three patients have

been accrued (two from University of Utah and

one from University of Mississippi).


S0919/II

S0919 Phase II

A Phase II Study of Idarubicin and Ara-C in Combination with Pravastatin

for Relapsed Acute Myelogenous Leukemia (AML)

Study Coordinators: A Advani, E Copelan, C Willman

Statisticians: H Gundacker, M Othus

Data Coordinator: J Barce


Objectives To test whether the complete remission (CR) rate

(including CR with incomplete recovery [CRi]) in patients with relapsed acute myeloid leukemia

(AML) treated with a combination of chemothe-

rapy and pravastatin is sufficiently high to war-

rant Phase III investigation.

To estimate relapse-free survival and overall sur-

vival rates in this group of patients.


ties of this regimen in this group of patients.

To evaluate in a preliminary manner whether

prestudy cytogenetic features correlate with re-

sponse in this group of patients.


diagnosis of acute myeloid leukemia (AML). Pa-

tients with acute promyelocytic leukemia (APL, FAB M3) or blastic transformation of chronic

myelogenous leukemia are not eligible.

Patients must have received at least one prior

chemotherapy regimen for their AML and they

may have received any type of chemotherapy.

They must have achieved complete remission,

lasting at least three months with their last induc-

tion regimen and they must have relapsed after

the last regimen. Relapse must be documented by

a bone marrow examination demonstrating > 5% blasts in the bone marrow not attributable to

another cause. Refractory patients and patients

who have received autologous or allogeneic stem

cell transplantation are not eligible. Administra-

tion of hydroxyurea to control high WBC count prior to, during and after registration is permitted.

Patients must have adequate cardiac function as

defined in the protocol. Patients must be at least

18 years of age, must have a Zubrod performance

status of 0, 1, or 2, and must have adequate renal

and hepatic function. Patients must not have clin-

ical evidence of leptomeningeal disease and must

not have a systemic fungal, bacterial, viral or oth-

er infection that is not controlled. Patients not

known to be HIV+ must be tested for HIV infec-tion. Patients who are HIV+ may be eligible pro-

viding they meet all of the criteria in the protocol.

Accrual Goals The accrual goal of this study is 50 eligible pa-

tients.

Summary Statement As of December 31, 2010, ten patients have been accrued. Two patients were taken off protocol

therapy due to toxicities (infection and decreased

cardiac function) and two were taken off protocol

therapy to pursue transplant.

One of the nine patients evaluated for toxicity

died while on treatment due to hypoxia which is

currently under review for relationship to proto-

col treatment. No other patients have reported

Grade 4 or higher non-hematologic toxicities dur-

ing induction or consolidation therapy.


S0919/II



Institutions Total

Reg

Cleveland Clinic OH

6

New Mexico MBCCOP 3

Puget Sound 1




Pravastatin+

Idarubicin+

Ara-C

Pravastatin+

Idarubicin+

Ara-C

NUMBER REGISTERED


ELIGIBLE 10 Evaluable 9 Too Early 1



Pravastatin+Idarubicin+Ara-C Pravastatin+Idarubicin+Ara-C

(n=10) (n=10)

AGE HISPANIC

Median 52.7 Yes 2 20% Minimum 23.2 No 7 70% Maximum 71.3 Unknown 1 10% SEX RACE Males 4 40% White 10 100% Females 6 60%

Treatment Summary


Pravastatin+

Idarubicin+

Ara-C


2



S0919/II






Pravastatin+

Idarubicin+Ara-C

Pravastatin+

Idarubicin+Ara-C

(n=9) (n=9)

Grade

Grade


Cardiac General-other

8 0 1 0

Ocular-other

8 1 0 0

Febrile neutropenia 6 3 0 0 Pulmonary hypertension 8 1 0 0Hypokalemia 6 2 1 0 Pulmonary-other 8 0 0 1Hypophosphatemia 8 1 0 0 Inf, 3-4 ANC: blood 8 1 0 0 MAXIMUM GRADE ANY ADVERSE EVENT Lung Inf, 3-4 ANC: lung 8 1 0 0 Number 4 4 0 1Nausea 8 1 0 0


C10403/II

C10403 Phase II Intergroup

Coordinating Group: CALGB

An Intergroup Phase II Clinical Trial for Adolescents and Young Adults

with Untreated Acute Lymphoblastic Leukemia (ALL)

Intergroup Participants: CALGB, SWOG, ECOG

Study Coordinators: W Stock (CALGB), A Advani, S Luger (ECOG)




Schema

R E G I S T R A T I

O N

VCR, IV MTX, IT MTX, PEG-Asp

DNR, VCR, Prednisone, PEG-Asp, Ara-C, IT MTX

DOXO, VCR, Dexamethasone, PEG-Asp, IT MTX, CTX, Ara-C, 6TG

Induction Consolidation

CTX, Ara-C, 6-MP, VCR, IT MTX, PEG-Asp

Interim Maintenance

Delayed Intensification

VCR, Dexamethasone, 6-MP, PO MTX, IT MTX

Maintenance

Objectives To describe the outcomes (CR rate, EFS, DFS,

and OS) when adolescents and young adults

(AYA) with newly diagnosed ALL are treated

with a pediatric chemotherapy regimen by adult

hematologists/oncologists at multiple sites. The

feasibility of extending the "pediatric approach" in adults up to age 40 and estimating DFS and OS

also will be explored.

To describe the toxicities observed in these pa-

tients.

To compare the outcomes of the AYA patients

treated on this protocol with appropriate similar

patients (by age and disease characteristics)

treated by pediatric oncologists on Children's On-

cology Group study AALL0232.

To evaluate the adherence of adult hematolo-

gists/oncologists and their patients to a "pedia-

tric" ALL treatment regimen and identify reasons

for variances.

To analyze and describe the outcomes of AYA

patients treated on this study according to pre-

treatment characteristics, such as age, gender,


C10403/II

white blood cell count, other hematologic para-

meters, blood chemistry, immunophenotype, cy-

togenetics and molecular genetic characteristics,

and treatment variables, such as treatment site

(academic center or community), and protocol

adherence.

To analyze and describe the outcome of AYA pa-

tients treated on this study according to baseline

psychosocial characteristics, demographics, and

family support.

Patient Population Patients must have either B-precursor or T-

precursor acute lymphoblastic leukemia. Patients

with Burkitt type leukemia (FAB L3; SIg posi-tive; t(8;14) or variant, etc.) are not eligible. Pa-

tients known to have Ph+ ALL at the time of di-

agnosis are not eligible.

Patients may have had no prior therapy for acute

leukemia except emergency therapy for blast cell

crisis (corticosteroids or hydroxyurea), superior

vena cava syndrome, or renal failure due to leu-

kemic infiltration of the kidneys. When indicated,

leukapheresis or exchange transfusion are rec-ommended to reduce the WBC. Single-dose intra-

thecal cytarabine is allowed prior to registration

or prior to initiation of systemic therapy for pa-

tient convenience. Systemic chemotherapy must

begin within 72 hours of this intrathecal therapy.

Patients receiving prior steroid therapy are eligi-

ble for this study. The dose and duration of pre-

vious steroid therapy should be carefully docu-

mented.

Adult patients who meet any of the following cri-

teria should be considered for a successor study

for Ph+ ALL: 1) BCR-ABL fusion transcript de-

termined by FISH or RT-PCR or 2)

t(9;22)(q34;q11) or variant determined by cyto-

genetics.

Patients must be between 16 and 40 years of age

and have an ECOG performance status of 0, 1, or

2. Patients with Downs Syndrome are excluded

from this study due to the likelihood of excessive toxicity resulting.

Accrual Goals Up to 300 AYA patients will be enrolled onto this

study.

Summary Statement The study activated in CALGB on November 15,

2007 and at SWOG institutions on January 15, 2008. As of December 31, 2010, 151 patients

have been accrued to this study including 35 from

SWOG institutions.

A complete June 2010 summary of this study

from CALGB is available on the SWOG web

site.



Institutions Total

Reg

Stanford University

15

Cleveland Clinic OH 8MUSC, Hollings CC 3Kentucky, U of 2New Mexico MBCCOP 2Wayne State Univ 2Michigan CRC CCOP 1Michigan, U of 1

Wichita CCOP 1



C10404/II

C10404 Phase II Intergroup


A Genetic Risk-Stratified, Randomized Phase II Study of Four

Fludarabine/Antibody Combinations for Patients with Symptomatic,

Previously Untreated Chronic Lymphocytic Leukemia

Intergroup Participants: CALGB, SWOG, ECOG, NCIC CTG

Study Coordinators: J Byrd (CALGB), J Godwin, S Couban (NCIC CTG),

M Smith (ECOG)




Schema

R

A N D O M I Z E

Arm A: Fludarabine Rituximab (1 cycle)

No further treatment

Induction

Arm B: Fludarabine Rituximab (1 cycle)

Arm C: Fludarabine Rituximab Cyclophosphamide (cycles 1-6)

CR/PR/SD Consolidation:

Lenalidomide

Progression No further treatment

Observe (3 months)

del(11q22.3)

no Arm A: (cycles 2-6)

Observe (3 months)

No further treatment

yes

Arm D: Fludarabine Rituximab Cyclophosphamide

(cycles 2-6)

del(11q22.3)

no Arm B: (cycles 2-6)

yes Arm D:

Fludarabine Rituximab Cyclophosphamide (cycles 2-6)

Observe (3 months)

Observe (3 months)

Observe (3 months)

*(See below)

* Response evaluation

Objectives To determine the two-year progression-free sur-

vival (PFS) after remission induction with four

different chemo-immunotherapy combinations

for patients with untreated, symptomatic, lower

risk and high risk chronic lymphocytic leukemia

(CLL) to decide which of the four arms, if any, to

take forward into a randomized Phase III investi-

gation.

To determine the induction response to FR and

FCR in each of these arms, along with the consol-


C10404/II

idation response to lenalidomide in patients with

CLL.

To determine the toxicity from these four che-

moimmunotherapy combinations and that of con-solidation therapy with lenalidomide.

To determine the induction response and toxicity

of FCR in patients with del(11q22.3) along with

consolidation response, 2-year PFS and toxicity

of lenalidomide in this specific genetic group.

To determine the effect of pretreatment biologic

characteristics on clinical outcomes, such as at-

taining a complete response to induction therapy and progression-free survival.

To collect relapse samples to determine the fre-

quency of clonal evolution among patients with

IgVH mutated and unmutated disease and to study

mechanisms of resistance to chemoimmunothera-

py.

To determine if flow cytometry negative status

immediately post-therapy at 24 months after study entry is an effective surrogate marker for

prolonged progression-free survival and overall

survival.

Patient Population Patients must have an absolute lymphocytosis of

> 5,000/µL. Morphologically, the lymphocytes

must appear mature with < 55% prolymphocytes.

Bone marrow examination must include at least a

unilateral aspirate and biopsy. The aspirate smear must show > 30% of all nucleated cells to be

lymphoid or the bone marrow core biopsy must

show lymphoid infiltrates compatible with mar-

row involvement by CLL. Overall cellularity

must be normocellular or hypercellular. Local in-

stitution lymphocyte phenotype must reveal a

predominant B-cell monoclonal population shar-

ing a B-cell marker (CD19, CD20, CD23) with

the CD5 antigen, in the absence of other pan-T-

cell markers. Additionally, the B-cells must be

monoclonal with regard to expression of either

kappa or lambda and have surface immunoglobu-lin expression of low density. Patients with bright

surface immunoglobulin levels must have CD23

coexpression. Patients must have symptomatic

and active intermediate or high-risk categories of

the modified three-stage Rai staging system, as

defined in the protocol. Patients in the interme-

diate-risk group must have evidence of active

disease as demonstrated by a least one of the fol-

lowing criteria: massive or progressive spleno-

megaly, hepatomegaly and/or lymphadenopathy;

presence of weight loss > 10% over the preceding

six month period; Grade 2 or 3 fatigue; fevers >

100.5 degrees F or night sweats for greater than

two weeks without evidence of infection; pro-

gressive lymphocytosis with an increase of > 50% over a two month period or an anticipated

doubling time of less than six months.

Patients must have had no prior therapy for CLL,

including no corticosteroids for autoimmune

complications that have developed since the ini-

tial diagnosis of CLL. Patients must not have any

medical condition requiring chronic use of oral

corticosteroids.

Patients must be 18 years of age or older and

must have performance status of 0, 1, or 2. Pa-

tients with HIV infection may be eligible pro-

vided they meet the following criteria: no evi-

dence of infection with hepatitis B or C; CD4+

cell count > 350/mm³; no evidence of resistant

strains of HIV; if not on anti-HIV therapy, an

HIV viral load < 10,000 copies HIV RNA/mL; if

on HIV therapy, HIV viral load < 50 copies HIV

RNA/mL; and no history of AIDS-defining con-

dition. Patients receiving concurrent zidovudine or stavudine may not be enrolled because of over-

lapping protocol toxicities. Patients must have

adequate renal function.

Stratification/Descriptive Factors The randomization will be stratified by Rai stage

at diagnosis: Stage I vs Stage II vs Stage III vs

Stage IV.

Accrual Goals The accrual goal for this study is 405 patients.

Summary Statement The study activated in CALGB on January 15,

2008 and for SWOG institutions on March 15,

2009. On November 2, 2009, the study was rede-

signed to include a reassignment of patients ran-

domized to Arms A and B with the del(11q22.3)

abnormality to receive the Fludara-

bine/Cyclophosphamide/Rituximab remission in-duction therapy for cycles two through six.

As of December 31, 2010, 213 patients have been

accrued to this study, ten from SWOG institu-

tions.

A complete June 2010 summary of this study

from CALGB is available on the SWOG web

site.


C10404/II



Institutions Total

Reg

MUSC, Hollings CC

4

New Mexico MBCCOP 2Lahey Clinic Med Ctr/Davis, U of CA 1St Louis University 1Thompson Ca Surv Ctr/San Antonio, U of TX 1

Wichita CCOP 1



C10603/III

C10603 Phase III SWOG Endorsed CTSU Study


A Phase III Randomized, Double-Blind Study of Induction

(Daunorubicin/Cytarabine) and Consolidation (High-Dose Cytarabine)

Chemotherapy + Midostaurin (PKC412)(IND #101261) or Placebo in Newly

Diagnosed Patients < 60 Years of Age with FLT3 Mutated Acute Myeloid

Leukemia (AML)

Participants: CALGB, CTSU

Study Coordinators: R Stone (CALGB), B Medeiros (SWOG)


Schema

R

E G

I

S

T

R

A

T

I

O

N

Cytarabine +

Daunorubicin + Midostaurin

(1 or 2 cycles)

Cytarabine +

Daunorubicin +

Placebo

(1 or 2 cycles)

Placebo

(12 months)

Consolidation

P

R

E

R

E

G

I

S

T

R

A

T

I

O

N

F

L

T 3

S

C

R

E

E

N

I

N

G

R

A

N D

O

M

I

Z

A

T

I

O

N

Induction

CR

CR

High-dose

Cytarabine + Midostaurin

(4 cycles)

High-dose

Cytarabine +

Placebo

(4 cycles)

Midostaurin (12 months)

Continuation

Objectives To determine if the addition of midostaurin to

daunorubicin/cytarabine induction, high-dose cy-

tarabine consolidation, and continuation therapy

improves overall survival (OS) in both the mutant

FLT3-ITD and FLT3-TKD AML patients.

To compare the overall survival (OS) in the two

groups using an analysis in which patients who

receive a stem cell transplant are censored at the

time of transplant.

To compare the complete response rate between

the two treatment groups.

To compare the event-free survival (EFS) be-

tween the two treatment groups.

To compare the disease-free survival of the two

treatment groups.

To compare the disease-free survival rate one

year after completion of the continuation phase of

the two groups.

To assess the toxicity of the experimental combi-

nation.

To describe the interaction between treatment

outcome and pretreatment characteristics such as

age, performance status, white blood cell (WBC)

count, morphology, cytogenetics, and molecular

and pharmacodynamic features.

To assess the population pharmacokinetics

(popPK) of midostaurin and its two major meta-

bolites, CGP52421 and CGP62221. The potential


C10603/III

associations between PK exposure, FLT3 status,

OS, EFS, and clinical response will be explored.

Patient Population Patients must have an unequivocal diagnosis of AML (>20% blasts in the bone marrow based on

the WHO classification), excluding M3 (acute

promyelocytic leukemia). AML patients with a

history of antecedent myelodysplasia (MDS) are

eligible for treatment on this trial, but must not

have had prior cytotoxic therapy. Patients must

have documented FLT3 mutation (ITD or point

mutation), determined by analysis in a protocol-

designated FLT3 screening laboratory (see proto-

col Section 6.0).

Patients must not have had prior chemotherapy

for leukemia or myelodysplasia with the follow-

ing exceptions: emergency leukapheresis, emer-

gency treatment for hyperleukocytosis with hy-

droxyurea for ≤ 5 days, cranial RT for CNS leu-

kostasis (one dose only), or growth factor or cy-

tokine support.

Patients who have developed therapy-related

AML after prior RT or chemotherapy for another cancer or disorder are not eligible. Patients must

be at least 18 and less than 60 years old. Patients

must have adequate renal function and must not

have symptomatic congestive heart failure. Pa-

tients with neurologic symptoms suggestive of

CNS leukemia are recommended to have a lum-

bar puncture. Patients whose CSF is positive for

AML blasts are not eligible.

Stratification/Descriptive Factors Treatment randomization will be stratified by

FLT3 mutation status: ITD allelic ratio < 0.7 vs

ITD allelic ratio ≥ 0.7 vs TKD.

Accrual Goals The accrual goal of the study is 514 patients for

the randomization registration.

Summary Statement SWOG has endorsed this study through the Can-

cer Trials Support Unit (CTSU) of the National

Cancer Institute. Please contact the CTSU direct-

ly by either phone (1-888-823-5923) or on the

CTSU web site (http://www.ctsu.org/) for infor-

mation and registration procedures.

The study was activated for CALGB institutions

on April, 1, 2008. As of December 31, 2010, a to-

tal of 553 patients have been randomized to re-ceive treatment on this study, 20 from SWOG in-

stitutions.

A complete November 2010 summary of this

study from CALGB is available on the SWOG

web site.



Institutions Total


Reg

MUSC, Hollings CC

5 Davis, U of CA

1Stanford University 3 Irvine, U of CA 1H Lee Moffitt CC 2 Loyola University 1Providence Hosp 2 St Joseph's/Candler/H Lee Moffitt CC 1

Atlanta Reg CCOP 1 Wichita CCOP 1

Baylor College 1 Total (12 Institutions) 20Boston Univ Med Ctr 1


C10701/II

C10701 Phase II SWOG Endorsed CTSU Study


A Phase II Study of Dasatinib (Sprycel®)(IND #73969, NSC #732517) as

Primary Therapy Followed by Transplantation for Adults ≥ 50 Years with

Newly Diagnosed Ph+ Acute Lymphoblastic Leukemia by CALGB, ECOG,

SWOG and NCIC CTG

Participants: CALGB, CTSU

Study Coordinator: M Wetzler (CALGB)

Schema


Course I Dasatinib (Das) + Dexamethasone (Dex)

Dasatinib maintenance

Allogeneic transplant age 50-70 with matched donor

Course VI

< 20% blasts

Evaluate Marrow

A: CotrimoxazoleDS (Cot) + Das + Dex

> 20% blasts B: Cot + Das + Dex + VCR + DNR

No CR

CR

Course II

Course III

Cot + Das + CTX + VCR + DNR + Dex

CR

CNS prophylaxis: Cot + Das + VCR + MTX + LCV

Course IV

*

*

Course V

Autologous transplant age 50-70 without matched donor

Alternative chemotherapy age >70 or not transplant candidate: VP16 + Ara-C + G-CSF

Objectives Estimate the activity of dasatinib to prolong dis-

ease-free survival (DFS) and overall survival

(OS) in newly diagnosed patients 50 years or old-

er who have Ph+ (BCR/ABL+) ALL.

Determine the activity of dasatinib to prolong

disease-free survival (DFS) and overall survival

(OS) in ALL patients with t(9;22).

Determine the ability of dasatinib to produce or

maintain a BCR/ABL-negative status, as judged

by Q-PCR following sequential dasatinib, chemo-

therapy, and HCT.

Determine the feasibility of collecting adequate

peripheral blood stem cells for autologous HCT

following dasatinib therapy, and assess for resi-dual Ph+ (BCR/ABL+) cells by Q-PCR.

Study the safety and efficacy of autologous HCT

following therapy with dasatinib.


C10701/II

Study the safety and efficacy of reduced-intensity

preparatory regimen followed by an allogeneic

HCT following induction therapy with dasatinib.

Study the safety and efficacy of dasatinib main-tenance administered after allogeneic or autolog-

ous HCT or chemotherapy.

Correlate serum and CSF levels of dasatinib

when given orally during induction.

Validate clinical laboratory results of Q-PCR

measurements in a central laboratory (via

CALGB 9862 for CALGB institutions).

Evaluate the ability of T/NK cell expansion to

predict outcome in patients diagnosed with Ph+

ALL.

Patient Population Patients must have an unequivocal histologic di-

agnosis of ALL and must have the detection of

the t(9;22)(q34;q11) or 3-way variant by meta-

phase cytogenetics or BCR-ABL positive status

by molecular analysis (Q-PCR or FISH) in a CLIA-approved laboratory.

Patients must have no prior therapy except up to

one week of corticosteroids and/or hydroxyurea

to enable time for the detection of

t(9;22)(q34;q11) or BCR/ABL.

Patients must be 50 years of age or older.

Accrual Goals The accrual goal for this study is 60 evaluable pa-

tients.


E1905/II

E1905 Phase II Intergroup

Coordinating Group: ECOG

A Randomized Phase II Trial of Azacitidine With or Without the Histone

Deacetylase Inhibitor Entinostat for the Treatment of Myelodysplastic

Syndrome, Chronic Myelomonocytic Leukemia (Dysplastic Type), and Acute

Myeloid Leukemia with Multilineage Dysplasia

Intergroup Participants: ECOG, SWOG, CALGB

Study Coordinators: S Gore (ECOG), H Erba, J Gabrilove (CALGB)




Schema

R A N D O M I Z E

CR, PR, HI-major: Continue treatment

Arm A Azacitidine

Evaluate for response

Arm B Azacitidine and Entinostat

HI-minor, no response, progression: Off study treatment

Objectives To estimate the overall response rate (complete,

partial, and hematologic improvement-major by

the International Working Group (IWG) response

criteria) in response to Azacitidine and Entinos-

tat.

To estimate the major response rate (complete and partial responses by the IWG criteria) to a

10-day regimen of Azacitidine and to the same

regimen of Azacitidine in combination with Enti-

nostat administered orally on days 3 and 10 of

each cycle in patients with de novo MDS,

CMMoL (dysplastic type) and AML-TLD, as

well as in patients with treatment-induced MDS,

CMMoL (dysplastic type) and AML-TLD.

To evaluate the toxicity of Azacitidine and Enti-

nostat in this patient population.

To identify changes in gene promoter methylation

and gene expression which may be associated

with response to Azacitidine and Entinostat.

To identify other molecular mechanisms (such as

DNA damage) which may be associated with re-

sponse to Azacitidine and Entinostat.

Patient Population Patients must have one of the following diagnos-

es confirmed by a bone marrow aspirate and/or

biopsy within two weeks prior to registration. 1)

Myelodysplastic Syndrome: Patients with any In-

ternational Prognostic Score (IPSS) are eligible.

Patients with low or INT-1 IPSS must have a

platelet count < 50,000/mm³ and/or absolute neu-

trophil count < 500/mm³ within seven days prior

to registration. 2) Chronic Myelomonocytic Leu-

kemia (Dysplastic subtype): Patients with CMMoL must have a WBC < 12,000/mm³, do-


E1905/II

cumented within four weeks prior to study entry.

3) AML-TLD will be interpreted to include pa-

tients formally diagnosed by FAB criteria as

RAEB-t, as well as patients with no history of an-

tecedent hematologic disorder who have AML

which meets criteria for AML-TLD by WHO cri-teria. Patients with AML-TLD must have a WBC

≤ 30,000/mm³ documented within four weeks

prior to study entry. Patients whose WBC has

doubled within this period of time and is greater

than 20,000/mm³ at the time of screening will not

be eligible. Patients who have therapy-induced

MDS, CMMoL (dysplastic type), and AML-TLD

are eligible and will be treated as separate cohorts

from the patients with de novo MDS, CMMoL

(dysplastic type) and AML-TLD.

Patients must have no prior treatment with Azaci-

tidine, decitabine, or Entinostat. Patients must not

have received any AML induction chemotherapy

or stem cell transplantation. Patients must not

have received any other treatment for their dis-

ease, including hematopoietic growth factors,

within three weeks prior to registration, and

should have recovered from all toxicities of prior

therapy.

Patients must be at least 18 years of age and an

ECOG performance status of 0, 1, or 2. Women

must not be pregnant or breast-feeding. Patients

must have no active infections at the time of reg-

istration and no clinical evidence of CNS or pul-

monary leukostasis, disseminated intravascular

coagulation, or CNS leukemia. Patients must not

have advanced malignant hepatic tumors and

must not have known hypersensitivity to Azaciti-

dine or mannitol. Patients must have adequate

hepatic and renal function and have no serious or

uncontrolled medical condition. Patients must have a life expectancy of at least six months.

Stratification/Descriptive Factors Patients with secondary disease will accrue to a

separate cohort. At randomization, patients will

be stratified by diagnosis: MDS High/Int-2 vs

MDS Low/Int-1 vs CMMoL vs AML-TLD.

Accrual Goals Non-treatment-induced Cohort:

Initially, 31 eligible patients per arm (62 patients

for both arms) will be accrued. If fewer than six

patients achieve CR, PR, or trilineage response,

accrual to that arm will be closed. Otherwise, 37

additional eligible patients per arm will be ac-

crued for a maximum total of 136 eligible pa-

tients.

Treatment-induced Cohort:

A maximum of 40 treatment-induced eligible pa-

tients will be accrued.

Summary Statement This study opened at ECOG institutions on Au-

gust 18, 2006 and at SWOG institutions on Octo-ber 1, 2006. The study met its first stage accrual

goal and was temporarily closed on September 5,

2007. The study was opened to the second stage

of accrual at ECOG institutions on May 20, 2008

and at SWOG institutions on June 15, 2008.

The study enrolled the planned number of pa-

tients and accrual was closed to the non-

treatment-induced cohort effective May 14, 2009.

The study team prepared an amendment to accrue only to a new cohort of patients with treatment-

related MDS. The amendment was activated at

ECOG institutions on July 22, 2009 and at

SWOG institutions on August 15, 2009.

As of December 31, 2010, 184 patients were reg-

istered including 22 from SWOG institutions.

The complete November 2010 summary of this

study from ECOG is available on the SWOG web site.



Institutions Total


Reg

Tennessee, U of

4 Michigan, U of

1Montana CCOP 3 Mississippi, Univ of 1Adirondack Ca Care/Rochester, Univ of 2 Ozarks Reg CCOP 1St Louis CCOP 2 Poudre Valley Hosp/Colorado, U of 1Akron Gen Med Ctr/Cleveland Clinic OH 1 Santa Rosa CCOP 1Boston Univ Med Ctr 1 Southeast CCC CCOP 1

Kansas City CCOP 1 Sutter Hlth CRG-East/Davis, U of CA 1

MD Anderson, Florida/Arkansas, U of 1 Total (15 Institutions) 22


E1908/II

E1908 Phase II SWOG Endorsed CTSU Study


A Phase II Randomized Trial Comparing Standard and Low Dose

Rituximab: Initial Treatment of Progressive Chronic Lymphocytic

Leukemia in Elderly Patients Using Alemtuzumab and Rituximab

Participants: ECOG, CTSU

Study Coordinators: C Zent (ECOG), E Libby (SWOG)


Schema

P R E


Risk stratification

R A N D O M I Z E

Arm A: Alemtuzumab + standard dose Rituximab (2 or 3 cycles)

CCR

Event monitoring (5 years)

Observation

Arm A or B as randomized previously

PR or stable

Arm B: Alemtuzumab + low dose Rituximab (2 or 3 cycles)

MRD+

Confirm

MRD+

MRD -

Progression

Response evaluation

MRD -

See below

Objectives To compare the rate of complete and overall re-

sponse of patients treated with the two regimens

to determine if the use of modified dose ritux-

imab significantly affects outcome.

To monitor and assess toxicity of these regimens.

To determine the overall and progression-free

survival, time to clinical response, time to next treatment, and duration of response in elderly

CLL patients using these treatment regimens.

To assess the correlation between the risk stratifi-cation prognostic markers (i.e. CD38, ZAP-70,

FISH and IgVH mutation) and clinical outcome.

To assess response to this therapy using both the

NCI-WG96 criteria and an expanded definition of

response for patients in complete remission in-

cluding immunohistochemical examination of the

bone marrow and sensitive flow cytometry (4-6

color) of blood for minimal residual disease

(MRD) and CT scans for residual adenopathy.


E1908/II

To determine the mechanism of action of ritux-

imab and alemtuzumab and to detail the in vivo

effect of the combination of alemtuzumab and ri-

tuximab on critical aspects of the immune system

in CLL from select patients.

Patient Population Patients must have a diagnosis of CLL with min-

imum threshold peripheral lymphocyte count of 5

x 109/L (CLL variant) or palpable adenopathy > 1

cm or palpable splenomegaly (SLL variant) and

immunophenotypic demonstrations of a popula-

tion of B-lymphocytes (as defined by CD19+)

which are monoclonal (by light chain exclusion).

CLL will be diagnosed if these cells have ≥ 3 of

the following characteristics: CD5+, CD23+, dim

surface light chain expression, and dim surface CD20 expression. FISH analysis must be nega-

tive for IGH/CCND1 and/or immunostaining is

negative for cyclin D1 expression to exclude

mantle cell lymphoma. Patients must have pro-

gressive CLL defined as at least one of the fol-

lowing characteristics based on standard criteria

for treatment based on NCI-WG96: weight loss >

10% within the previous six months attributable

to progressive CLL (grade 2 or higher); extreme

fatigue attributable to progressive CLL (grade 3

or higher); fevers > 100.5 degrees F for two weeks without evidence of infection (grade 1 or

higher); night sweats without evidence of infec-

tion (drenching); evidence of progressive bone

marrow failure with hemoglobin < 11 g/dL or

platelet count < 100 x109/L; rapidly progressive

lymphadenopathy providing that the largest node

is not > 5 cm in any dimension.

Patients must not have had any previous treat-

ment for CLL. Patients must not have had con-

comitant use of continuous systemic corticostero-ids.

Patients must be 70 years of age or older and

have an ECOG performance status ≤ 3. Patients

must not have splenomegaly > 6 cm below left

costal margin, at rest, on clinical examination and

not have lymphadenopathy > 5 cm in any diame-

ter. Patients must have adequate renal and hepatic

function. Patients must not have any of the fol-

lowing comorbid conditions: New York Heart

Association Class III or IV heart disease; recent

myocardial infarction (< 1 month prior to regis-tration); uncontrolled infection; infection with the

human immunodeficiency virus (HIV/AIDS); se-

rological evidence of active hepatitis B infection

(HBsAg or HBeAg positive); positive hepatitis C

serology. Patients must not have evidence of ac-

tive autoimmune hemolytic anemia, immune

thrombocytopenia, or pure red blood cell aplasia.

Patients must not have had major surgery within

four weeks prior to pre-registration.

Stratification/Descriptive Factors At randomization, patients will be stratified by

FISH risk classification: 17p13- or 11q22- (high

risk) vs 12+, any other abnormality (without

17p13-, 11q22- or 13q14-), or no abnormality (in-

termediate risk) vs 13q14- as only abnormality

(mono- or biallelic) (low risk).

Accrual Goals Forty patients will be randomized equally to each

of the two treatment arms for a total of 80 eligible patients.







The study was activated at ECOG on October 8,

2010. SWOG endorsed the study on November

15, 2010. No patients have been accrued as of

December 31, 2010.


study from ECOG is available on the SWOG web

site.


E2905/III

E2905 Phase III SWOG Endorsed CTSU Study


Randomized Phase III Trial Comparing the Frequency of Major Erythroid

Response (MER) to Treatment with Lenalidomide (Revlimid®) Alone and in

Combination with Epoetin Alfa (Procrit®) in Subjects with Low- or

Intermediate-1 Risk MDS and Symptomatic Anemia

Participants: ECOG, CTSU

Study Coordinators: A List (ECOG), C Schiffer (SWOG)


Schema

Arm B: Lenalidomide and Epoetin Alpha

R A N D O M I Z E

*

MER Continue Arm A treatment until relapse/progression, then offer crossover to Arm B (Step 2)

Offer crossover to Arm B (Step 2) or discontinue study treatment

Continue Arm B treatment until relapse/progression

Discontinue study treatment

Step 1

Arm A: Lenalidomide

no MER

MER

no MER

* Patients with the del 5q31.1 abnormality will not be randomized but will be assigned to Arm A.

Objectives To compare the rate of major erythroid response

(MER) between lenalidomide monotherapy and

combined treatment of lenalidomide and epoetin

alfa in EPO non-responsive Low/Int-1 risk MDS

patients or EPO-treatment naive patients with low

probability of EPO benefit.

To compare the time to MER by treatment as-

signment.

To evaluate the duration of MER by treatment as-

signment.

To estimate the frequency of MER to salvage

combination therapy in patients who fail to expe-

rience a MER with lenalidomide monotherapy.

To evaluate and compare the frequency of minor

erythroid response by treatment assignment.

To investigate the mechanism and target of lena-

lidomide action in patients with chromosome

5q31.1 deletion.

To evaluate the frequency of cytogenetic re-

sponse and progression, and the relation between

cytogenetic pattern and erythroid response.

To evaluate the frequency of bone marrow re-

sponse (CR+PR).


E2905/III

To evaluate the relationship between erythroid re-

sponse and laboratory correlates of the following:

Pretreatment and onstudy endogenous EPO level

(Arm A); (a) To evaluate the effect of CD45 iso-

form profile on lenalidomide enhancement of

EPO-induced STAT5 phosphorylation in CD71Hi erythroid precursors and the relationship to eryt-

hroid response. (b) To characterize molecular tar-

gets relevant to lenalidomide cytotoxicity in

del5q cells. (c) To evaluate the frequency of cryp-

tic chromosome 5q31 deletions in patients with

non-del5q MDS by array-based genomic scan,

and to determine the relationship to hematologic

response.

Patient Population Patients must have documented diagnosis of MDS lasting at least three months according to

WHO criteria or non-proliferative chronic mye-

lomonocytic leukemia. Patients must have Inter-

national Prognostic Scoring System (IPSS) cate-

gories of Low- or Intermediate-1 risk disease. Pa-

tients must have IPSS score determined by cyto-

genetic analysis prior to randomization. Patients

with cytogenetic failure and < 10% marrow blasts

will be eligible. Patients with cytogenetic failure

must have previous cytogenetic results (FISH is

not a substitute) within the last six months post last type of MDS treatment (in this case, not re-

ferring to growth factors as type of MDS treat-

ment). Patients must have symptomatic anemia

untransfused with hemoglobin ≤ 9.5 g/dL within

eight weeks of registration or with RBC transfu-

sion-dependence (i.e., ≥ 2 units/month) confirmed

for a minimum of eight weeks before randomiza-

tion. Patients must not have proliferative (WBC ≥

12,000/mcL) chronic myelomonocytic leukemia.

Patients must not have MDS secondary to treat-

ment with radiotherapy, chemotherapy, and/or

immunotherapy for malignant or autoimmune diseases.

Patients must have failed treatment with an eryt-

hropoietic growth factor, or have a low probabili-

ty of response to rhu-EPO, as defined in the pro-

tocol, eight weeks prior to randomization. Pa-

tients must be off all non-transfusion therapy for

MDS for 28 days prior to initiation of study

treatment. Patients may receive hydrocortisone

prophylactically to prevent transfusion reactions. Patients must not have prior therapy with lenali-

domide or have used cytotoxic chemotherapeutic

agents, or experimental agents for the treatment

of MDS within eight weeks prior to randomiza-

tion.

Patients must be at least 18 years of age. Patients

must have an EPO level prior to randomization

and ≤ 56 days before day 1 of study treatment.

Patients must not have documented iron deficien-

cy and must have documented marrow iron

stores. If marrow iron stain is not available, the

transferrin saturation must be > 20% or a serum

ferritin > 100 ng/mL. Women must not be preg-

nant or breastfeeding and all females of child-

bearing potential must have two negative preg-nancy tests, the first performed within 14 days

and the second within 24 hours prior to prescrib-

ing lenalidomide. Patients must have the follow-

ing lab values documented on two occasions (se-

parated by at least seven days) over 21 days prior

to randomization: Platelet count ≥ 50,000/mcL

without platelet transfusion, ANC ≥ 500

cells/mcL, serum creatinine ≤ 1.5 x ULN, serum

SGOT or SGPT ≤ 2.0 x ULN, serum total biliru-

bin < 3.0 mg/dL. Patients must not have had prior

≥ Grade 3 allergic reaction to thalidomide, must

not have had a known allergic reaction to epoetin alfa or human serum albumin, and must not have

prior desquamating rash at time of study entry.

Patients must not have anemia resulting from

iron, B12, or folate deficiencies, autoimmune or

hereditary hemolysis, or gastrointestinal bleeding.

Patients must not have a history of thromboem-

bolic events within three years prior to randomi-

zation. Patients must not have known HIV-1 se-

ropositivity, uncontrolled seizure, or uncontrolled

hypertension.

Stratification/Descriptive Factors At randomization patients will be stratified by (1)

serum erythropoietin level: ≤ 500 mU/mL vs >

500 mU/mL, and (2) prior erythropoietic growth

factor treatment: yes vs no. All patients with del

5q31.1 karyotype will be assigned to treatment

with lenalidomide monotherapy (Arm A).

Accrual Goals The study requires 212 patients without 5q31.1 deletion. The estimated accrual goal is a total of

236 eligible patients.







The study was activated at ECOG on January 29,

2009. SWOG endorsed the study on February 15,

2009. Accrual was suspended on September 23,

2010 due to a recall of epoetin alfa and was reo-

pened on February 4, 2011 when a new supply

became available.

As of December 31, 2010, 67 patients were regis-

tered to this study, twelve from SWOG institu-tions.


E2905/III


study from ECOG is available on the SWOG web

site.



Institutions Total

Reg

H Lee Moffitt CC

5

Davis, U of CA 2Montana CCOP 2Lahey Clinic Med Ctr/Davis, U of CA 1Wayne State Univ 1

Winthrop - Univ Hosp/Columbia University 1


Documents

Leukemia - swogstat.org 2011/Leukemia.pdf · Title: Microsoft Word - Leukemia.doc Author: markb Created Date: 3/3/2011 1:58:45 PM