APRIL 24 - 27, 2019 SWOG MELANOMA 1
MELANOMA COMMITTEE
APRIL 24 - 27, 2019 SWOG MELANOMA 2
CONTENTS
S1204 Surveillance ........................................................................................................................................................ 6
S1320 Phase II ............................................................................................................................................................... 8
S1404 Phase III ............................................................................................................................................................ 19
S1512 Phase II ............................................................................................................................................................. 29
S1607 Phase II ............................................................................................................................................................. 33
S1609 Phase II ............................................................................................................................................................. 38
S1614 Phase III ............................................................................................................................................................ 40
S1616 Phase II ............................................................................................................................................................. 42
S1801 Phase II ............................................................................................................................................................. 47
APRIL 24 - 27, 2019 SWOG MELANOMA 3
Patient Registrations to Studies
by 12 Month Intervals
MELANOMA COMMITTEE
Screening registrations and registrations to Biologic only studies are excluded.
SWOG LAPS MEMBER NCORP NON-SWOG
187145
104
674
845
97
0
100
200
300
400
500
600
700
800
900
Time of Registration
Jan 2013Dec 2013
Jan 2014Dec 2014
Jan 2015Dec 2015
Jan 2016Dec 2016
Jan 2017Dec 2017
Jan 2018Dec 2018
101
51
76 108
129
126
311
116
152
185
392
APRIL 24 - 27, 2019 SWOG MELANOMA 4
Patient Registrations by Study and Arm MELANOMA COMMITTEE
Jul 2018
Dec 2018
Jan 2018
Jun 2018
Jul 2017
Dec 2017
All
Patients
S1320 Adv, BRAF mut, Intermittent vs Continuous Dabrafenib + Trametinib
Lead In Registration
Lead-in Continuous Dosing 18 28 31 237
Randomization
Continuous Dosing 6 15 13 97
Intermittent Dosing 6 13 10 93
12 28 23 190
S1404 Adv, HD-IFN/Ipilimumab vs MK-3475
Tissue Submission
Tissue for PD-L1 testing 0 0 185 1,426
Randomization
FDA approved regimen 0 0 110 678
MK-3475 (Pembrolizumab) 0 0 102 667
0 0 212 1,345
S1512 Melan, Adv, Desmoplastic, MK-3475 (Pembrolizumab)
Registration
MK-3475 (pembrolizumab) 7 6 4 18
S1607 Adv, T-VEC, MK-3475 (Pembrolizumab)
Registration
T-VEC + MK-3475(Pembrolizumab) 7 1 0 8
S1616 Adv, Ipilimumab ± Nivolumab
Randomization
Ipilimumab 3 4 1 8
Nivolumab + Ipilimumab 10 7 3 20
13 11 4 28
APRIL 24 - 27, 2019 SWOG MELANOMA 5
Non-SWOG Studies with SWOG-Credited Registrations MELANOMA COMMITTEE
Studies with Accrual from July 2017 - December 2018
SWOG Accrual
SWOG
Champion
Jul 2018
Dec 2018
Jan 2018
Jun 2018
Jul 2017
Dec 2017
SWOG
Total
Total
Accrued
E3612 Adv, Ipilimumab ± Bevacizumab 0 0 1 6 169
Date Activated: 12/13/13 Date Closed: 09/25/17
Most Recent Progress Report
EA6134 Adv, BRAF mut, Dabrafenib + Trametinib/Ipilimumab +
Nivolumab vs Ipilimumab + Nivolumab /Dabrafenib + Trametinib
B Chmielowski 4 2 8 30 166
Date Activated: 12/15/15
Most Recent Progress Report
EA6141 Adv, Nivolumab + Ipilimumab ± Sargmostim K Kim 0 0 0 36 250
Date Activated: 03/01/16
Most Recent Progress Report
APRIL 24 - 27, 2019 SWOG MELANOMA 6
S1204
S1204 Surveillance
A Sero-Epidemiologic Survey and Cost-Effectiveness Study of Screening for
Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and
Hepatitis C Virus (HCV) Among Newly Diagnosed Cancer Patients
Study Chairs:
S Ramsey, D Hershman
Statisticians:
J Unger, K Arnold
Data Coordinator:
M Yee
Date Activated:
08/29/2013
Date Closed:
02/15/2017
Objectives Among newly diagnosed cancer patients presenting
to SWOG-affiliated community and academic
oncology clinics, estimate the prevalence of human
immunodeficiency virus (HIV), hepatitis B (HBV),
and hepatitis C (HCV) infection.
Evaluate known sociodemographic, clinical, and
behavioral factors that are significantly associated
with previously undiagnosed HIV, HBV, and/or
HCV infection in a population of people with newly
diagnosed cancer
Among patients who are identified as having HIV,
HBV, and/or HCV, describe the timing and type of
treatments received (if any), both for the viral
infections and the cancers.
Describe the type of adverse events possibly
attributable to the patient's viral status in patients
with HIV, HBV, and/or HCV infection.
Using simulation modeling that is directly informed
by the data obtained from this study, determine the
cost-effectiveness (expressed as cost per infection
detected and cost per year of life gained) of (1)
routine, universal screening and (2) risk factor-
directed screening of newly diagnosed cancer
patients for HIV, HBV and/or HCV versus current
care.
Patient Population Patients must be presenting for evaluation or
treatment for the first diagnosis of a new solid or
hematologic cancer malignancy. Confirmed diagnosis
date must be within 120 days prior to first clinic visit
as a newly diagnosed cancer patient at the registering
clinic. Patients presenting for "second opinions" of
confirmed malignancies are eligible, including those
who have started cancer treatment at other facilities.
Patients must be registered within 90 days after their
first clinic visit. Patients must not have been
diagnosed with a malignancy other than the current
malignancy within the past five years, with the
exception of basal cell or squamous cell skin cancer,
in situ cervical cancer, or in situ breast cancer.
Patients must have no evidence of disease for a prior
malignancy for at least five years prior to
randomization except as noted above.
APRIL 24 - 27, 2019 SWOG MELANOMA 7
S1204
Patients must be 18 years of age or older. Patients
must have had their blood drawn for viral status
testing for HIV, HBV and HCV or provide
acceptable viral status documentation prior to
registration, as defined in the protocol. Note that
patients must have blood drawn for testing prior to
registration for any of the three viruses not covered
by the documentation. Patients are allowed to
participate in other clinical trials.
Accrual Goals A total of 3,061 patients will be accrued to achieve
3,000 eligible patients.
Summary Statement For the current status of this study, please refer to the
Cancer Care Delivery chapter.
APRIL 24 - 27, 2019 SWOG MELANOMA 8
S1320/II
S1320 Phase II
Coordinating Group: SWOG
A Randomized Phase II Trial of Intermittent versus Continuous Dosing of
Dabrafenib (NSC-763760) and Trametinib (NSC-763093) in BRAFV600E/K
Mutant Melanoma
Participants:
SWOG, CTSU (Supported by ECOG-ACRIN)
Study Chairs:
A Algazi, A Daud, R Lo, J Mehnert (ECOG-ACRIN)
Statisticians:
M Othus, J Moon
Data Coordinator:
J Sanchez
Date Activated:
07/22/2014
SCHEMA
Objectives To compare progression-free survival with
intermittent dosing versus continuous dosing of
dabrafenib and trametinib among patients with
metastatic BRAFV600E/K mutant melanoma.
To compare the response rate (complete and partial
response, confirmed and unconfirmed), overall
survival, and survival after progression between the
two dosing schedules.
R
A
N
D
O
M
I
Z
A
T
I
O
N
Continuous Treatment
Intermittent Treatment
R
E
G
I
S
T
R
A
T
I
O
N
Continuous Treatment Lead-in
APRIL 24 - 27, 2019 SWOG MELANOMA 9
S1320/II
To compare the frequency and severity of fever
greater than Grade 1 per CTCAE 4.0 of the two
dosing schedules.
To estimate the frequency and severity of toxicities
of the two dosing schedules.
To bank tissue and whole blood in anticipation of
future studies to evaluate molecular events associated
with clinical benefit and disease progression in
patients treated with continuous versus intermittent
dabrafenib and trametinib.
Patient Population Patients must have histologically or cytologically
confirmed Stage IV or unresectable Stage III
melanoma. Patients must have BRAF mutation-
positive melanoma (i.e., V600E or V600K).
BRAFV600
mutant status must be documented by a
CLIA-certified laboratory. Patients must have
measurable disease as defined by RECIST 1.1.
Contrast-enhanced CT scans of the neck, chest,
abdomen and pelvis are required. A whole body
PET/CT scan with diagnostic quality images and
intravenous iodinated contrast may be used in lieu of
a contrast enhanced CT of the neck, chest, abdomen
and pelvis. Contrast may be omitted if the treating
investigator believes that exposure to contrast poses
an excessive risk to the patient. Patients with a
history of brain metastases are eligible if the patient
is asymptomatic with no residual neurological
dysfunction and has not received enzyme-reducing
anti-epileptic drugs or corticosteroids for at least
seven days prior to registration. Patients must have
serum LDH obtained prior to registration for
treatment randomization stratification and accurate
staging.
Patients must not have received a prior BRAF or
MEK inhibitor. Prior surgery, radiotherapy,
immunotherapy, or chemotherapy are allowed.
Patients must have adequate hematologic, hepatic,
cardiac, and renal function and a Zubrod performance
status of 0-2. Patients must not have a known history
or current evidence of retinal vein occlusion (RVO)
or central serous retinopathy (CSR). Patients must
not have any predisposing factors for RVO or CSR
such as uncontrolled glaucoma, ocular hypertension,
uncontrolled systemic hypertension, diabetes
mellitus, or a history of hyperviscosity or
hypercoagulability syndromes. An ophthalmic exam
is required for all patients. Patients must not have
evidence of optic disc cupping, visual field defects,
or an intraocular pressure greater than 21 mmHg.
Patients must be able to take oral medications and
must not have any impairment of gastrointestinal
disease that may significantly alter the absorption of
protocol treatment. Patients must discontinue
treatment with therapeutic warfarin prior to
registration. Patients must not have a history of
pneumonitis or interstitial lung disease. Patients with
known hepatitis B, or hepatitis C are not eligible.
Patients known to be HIV positive must have CD4
cells ≥ 500 uL, a serum HIV viral load < 25,000
IU/ml, and must be able to discontinue antiretroviral
therapy. Patients must have a dermatology exam
within 28 days prior to registration.
Patients must be offered the opportunity to participate
in specimen banking.
Stratification/Descriptive Factors Treatment randomization will be stratified by the
following: (1) prestudy serum LDH: elevated (>
IULN) vs normal; (2) known prior exposure to
immune checkpoint inhibitors targeting CTLA-4,
PD-1, or PD-L1: yes vs no.
Accrual Goals The accrual goal is 206 eligible randomized patients.
An interim analysis testing for harm will be
performed when 78 progression events have
occurred.
Summary Statement
Because accrual to this study has been slower than
anticipated, it is expected that 100% of the events
needed to perform the final analysis will be reached
before the original accrual goal could be reached. To
account for the slower than anticipated accrual rate,
the study was amended to reduce the sample size
from 236 eligible randomized patients to 206 eligible
randomized patients. This new design will have the
same power as the original design using the same
alpha level. In addition, in an effort to increase
accrual, a protocol amendment was also amended to
allow patients with a history of untreated brain
metastases as long as the patient is asymptomatic.
As of December 31, 2018, 237 patients have been
registered to lead-in continuous dosing. Seven
patients are currently ineligible for the following
reasons: inadequate baseline disease assessment (3),
inadequate cardiac function (2), not having a V600E
or V600K BRAF mutation (1), inadequate
hematologic function (1). In addition, three eligible
patients never received protocol treatment and were
never randomized are not evaluable for any of the
study endpoints. One additional patient is excluded
APRIL 24 - 27, 2019 SWOG MELANOMA 10
S1320/II
from the analysis. At the time of registration,
documentation was provided of histologic
confirmation of melanoma. However, after the
patient progressed on study, the pathology report
from the patient's resected disease revealed that it
was myxofibrosarcoma rather than melanoma. Most
patients who were unable to complete the one cycle
of lead-in continuous dosing came off protocol
treatment either due to adverse events or disease
progression. One patient was never randomized and
remained on continuous dosing off protocol (coded as
Reason Off Treatment = “Other – not protocol
specified”).
A total of 217 patients have been assessed for adverse
events related to lead-in continuous dosing. There has
been one treatment-related death due to sepsis. This
patient also experienced Grade 4 acute kidney injury
and Grade 4 ejection fraction decrease. An additional
six patients experienced treatment-related Grade 4
adverse events due to the following: CPK increased
and MS/connective tissue disorder (1), sepsis (1),
hypocalcaemia (1), neutrophil count decreased (1),
hyponatremia (1), and hypocalcaemia and
pneumonitis (1).
A total of 190 patients have been randomized
between intermittent and continuous dosing. Seven
patients are currently ineligible for the following
reasons: ineligible for the trial at the initial
registration (5), and disease progression during the
lead-in continuous dosing phase (2). Seven patients
have discontinued protocol treatment for reasons
coded as “other – not protocol specified”: treatment
delay longer than 14 days, not due to toxicity (2),
other primary cancer (1), and a change in treatment
plan by the medical team (4). In addition, one eligible
patient who was found to have myxofibrosarcoma is
excluded from the analysis, for reasons described
above.
On the continuous dosing arm, 89 patients have been
assessed for adverse events. Five patients have
experienced Grade 4 treatment-related adverse events
due to the following reasons: anemia and increases in
ALT and AST (1), dyspnea (1), lipase increase (1),
sepsis (1) and creatinine increase (1). On the
intermittent dosing arm, 88 patients have been
assessed for adverse events. Three patients have
experienced Grade 4 treatment-related adverse events
due to the following reasons: fever (1), lipase
increase (1), and acute kidney injury (1).
APRIL 24 - 27, 2019 SWOG MELANOMA 11
S1320/II
Registration by Institution
Lead-In Continuous Dosing
Registrations ending December 31, 2018
Institutions
Total
Reg Institutions
Total
Reg
Kaiser Perm NCORP 28 Colorado, U of 2
Kansas, U of 17 CRC West MI NCORP 2
Ohio State Univ 17 Ozarks NCORP 2
Utah, U of 11 PCRC NCORP 2
Loyola University 8 Bay Area NCORP 1
San Francisco, U-CA 8 Boston Medical Ctr 1
Southeast COR NCORP 8 CORA NCORP 1
Arkansas, U of 6 Dayton NCORP 1
Heartland NCORP 6 Hawaii MU-NCORP 1
Wichita NCORP 6 Lahey Hosp & Med Ctr 1
Michigan, U of 5 UF Cancer Center/Arkansas, U of 1
Los Angeles, U of CA 4 Wisconsin NCORP 1
Nevada CRF NCORP 4 ECOG-ACRIN 48
Rochester, Univ of 4 NRG 20
Columbus NCORP 3 ALLIANCE 13
KaiserPermanenteSCAL/Kaiser Perm NCORP 3 Total (32 Institutions) 237
Arizona MC, U of 2
Registration, Eligibility, and Evaluability
Lead-In Continuous Dosing
Registrations ending December 31, 2018; Data as of January 18, 2019
Lead-in
Continuous
Dosing
NUMBER REGISTERED 237
INELIGIBLE 7
ELIGIBLE 230
Analyzable, Pend. Elig. 9
Not Analyzable 4
ADVERSE EVENT ASSESSMENT
Evaluable 217
Too Early 9
APRIL 24 - 27, 2019 SWOG MELANOMA 12
S1320/II
Treatment Summary
Lead-In Continuous Dosing
Registrations ending December 31, 2018; Data as of January 18, 2019
Lead-in
Continuous
Dosing
NUMBER ON PROTOCOL TREATMENT 10
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
216
Treatment completed as planned 184
Adverse Event or side effects 17
Refusal unrelated to adverse event 1
Progression/relapse 11
Death 2
Other - not protocol specified 1
Reason under review 0
MAJOR PROTOCOL DEVIATIONS 0
APRIL 24 - 27, 2019 SWOG MELANOMA 13
S1320/II
Number of Patients with a Given Type and Grade of Adverse Event
Lead-In Continuous Dosing
Adverse Events Unlikely or Not Related to Treatment Excluded
Adverse Events with No Entries for Grades 3 to 5 or Unknown Have Been Suppressed
Registrations ending December 31, 2018; Data as of January 18, 2019
Lead-in Continuous
Dosing
(n=217)
Grade
ADVERSE EVENTS <=2 3 4 5
AST increased 211 6 0 0
Abdominal pain 216 1 0 0
Acute kidney injury 216 0 1 0
Anemia 213 4 0 0
Anorexia 215 2 0 0
Arthralgia 216 1 0 0
Blood bilirubin increased 216 1 0 0
Blood/lymph disorder-Other 216 1 0 0
CPK increased 216 0 1 0
Cardiac troponin T increased 216 1 0 0
Chills 216 1 0 0
Constipation 216 1 0 0
Dehydration 210 7 0 0
Diarrhea 214 3 0 0
Dyspnea 216 1 0 0
ECG QT corrected int prolong 216 1 0 0
Ejection fraction decreased 216 0 1 0
Epistaxis 216 1 0 0
Erythema multiforme 216 1 0 0
Fatigue 212 5 0 0
Febrile neutropenia 214 3 0 0
Fever 213 4 0 0
Fracture 216 1 0 0
Gastric hemorrhage 216 1 0 0
Generalized muscle weakness 215 2 0 0
Headache 215 2 0 0
Hyperglycemia 216 1 0 0
Hypertension 213 4 0 0
Hypoalbuminemia 216 1 0 0
Hypocalcemia 215 0 2 0
Hypokalemia 216 1 0 0
Hyponatremia 206 10 1 0
Hypophosphatemia 216 1 0 0
Hypotension 213 4 0 0
Hypoxia 216 1 0 0
Leukocytosis 216 1 0 0
Lipase increased 215 2 0 0
Lung infection 216 1 0 0
Lymphocyte count decreased 211 6 0 0
MS/connective tissue disorder 215 1 1 0
APRIL 24 - 27, 2019 SWOG MELANOMA 14
S1320/II
Lead-in Continuous
Dosing
(n=217)
Grade
ADVERSE EVENTS <=2 3 4 5
Metab/nutrition disorders-Other 216 1 0 0
Mucositis oral 216 1 0 0
Nausea 215 2 0 0
Neutrophil count decreased 208 8 1 0
Platelet count decreased 216 1 0 0
Pneumonitis 216 0 1 0
Proteinuria 216 1 0 0
Rash acneiform 214 3 0 0
Rash maculo-papular 213 4 0 0
Retinopathy 216 1 0 0
Sepsis 215 0 1 1
Skin infection 215 2 0 0
Skin/subq tissue ds-Other 216 1 0 0
Thromboembolic event 216 1 0 0
Tx related secondary malig 215 2 0 0
Upper GI hemorrhage 216 1 0 0
Urinary tract infection 215 2 0 0
Vasc disorders-Other, spec 216 1 0 0
Vomiting 215 2 0 0
White blood cell decreased 213 4 0 0
MAX. GRADE ANY ADVERSE EVENT 152 58 6 1
APRIL 24 - 27, 2019 SWOG MELANOMA 15
S1320/II
Registration, Eligibility, and Evaluability
Randomization
Registrations ending December 31, 2018; Data as of January 18, 2019
TOTAL
Continuous
Dosing
Intermittent
Dosing
NUMBER REGISTERED 190 97 93
INELIGIBLE 7 5 2
ELIGIBLE 183 92 91
Analyzable, Pend. Elig. 5 2 3
Not Analyzable 1 1 0
RESPONSE ASSESSMENT
Determinable 161 83 78
Not Determinable 3 2 1
Too Early 18 6 12
ADVERSE EVENT ASSESSMENT
Evaluable 177 89 88
Too Early 5 2 3
APRIL 24 - 27, 2019 SWOG MELANOMA 16
S1320/II
Patient Characteristics
Randomization
Registrations ending December 31, 2018; Data as of January 18, 2019
Continuous
Dosing
(n=91)
Intermittent
Dosing
(n=91)
AGE
Median 59.2 62.8
Minimum 22.7 20.9
Maximum 88.6 88.8
SEX
Males 55 60% 60 66%
Females 36 40% 31 34%
HISPANIC
Yes 2 2% 4 4%
No 87 96% 87 96%
Unknown 2 2% 0 0%
RACE
White 89 98% 88 97%
Native American 1 1% 0 0%
Multi-Racial 0 0% 1 1%
Unknown 1 1% 2 2%
LDH
Elevated (>IULN) 36 40% 33 36%
Normal 55 60% 58 64%
PRIOR IMMUNE CHECKPOINT INHIBITOR
Yes 26 29% 26 29%
No 65 71% 65 71%
PRIOR IMMUNOTHERAPY
Yes 28 31% 35 38%
No 54 59% 49 54%
Unknown 9 10% 7 8%
PERFORMANCE STATUS
0 50 55% 54 59%
1 38 42% 36 40%
2 1 1% 1 1%
Data pending 2 2% 0 0%
STAGE
III 11 12% 11 12%
IV 80 88% 80 88%
APRIL 24 - 27, 2019 SWOG MELANOMA 17
S1320/II
Treatment Summary
Randomization
Registrations ending December 31, 2018; Data as of January 18, 2019
Total
NUMBER ON PROTOCOL TREATMENT 38
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
144
Treatment completed as planned 0
Adverse Event or side effects 27
Refusal unrelated to adverse event 7
Progression/relapse 101
Death 3
Other - not protocol specified 6
Reason under review 0
MAJOR PROTOCOL DEVIATIONS 0
Number of Patients with a Given Type and Grade of Adverse Event
Randomization
Adverse Events Unlikely or Not Related to Treatment Excluded
Adverse Events with No Entries for Grades 3 to 5 or Unknown Have Been Suppressed
Registrations ending December 31, 2018; Data as of January 18, 2019
Continuous Dosing
(n=89)
Grade
Intermittent Dosing
(n=88)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
ALT increased 87 1 1 0 88 0 0 0
AST increased 84 4 1 0 87 1 0 0
Acute kidney injury 89 0 0 0 87 0 1 0
Alkaline phosphatase increased 88 1 0 0 87 1 0 0
Anemia 86 2 1 0 86 2 0 0
Arthralgia 88 1 0 0 87 1 0 0
Back pain 88 1 0 0 88 0 0 0
Blood bilirubin increased 88 1 0 0 88 0 0 0
Chills 88 1 0 0 87 1 0 0
Confusion 89 0 0 0 87 1 0 0
Creatinine increased 88 0 1 0 88 0 0 0
Dehydration 88 1 0 0 88 0 0 0
Diarrhea 87 2 0 0 87 1 0 0
Dry skin 88 1 0 0 88 0 0 0
Dyspnea 88 0 1 0 88 0 0 0
ECG QT corrected int prolong 88 1 0 0 87 1 0 0
Ejection fraction decreased 85 4 0 0 84 4 0 0
Eye disorders - Other, specify 89 0 0 0 87 1 0 0
Fatigue 82 7 0 0 86 2 0 0
Fever 83 6 0 0 87 0 1 0
APRIL 24 - 27, 2019 SWOG MELANOMA 18
S1320/II
Continuous Dosing
(n=89)
Grade
Intermittent Dosing
(n=88)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
Flu like symptoms 87 2 0 0 88 0 0 0
Gastric hemorrhage 88 1 0 0 88 0 0 0
Generalized muscle weakness 87 2 0 0 86 2 0 0
Glucose intolerance 88 1 0 0 88 0 0 0
Hand-Foot syndrome 88 1 0 0 88 0 0 0
Hypercalcemia 89 0 0 0 87 1 0 0
Hyperglycemia 86 3 0 0 86 2 0 0
Hypertension 83 6 0 0 85 3 0 0
Hypoalbuminemia 88 1 0 0 88 0 0 0
Hyponatremia 85 4 0 0 86 2 0 0
Hypotension 88 1 0 0 87 1 0 0
Infections/infestations-Other 89 0 0 0 87 1 0 0
Investigations-Other, specify 89 0 0 0 87 1 0 0
LV systolic dysfunction 88 1 0 0 87 1 0 0
Lipase increased 86 2 1 0 85 2 1 0
Localized edema 88 1 0 0 88 0 0 0
Lung infection 88 1 0 0 88 0 0 0
Lymphocyte count decreased 85 4 0 0 87 1 0 0
Mucositis oral 88 1 0 0 88 0 0 0
Myalgia 89 0 0 0 87 1 0 0
Neutrophil count decreased 86 3 0 0 88 0 0 0
Pain in extremity 88 1 0 0 88 0 0 0
Platelet count decreased 88 1 0 0 88 0 0 0
Rash acneiform 87 2 0 0 88 0 0 0
Rash maculo-papular 88 1 0 0 88 0 0 0
Resp/thoracic/mediastinal ds 88 1 0 0 88 0 0 0
Retinal detachment 89 0 0 0 86 2 0 0
Sepsis 88 0 1 0 88 0 0 0
Serum amylase increased 89 0 0 0 86 2 0 0
Skin/subq tissue ds-Other 88 1 0 0 88 0 0 0
Syncope 88 1 0 0 88 0 0 0
Thromboembolic event 87 2 0 0 88 0 0 0
Tx related secondary malig 89 0 0 0 86 2 0 0
Urinary tract infection 89 0 0 0 87 1 0 0
Urinary tract obstruction 88 1 0 0 88 0 0 0
White blood cell decreased 86 3 0 0 87 1 0 0
MAX. GRADE ANY ADVERSE EVENT 50 34 5 0 59 26 3 0
APRIL 24 - 27, 2019 SWOG MELANOMA 19
S1404/III
S1404 Phase III
Coordinating Group: SWOG
A Phase III Randomized Trial Comparing Physician/Patient Choice of Either
High Dose Interferon or Ipilimumab to MK-3475 (Pembrolizumab) in
Patients with High Risk Resected Melanoma
Participants:
SWOG, CTSU (Supported by CCTG and ECOG-
ACRIN)
Study Chairs:
K Grossmann, S Patel, A Tarhini (ECOG-ACRIN),
T Petrella (CCTG)
Statisticians:
M Othus, J Moon, H Li
Data Coordinators:
V Kim, L Kingsbury
Date Activated:
10/15/2015
Date Closed:
08/15/2017
SCHEMA
R
A
N
D
O
M
I
Z
A
T
I
O
N
FDA approved regimen:
Physician/Patient choice of
Interferon alfa-2b/Ipilimumab
MK-3475 (Pembrolizumab)
R
E
G
I
S
T
R
A
T
I
O
N
Tissue Submission*
*PD-L1 status determined by central laboratory
and blinded to the investigator and patient
APRIL 24 - 27, 2019 SWOG MELANOMA 20
S1404/III
Objectives
Co-Primary Objectives:
To compare overall survival (OS) of patients with
resected Stage III and IV melanoma treated with
physician/patient choice of either high dose
interferon alfa-2b or ipilimumab versus MK-3475
(pembrolizumab).
To compare OS of patients with resected Stage III
and IV melanoma treated with physician/patient
choice of either high dose interferon alfa-2b or
ipilimumab versus MK-3475 (pembrolizumab)
among patients who are PD-L1 positive.
To compare relapse-free survival (RFS) of patients
with resected Stage III and IV melanoma treated with
physician/patient choice of either high dose
interferon alfa-2b or ipilimumab versus MK-3475
(pembrolizumab).
Secondary Objectives:
To estimate OS and RFS for patients who are PD-L1
negative or PD-L1 indeterminate in this population.
To compare OS and RFS between the two arms
within the PD-L1 positive and PD-L1 negative
subgroups and to investigate the interaction between
PD-L1 status (positive versus negative) and treatment
arm.
To assess the safety and tolerability of the regimens.
Patient Population
Patients must have histologically confirmed selected
Stage III (IIIA/N2a, IIIB, IIIC) or Stage IV
melanoma of cutaneous or mucosal origin or
unknown primary. Patients must not have melanoma
of ocular origin. Patients are eligible for this trial
either at initial presentation of their melanoma, at
time of first detected nodal, satellite/in-transit, distant
metastases, or recurrent disease in prior
lymphadenectomy basin or distant site. Patients must
not have a history of brain metastases. Patients who
have multiple regional nodal basin involvement are
eligible. Gross or microscopic extracapsular nodal
extension is permitted. All disease must have been
completely resected with negative pathologic margins
and no clinical, radiologic, or pathologic evidence of
any incompletely resected melanoma. Patients must
have available and be willing to submit adequate
tissue for PD-L1 testing.
Patients may have received prior radiotherapy,
including after the surgical resection that rendered the
patient disease-free. Patients must not have received
neoadjuvant treatment for their melanoma. Patients
must not have received prior immunotherapy,
including but not limited to ipilimumab, interferon
alfa-2b, pegylated interferon, high dose IL-2, anti-
PD-1, anti-PD-L1, intra-tumoral, or vaccine
therapies. Patients must be registered within 98 days
of the last surgery performed to render the patient
free of disease.
Patients must have a Zubrod performance status of 0-
1, and have adequate renal, hepatic, hematologic, and
cardiac function. Patients must not have active
autoimmune disease that has required systemic
treatment in the past two years.Patients must not have
an active infection requiring systemic therapy.
Patients must not have pneumonitis or a history of
non-infectious pneumonitis that required steroids.
Patients known to be HIV positive must have
adequate CD4 counts and low viral load. Patients
must not have known active hepatitis B or C
infections. Patients must not have received live
vaccines within 42 days prior to enrollment. Women
of childbearing potential must have a negative
pregnancy test within 28 days prior to randomization.
Stratification/Descriptive Factors Treatment randomization will be stratified by the
following: (1) surgically resected AJCC stage:
IIIA(N2a) vs IIIB vs IIIC vs IV; (2) PD-L1 status:
positive vs negative vs indeterminate; (3) planned
control arm regimen: high dose interferon vs
ipilimumab.
Accrual Goals The accrual goal of this study is to randomize 1,240
eligible patients. Up to two interim analyses of
overall survival will be performed when 55% and
80% of the expected deaths across both arms
combined have been observed. An interim analyses
of relapse-free survival (RFS) will be performed
when 75% of the expected RFS events have been
observed.
Summary Statement This study was permanently closed after reaching its
accrual goal. A total of 1,426 patients were registered
to the PD-L1 status screening step. Sixty-three
patients are currently ineligible for the following
reasons: incorrect stage of disease (20),
inadequate/incomplete resection of disease (21),
radiologic or clinical evidence that patient was not
disease free (10), lack of adequate tissue for PD-L1
APRIL 24 - 27, 2019 SWOG MELANOMA 21
S1404/III
testing (8), inadequate renal function (1), concurrent
radiation therapy (1), recurrent satellite metastases
(1), recurrent distant metastases (1).
A total of 1,345 patients were randomized. Thirty-
seven are currently ineligible, including 36 who were
ineligible at the screening step and one patient due to
a positive pregnancy test. Ninety-seven patients, 89
of them randomized to the control arm, did not
receive any protocol treatment, coded as a major
protocol deviation, and are not evaluable for adverse
events.
On the control arm, 569 patients have been assessed
for adverse events. There have been two treatment
related deaths, one due to enterocolitis, the other due
to respiratory failure (with a prior Grade 4 sepsis);
both patients were receiving ipilimumab. An
additional 36 patients have experienced treatment-
related Grade 4 adverse events. These have been
primarily hematologic among patients who received
high-dose interferon and immune-related among
patients who received ipilimumab. One patient
experienced Grade 4 AIDP (coded as "Nervous
system disorders - Other).
On the pembrolizumab arm, 642 patients have been
assessed for adverse events. There have been two
treatment related deaths, one due to myocarditis, the
other due to a secondary leukemia (AML, also coded
as "Neoplasms, all"). An additional 12 patients have
experienced treatment-related Grade 4 adverse
events. Notable Grade 4 adverse events include four
cases of hyperglycemia, one case of acidosis, one
case of diabetic ketoacidosis (coded as
Metabolic/nutrition disorders - Other), one case of
Type 1 diabetes (coded as "Endocrine disorders-
Other"). In addition, one patient experienced Grade 4
myasthenia gravis (coded as "Nervous system
disorders, Other") and another experienced Grade 4
episcleritis (coded as "Eye disorders, other").
APRIL 24 - 27, 2019 SWOG MELANOMA 22
S1404/III
Registration by Institution
Initial Registration
Institutions
Total
Reg Institutions
Total
Reg
Kaiser Perm NCORP 77 Cedars-Sinai Med Ctr 8
H Lee Moffitt CC 53 City of Hope Med Ctr 8
MD Anderson CC 48 Dayton NCORP 8
Colorado, U of 34 Michigan CRC NCORP 8
Utah, U of 34 TX Oncology-Central/San Antonio, U of TX 8
Ohio State Univ 33 Wisconsin NCORP 8
Heartland NCORP 29 Yale University 7
Kansas, U of 26 Columbus NCORP 6
Cleveland Clinic OH 25 Rochester, Univ of 6
Los Angeles, U of CA 24 San Diego, U of CA 6
Georgia NCORP 21 Tennessee, U of 6
Northwestern Univ 19 Arkansas, U of 5
PCRC NCORP 17 Sutter Cancer RC 5
CRC West MI NCORP 15 UF Cancer Center/Arkansas, U of 5
Michigan, U of 13 Cincinnati MC, U of 4
Wichita NCORP 13 Gulf South MU-NCORP 4
Baylor Univ Med Ctr 12 Montana NCORP 4
Oregon Hlth Sci Univ 12 Ozarks NCORP 4
Arizona MC, U of 11 All Other SWOG Institutions 22
Mt Sinai Med Ctr 11 ECOG-ACRIN 323
Northwest NCORP 11 ALLIANCE 150
CORA NCORP 10 CCTG 130
New Mexico MU-NCORP 10 NRG 113
Southeast COR NCORP 10 Total (61 Institutions) 1426
Wayne State Univ 10
Registration, Eligibility, and Evaluability
Initial Registration
Data as of January 24, 2019
Tissue for PD-L1
testing
NUMBER REGISTERED 1426
INELIGIBLE 63
ELIGIBLE 1363
Analyzable, Pend. Elig. 18
APRIL 24 - 27, 2019 SWOG MELANOMA 23
S1404/III
Registration by Institution
Randomization
Institutions
Total
Reg Institutions
Total
Reg
Kaiser Perm NCORP 74 Wayne State Univ 9
H Lee Moffitt CC 52 Cedars-Sinai Med Ctr 8
MD Anderson CC 43 City of Hope Med Ctr 8
Ohio State Univ 33 Michigan CRC NCORP 8
Utah, U of 31 Wisconsin NCORP 8
Colorado, U of 29 Dayton NCORP 7
Heartland NCORP 27 TX Oncology-Central/San Antonio, U of TX 7
Cleveland Clinic OH 25 Rochester, Univ of 6
Kansas, U of 25 San Diego, U of CA 6
Los Angeles, U of CA 23 Tennessee, U of 6
Georgia NCORP 20 Yale University 6
PCRC NCORP 17 Arkansas, U of 5
Northwestern Univ 16 Sutter Cancer RC 5
CRC West MI NCORP 13 UF Cancer Center/Arkansas, U of 5
Wichita NCORP 13 Columbus NCORP 4
Baylor Univ Med Ctr 12 Gulf South MU-NCORP 4
Michigan, U of 12 Montana NCORP 4
Oregon Hlth Sci Univ 12 Ozarks NCORP 4
Arizona MC, U of 11 All Other SWOG Institutions 24
Northwest NCORP 11 ECOG-ACRIN 302
Mt Sinai Med Ctr 10 ALLIANCE 144
Southeast COR NCORP 10 CCTG 122
CORA NCORP 9 NRG 106
New Mexico MU-NCORP 9 Total (60 Institutions) 1345
Registration, Eligibility, and Evaluability
Randomization
Data as of January 24, 2019
TOTAL
FDA approved
regimen
MK-3475
(Pembrolizumab)
NUMBER REGISTERED 1345 678 667
INELIGIBLE 37 20 17
ELIGIBLE 1308 658 650
ADVERSE EVENT ASSESSMENT
Evaluable 1211 569 642
Not Evaluable 97 89 8
APRIL 24 - 27, 2019 SWOG MELANOMA 24
S1404/III
Patient Characteristics
Randomization
Data as of January 24, 2019
FDA approved
regimen
(n=658)
MK-3475
(Pembrolizumab)
(n=650)
AGE
Median 57.0 56.1
Minimum 18.3 20.0
Maximum 86.0 82.6
SEX
Males 398 60% 383 59%
Females 260 40% 267 41%
HISPANIC
Yes 18 3% 26 4%
No 621 94% 607 93%
Unknown 19 3% 17 3%
RACE
White 625 95% 623 96%
Black 5 1% 2 0%
Asian 6 1% 4 1%
Pacific Islander 1 0% 0 0%
Native American 0 0% 2 0%
Multi-Racial 3 0% 0 0%
Unknown 18 3% 19 3%
STAGE
IIIA 68 10% 76 12%
IIIB 327 50% 312 48%
IIIC 223 34% 221 34%
IV 40 6% 41 6%
PLANNED CONTROL-ARM REGIMEN
High Dose Interferon 157 25% 153 25%
Ipilimumab 466 75% 457 75%
PERFORMANCE STATUS
0 550 84% 544 84%
1 108 16% 106 16%
APRIL 24 - 27, 2019 SWOG MELANOMA 25
S1404/III
Treatment Summary
Randomization
Data as of January 24, 2019
Total
NUMBER ON PROTOCOL TREATMENT 36
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
1272
Treatment completed as planned 399
Adverse Event or side effects 466
Refusal unrelated to adverse event 139
Other - not protocol specified 37
Reason under review 1
MAJOR PROTOCOL DEVIATIONS 97
Number of Patients with a Given Type and Grade of Adverse Event
Randomization
Adverse Events Unlikely or Not Related to Treatment Excluded
Adverse Events with No Entries for Grades 3 to 5 or Unknown Have Been Suppressed
Data as of January 24, 2019
FDA approved
regimen
(n=569)
Grade
MK-3475 (Pembrolizumab)
(n=642)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
ALT increased 524 39 6 0 623 19 0 0
AST increased 535 30 4 0 629 13 0 0
Abdominal pain 563 6 0 0 640 2 0 0
Acidosis 568 1 0 0 640 1 1 0
Acute kidney injury 567 2 0 0 640 2 0 0
Adrenal insufficiency 560 8 1 0 638 4 0 0
Alkaline phosphatase increased 567 2 0 0 642 0 0 0
Anemia 568 1 0 0 641 1 0 0
Anorexia 565 4 0 0 641 1 0 0
Anxiety 567 2 0 0 642 0 0 0
Arthralgia 567 2 0 0 639 3 0 0
Arthritis 568 1 0 0 642 0 0 0
Atelectasis 568 1 0 0 642 0 0 0
Atrial fibrillation 568 1 0 0 642 0 0 0
Atrial flutter 569 0 0 0 641 1 0 0
Autoimmune disorder 567 0 2 0 641 1 0 0
Back pain 566 3 0 0 642 0 0 0
Blood bilirubin increased 567 2 0 0 640 1 1 0
Blood/lymph disorder-Other 568 1 0 0 642 0 0 0
Blurred vision 568 1 0 0 642 0 0 0
Bone pain 568 1 0 0 642 0 0 0
Bronchospasm 569 0 0 0 641 0 1 0
CPK increased 564 3 2 0 640 1 1 0
APRIL 24 - 27, 2019 SWOG MELANOMA 26
S1404/III
FDA approved
regimen
(n=569)
Grade
MK-3475 (Pembrolizumab)
(n=642)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
Cardiac disorder-Other, spec 568 1 0 0 642 0 0 0
Cardiac troponin T increased 568 1 0 0 642 0 0 0
Colitis 536 31 2 0 629 13 0 0
Colonic perforation 568 0 1 0 642 0 0 0
Confusion 567 2 0 0 641 1 0 0
Cough 568 1 0 0 641 1 0 0
Creatinine increased 567 1 1 0 642 0 0 0
Cystitis noninfective 568 1 0 0 642 0 0 0
Dehydration 566 3 0 0 641 1 0 0
Delirium 568 1 0 0 642 0 0 0
Depression 565 4 0 0 642 0 0 0
Diarrhea 515 53 1 0 624 18 0 0
Dizziness 568 1 0 0 642 0 0 0
Duodenal ulcer 568 1 0 0 642 0 0 0
Dyspepsia 568 1 0 0 642 0 0 0
Dyspnea 557 11 1 0 638 3 1 0
Encephalitis infection 567 1 1 0 642 0 0 0
Encephalopathy 568 1 0 0 642 0 0 0
Endocrine disorders-Other 565 4 0 0 639 2 1 0
Enterocolitis 563 5 0 1 641 1 0 0
Enterocolitis infectious 567 2 0 0 641 1 0 0
Erectile dysfunction 568 1 0 0 642 0 0 0
Esophagitis 568 1 0 0 642 0 0 0
Eye disorders - Other, specify 568 1 0 0 641 0 1 0
Eye pain 569 0 0 0 641 1 0 0
FEV1 decreased 569 0 0 0 641 1 0 0
Facial nerve disorder 569 0 0 0 641 1 0 0
Fall 568 1 0 0 642 0 0 0
Fatigue 541 28 0 0 639 3 0 0
Febrile neutropenia 567 1 1 0 642 0 0 0
Flu like symptoms 568 1 0 0 641 1 0 0
GI disorders-Other, specify 566 3 0 0 642 0 0 0
Gastritis 567 2 0 0 642 0 0 0
Gen disorders/admin site cond 568 1 0 0 641 1 0 0
Generalized muscle weakness 566 3 0 0 641 1 0 0
Headache 556 13 0 0 639 3 0 0
Hepatic pain 569 0 0 0 641 1 0 0
Hepatitis viral 567 2 0 0 642 0 0 0
Hepatobil disorders-Other 568 1 0 0 642 0 0 0
Hiccups 569 0 0 0 641 1 0 0
Hyperglycemia 564 5 0 0 635 3 4 0
Hypersomnia 568 1 0 0 642 0 0 0
Hypertension 562 7 0 0 640 2 0 0
Hyperthyroidism 568 0 1 0 641 1 0 0
Hypertriglyceridemia 561 6 2 0 641 1 0 0
Hypoalbuminemia 568 1 0 0 642 0 0 0
Hypokalemia 567 2 0 0 642 0 0 0
Hyponatremia 554 11 4 0 633 9 0 0
Hypophosphatemia 566 3 0 0 639 3 0 0
Hypotension 566 3 0 0 642 0 0 0
APRIL 24 - 27, 2019 SWOG MELANOMA 27
S1404/III
FDA approved
regimen
(n=569)
Grade
MK-3475 (Pembrolizumab)
(n=642)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
Hypothyroidism 566 3 0 0 642 0 0 0
Hypoxia 566 3 0 0 640 2 0 0
Immune sys disorders-Other 568 1 0 0 640 2 0 0
Infections/infestations-Other 568 1 0 0 642 0 0 0
Infusion related reaction 568 1 0 0 641 1 0 0
Insomnia 568 1 0 0 642 0 0 0
Joint effusion 569 0 0 0 641 1 0 0
Leukocytosis 568 1 0 0 642 0 0 0
Lipase increased 564 4 1 0 641 1 0 0
Lower GI hemorrhage 568 1 0 0 642 0 0 0
Lung infection 568 1 0 0 638 4 0 0
Lymphocyte count decreased 557 11 1 0 640 2 0 0
MS/connective tissue disorder 568 1 0 0 640 2 0 0
Meningitis 566 3 0 0 642 0 0 0
Metab/nutrition disorders-Oth 567 2 0 0 641 0 1 0
Mucositis oral 569 0 0 0 640 2 0 0
Muscle weakness lower limb 568 1 0 0 642 0 0 0
Myalgia 565 4 0 0 641 1 0 0
Myocardial infarction 569 0 0 0 641 1 0 0
Myocarditis 569 0 0 0 641 0 0 1
Myositis 568 1 0 0 641 1 0 0
Nausea 559 10 0 0 641 1 0 0
Neoplasms, all 569 0 0 0 641 0 0 1
Nervous sys disorders-Other 565 3 1 0 640 1 1 0
Neuralgia 567 2 0 0 642 0 0 0
Neutrophil count decreased 519 43 7 0 640 2 0 0
Pain 568 1 0 0 642 0 0 0
Pain in extremity 567 2 0 0 642 0 0 0
Pain of skin 569 0 0 0 641 1 0 0
Pancreatitis 566 2 1 0 637 5 0 0
Papulopustular rash 568 1 0 0 642 0 0 0
Peripheral motor neuropathy 568 1 0 0 642 0 0 0
Peripheral sensory neuropathy 568 0 1 0 642 0 0 0
Pharyngitis 568 1 0 0 642 0 0 0
Pleural effusion 568 1 0 0 642 0 0 0
Pneumonitis 563 6 0 0 637 5 0 0
Proctitis 569 0 0 0 641 1 0 0
Proteinuria 569 0 0 0 641 1 0 0
Pruritus 562 7 0 0 642 0 0 0
Rash acneiform 569 0 0 0 640 2 0 0
Rash maculo-papular 538 31 0 0 633 9 0 0
Rash pustular 568 1 0 0 642 0 0 0
Resp/thoracic/mediastinal ds 569 0 0 0 641 1 0 0
Respiratory failure 567 0 1 1 642 0 0 0
Restrictive cardiomyopathy 568 1 0 0 642 0 0 0
Secondary Leukemia 569 0 0 0 641 0 0 1
Seizure 569 0 0 0 641 1 0 0
Sepsis 567 0 2 0 641 0 1 0
Serum amylase increased 568 1 0 0 641 1 0 0
Sinus tachycardia 567 2 0 0 642 0 0 0
APRIL 24 - 27, 2019 SWOG MELANOMA 28
S1404/III
FDA approved
regimen
(n=569)
Grade
MK-3475 (Pembrolizumab)
(n=642)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
Sinusitis 569 0 0 0 641 1 0 0
Skin infection 568 1 0 0 641 1 0 0
Skin/subq tissue ds-Other 567 2 0 0 640 2 0 0
Syncope 563 6 0 0 641 1 0 0
Tremor 569 0 0 0 641 1 0 0
Vomiting 561 8 0 0 641 1 0 0
Weight loss 567 2 0 0 642 0 0 0
Wheezing 569 0 0 0 641 0 1 0
White blood cell decreased 550 17 2 0 642 0 0 0
MAX. GRADE ANY ADVERSE EVENT 259 272 36 2 519 109 12 2
APRIL 24 - 27, 2019 SWOG MELANOMA 29
S1512/II
S1512 Phase II
Coordinating Group: SWOG
A Phase II and Pilot Trial of PD-1 Blockade with MK-3475 (Pembrolizumab)
in Patients with Resectable or Unresectable Desmoplastic Melanoma (DM)
Participants:
SWOG, CTSU (Supported by ECOG-ACRIN)
Study Chairs:
K Kendra, S Hu-Lieskovan, A Cochran (ECOG-
ACRIN)
Statisticians:
M Wu, J Moon
Data Coordinator:
V Kim
Date Activated:
10/20/2016
Objectives This study will enroll two separate cohorts to assess
the efficacy of MK-3475 (pembrolizumab) in
desmoplastic melanoma (DM). Cohort A will
evaluate MK-3475 (pembrolizumab) as neoadjuvant
therapy for patients with DM that is deemed
resectable by the treating investigator; including
primary DM, locally advanced DM, and locally
recurrent DM. Cohort B will be a pilot study to
evaluate the use of MK-3475 (pembrolizumab) for
patients with DM that is deemed unresectable by the
treating investigator, including metastatic DM.
Cohort A
To evaluate the pathologic complete response rate in
patients with resectable desmoplastic melanoma
treated with neoadjuvant MK-3475 (pembrolizumab).
To estimate the nine week response rate
(unconfirmed complete and partial responses).
To estimate the median overall survival.
To evaluate safety and tolerability of MK-3475
(pembrolizumab) in the neoadjuvant setting.
Cohort B
To evaluate the complete response rate (confirmed
and unconfirmed) in patients with unresectable
desmoplastic melanoma treated with MK-3475
(pembrolizumab).
To estimate the median progression-free survival.
To estimate the median overall survival.
To evaluate safety and tolerability of MK-3475
(pembrolizumab) in this setting.
Patient Population
Patients must have histologically or cytologically
confirmed primary desmoplastic melanoma. Patients
with disease that, in the judgment of the surgeon is
deemed completely resectable resulting in free
surgical margins, are eligible for Cohort A. Patients
APRIL 24 - 27, 2019 SWOG MELANOMA 30
S1512/II
with unresectable disease are eligible for Cohort B.
Patients must not have known brain metastases unless
brain metastases have been treated and patient is
asymptomatic with no residual neurological
dysfunction without receiving enzyme-reducing anti-
epileptic drugs or corticosteroids. Patients enrolled on
Cohort A may have only non-measurable disease
provided it can be confirmed with a fine needle
aspiration. Patients enrolled on Cohort B must have
measurable disease
Patients must not have received prior systemic
therapy for desmoplastic melanoma. Patients must
not have received radiation therapy, non-cytotoxic
agents or investigational agents or systemic
corticosteroids within 14 days prior to registration.
Patients may have received prior surgery.
Patients must have adequate hematologic and hepatic
function with a Zubrod performance status of 0-2.
Patients must not have known, active non-infectious
pneumonitis, an active infection requiring systemic
therapy, or an active autoimmune disease that has
required systemic treatment in the past two years.
Patients must not have received live vaccines within
42 days prior to registration. Patients known to be
HIV positive must have stable and adequate CD4
counts, a serum viral load below 52,000 IU/ml and
must be on stable anti-viral therapy. Women of
childbearing potential must have a negative urine or
serum pregnancy test within 28 days prior to
registration.
Stratification/Descriptive Factors Patients will be stratified by Cohort: A (resectable) vs
B (unresectable).
Accrual Goals Accrual to this study will proceed in two independent
cohorts: A and B.
Cohort A will accrue approximately 51 patients to
achieve 41 eligible patients. Initially, 21 eligible
patients will be enrolled. If two or more pathologic
complete responses are observed, an additional 20
eligible patients will be enrolled.
Cohort B will accrue approximately 26 patients to
achieve 21 eligible patients.
Summary Statement In an effort to improve accrual, this study was
amended to allow patients with only non-measurable
disease to be enrolled on Cohort A (resectable
disease) provided that residual disease can be
confirmed with a fine-needle aspiration. Patients
enrolled on Cohort B (unresectable disease) must still
have measurable disease.
As of December 31, 2018, 18 patients have been
registered, eight to Cohort A and ten to Cohort B.
One patient withdrew consent prior to receiving any
protocol treatment and is not analyzable for any of
the study endpoints.
Sixteen patients have been assessed for adverse
events. No treatment-related adverse events greater
than Grade 3 have been reported.
Registration by Institution
Registrations ending December 31, 2018
Institutions Total Reg
H Lee Moffitt CC 6
Ohio State Univ 4
Los Angeles, U of CA 3
So Calif, U of 2
Georgia NCORP 1
Kansas, U of 1
Southeast COR NCORP 1
Total (7 Institutions) 18
APRIL 24 - 27, 2019 SWOG MELANOMA 31
S1512/II
Registration, Eligibility, and Evaluability
Classified by Cohort
Registrations ending December 31, 2018; Data as of January 7, 2019
TOTAL
Resectable
(Cohort A)
Unresectable
(Cohort B)
NUMBER REGISTERED 18 8 10
ELIGIBLE 18 8 10
Analyzable, Pend. Elig. 7 1 6
Not Analyzable 1 1 0
BASELINE DISEASE STATUS
Measurable 11 6 5
Too Early 6 1 5
RESPONSE ASSESSMENT
Determinable 8 5 3
Too Early 9 2 7
ADVERSE EVENT ASSESSMENT
Evaluable 16 7 9
Too Early 1 0 1
Patient Characteristics
Classified by Cohort
Registrations ending December 31, 2018; Data as of January 7, 2019
Resectable
(Cohort A)
(n=7)
Unresectable
(Cohort B)
(n=10)
AGE
Median 80.8 82.0
Minimum 49.2 70.0
Maximum 85.8 89.6
SEX
Males 6 86% 10 100%
Females 1 14% 0 0%
HISPANIC
No 7 100% 10 100%
RACE
White 7 100% 10 100%
PERFORMANCE STATUS
0 5 71% 6 60%
1 2 29% 4 40%
APRIL 24 - 27, 2019 SWOG MELANOMA 32
S1512/II
Number of Patients with a Given Type and Grade of Adverse Event
Classified by Cohort
Adverse Events Unlikely or Not Related to Treatment Excluded
Registrations ending December 31, 2018; Data as of January 7, 2019
Resectable
(Cohort A)
(n=7)
Grade
Unresectable
(Cohort B)
(n=9)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
ALT increased 7 0 0 0 9 0 0 0
Alkaline phosphatase increased 7 0 0 0 9 0 0 0
Anemia 7 0 0 0 9 0 0 0
Anorexia 7 0 0 0 9 0 0 0
Arthralgia 7 0 0 0 9 0 0 0
Bullous dermatitis 7 0 0 0 9 0 0 0
Constipation 7 0 0 0 9 0 0 0
Diarrhea 7 0 0 0 9 0 0 0
Dyspnea 7 0 0 0 8 1 0 0
Fatigue 7 0 0 0 9 0 0 0
Fever 7 0 0 0 9 0 0 0
Generalized muscle weakness 7 0 0 0 9 0 0 0
Hypercalcemia 7 0 0 0 9 0 0 0
Hyperkalemia 7 0 0 0 9 0 0 0
Hypernatremia 7 0 0 0 9 0 0 0
Hypertension 7 0 0 0 9 0 0 0
Hyperthyroidism 7 0 0 0 9 0 0 0
Hypoalbuminemia 7 0 0 0 9 0 0 0
Hypokalemia 7 0 0 0 9 0 0 0
Hyponatremia 7 0 0 0 9 0 0 0
Hypothyroidism 7 0 0 0 9 0 0 0
Hypoxia 7 0 0 0 8 1 0 0
Lymphocyte count decreased 7 0 0 0 9 0 0 0
Nausea 7 0 0 0 9 0 0 0
Platelet count decreased 7 0 0 0 9 0 0 0
Pneumonitis 7 0 0 0 9 0 0 0
Pruritus 7 0 0 0 9 0 0 0
Rash maculo-papular 7 0 0 0 8 1 0 0
Skin/subq tissue ds-Other 7 0 0 0 9 0 0 0
Tremor 7 0 0 0 9 0 0 0
MAX. GRADE ANY ADVERSE EVENT 7 0 0 0 7 2 0 0
APRIL 24 - 27, 2019 SWOG MELANOMA 33
S1607/II
S1607 Phase II
Coordinating Group: SWOG
A Phase II Study of Combining Talimogene Laherparepvec (T-VEC) (NSC-
785349) and MK-3475 (Pembrolizumab) (NSC-776864) in Patients with
Advanced Melanoma Who Have Progressed on Anti-PD/L1 Based Therapy
Participants:
SWOG, CTSU
Study Chairs:
S Hu-Lieskovan, A Ribas
Statisticians:
M Wu, J Moon
Data Coordinator:
V Kim
Date Activated:
10/02/2017
Objectives To evaluate the durable response rate of treatment
with talimogene laherparepvec (T-VEC) in
combination with MK-3475 (pembrolizumab)
following progression on prior anti-PD-1 or anti-PD-
L1 therapy alone or in combination with other agents
different from talimogene laherparepvec (T-VEC).
To estimate the response rate (confirmed and
unconfirmed, complete and partial responses) in the
injected lesions.
To estimate the response rate in the non-visceral,
non-injected lesions.
To estimate the response rate in the visceral lesions.
To estimate the overall objective response rate per
RECIST 1.1, progression-free survival, and overall
survival within each cohort.
To evaluate whether adding talimogene
laherparepvec (T-VEC) to PD1 blockade can increase
T-cell infiltration into tumors and whether change in
T-cell infiltration is associated with response.
To evaluate whether adding talimogene
laherparepvec (T-VEC) to PD1 blockade can increase
TCR clonality in tumors and in peripheral blood and
whether increased TCR clonality is associated with
response.
To evaluate whether intra-tumoral injection of
talimogene laherparepvec (T-VEC) is associated with
the tumor immune microenvironment.
To evaluate whether tumor mutational load and
mutations in the IFN pathway is associated with
response to talimogene laherparepvec (T-VEC) plus
MK-3475 (pembrolizumab) therapy in the anti-
PD1/L1 therapy refractory melanoma patients.
Patient Population Patients must have pathologically confirmed Stage
IV or unresectable Stage III melanoma with
cutaneous, mucosal or unknown primary. Patients
with uveal primary are not eligible. Patients will be
enrolled onto one of two independent cohorts: for
Cohort A, patients must have at least one measurable
visceral lesion, defined as any solid organ except for
APRIL 24 - 27, 2019 SWOG MELANOMA 34
S1607/II
skin, lymph node, or musculoskeletal tissue; for
Cohort B, patients must have at least one measurable
non-visceral lesion and no evidence of visceral
disease. Patients must not have known active central
nervous system (CNS) metastases. Patients with a
history of CNS metastases must have been
adequately treated with no evidence of progression
for at least 28 days prior to registration and must be
asymptomatic without requiring steroids for at least
14 days prior to registration. Patients must, in the
opinion of the treating investigator, be candidates for
intralesional administration into cutaneous,
subcutaneous, or nodal lesions. Patients must have at
least two injectable lesions.
Patient must have had prior treatment with anti-PD-1
or anti-PD-L1 agents and have documented disease
progression on these agents prior to registration.
Patient must have received anti-PD-1 or PD-L1 based
therapy as the immediate previous line of treatment
and within 56 days prior to registration. Patients must
not have had surgery, chemotherapy, biologic
therapy, hormonal therapy, or radiation therapy
within 14 days prior to registration. Patients must not
have had an investigational agent or monoclonal
antibodies, except anti-PD1/L1 antibodies, within 28
days prior to registration. Patients must not have
received prior treatment with talimogene
laherparepvec (T-VEC) or other oncolytic virus
agents. Patients must not have had any infectious
disease vaccination within seven days prior to
registration.
Patients must have adequate hematologic, hepatic,
and renal function and a Zubrod performance status
of 0-2. Patients must not have severe autoimmune
disease requiring systemic corticosteroids or ongoing
immunosuppression. Patients must not have a known
history of HIV, hepatitis B, or hepatitis C, or
pneumonitis. Patients must not have an active
infection requiring systemic therapy nor a viral-
infection requiring intermittent treatment with an
antiherpatic drug, and must not have active herpatic
skin lesions or prior complications of herpatic
infection which require treatment with an anti-
herpatic drug. Patients must not have organ
allografts, or a history of autoimmune disease, or
clinically significant immunosuppression. Women of
reproductive potential must have a negative serum
pregnancy test within seven days prior to registration.
Patients must have tissue available and must be
willing to submit blood and tissue specimens for the
translational medicine objectives. Patients must be
offered the opportunity to participate in specimen
banking.
Stratification/Descriptive Factors Patients will be stratified based on presence of
visceral lesions: one or more vs none.
Accrual Goals The study will accrue to two independent cohorts.
Cohort A, patients with at least one visceral lesion,
will use a two-stage design. Initially 18 patients will
be enrolled. If at least one response is observed, then
an additional 14 patients will be enrolled for a total of
32 patients.
Cohort B, patients with no visceral lesions, will use a
modified two-stage design. Initially 16 patients will
be enrolled. If two or more durable responses are
observed, then an additional nine patients will be
enrolled for a total of 25 patients.
Summary Statement As of December 31, 2018, eight patients have been
registered, two to the cohort with at least one visceral
lesion and six to the cohort with non-visceral disease
only.
Seven patients have been evaluated for adverse
events. So far, no Grade 4-5 adverse events have
been reported.
APRIL 24 - 27, 2019 SWOG MELANOMA 35
S1607/II
Registration by Institution
Registrations ending December 31, 2018
Institutions Total Reg
Los Angeles, U of CA 5
Ohio State Univ 1
So Calif, U of 1
ECOG-ACRIN 1
Total (4 Institutions) 8
Registration, Eligibility, and Evaluability
Classified by Cohort
Registrations ending December 31, 2018; Data as of January 16, 2019
TOTAL
Visceral
(Cohort A)
Non-Visceral
(Cohort B)
NUMBER REGISTERED 8 2 6
ELIGIBLE 8 2 6
Analyzable, Pend. Elig. 5 0 5
RESPONSE ASSESSMENT
Determinable 3 1 2
Too Early 5 1 4
ADVERSE EVENT ASSESSMENT
Evaluable 7 2 5
Too Early 1 0 1
APRIL 24 - 27, 2019 SWOG MELANOMA 36
S1607/II
Patient Characteristics
Classified by Cohort
Registrations ending December 31, 2018; Data as of January 16, 2019
Visceral
(Cohort A)
(n=2)
Non-Visceral
(Cohort B)
(n=6)
AGE
Median 47.7 73.8
Minimum 35.4 37.8
Maximum 60.0 93.7
SEX
Males 1 50% 1 17%
Females 1 50% 5 83%
HISPANIC
Yes 1 50% 0 0%
No 1 50% 6 100%
RACE
White 1 50% 6 100%
Unknown 1 50% 0 0%
PERFORMANCE STATUS
0 1 50% 4 67%
1 1 50% 1 17%
2 0 0% 1 17%
APRIL 24 - 27, 2019 SWOG MELANOMA 37
S1607/II
Number of Patients with a Given Type and Grade of Adverse Event
Classified by Cohort
Adverse Events Unlikely or Not Related to Treatment Excluded
Registrations ending December 31, 2018; Data as of January 16, 2019
Visceral
(Cohort A)
(n=2)
Grade
Non-Visceral
(Cohort B)
(n=5)
Grade
ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5
Chills 2 0 0 0 0 0 4 0 1 0 0 0
Dyspnea 2 0 0 0 0 0 4 0 0 1 0 0
Fever 2 0 0 0 0 0 4 0 1 0 0 0
Flu like symptoms 1 0 0 1 0 0 4 0 1 0 0 0
Hot flashes 1 1 0 0 0 0 5 0 0 0 0 0
Hyponatremia 2 0 0 0 0 0 4 0 0 1 0 0
Hypoxia 2 0 0 0 0 0 4 0 0 1 0 0
Injection site reaction 1 0 1 0 0 0 5 0 0 0 0 0
Pruritus 2 0 0 0 0 0 4 0 1 0 0 0
Rash maculo-papular 2 0 0 0 0 0 4 1 0 0 0 0
Sinus tachycardia 2 0 0 0 0 0 4 0 1 0 0 0
Skin infection 2 0 0 0 0 0 4 0 1 0 0 0
Tumor pain 2 0 0 0 0 0 4 0 0 1 0 0
MAX. GRADE ANY ADVERSE EVENT 1 0 0 1 0 0 2 0 2 1 0 0
APRIL 24 - 27, 2019 SWOG MELANOMA 38
S1609/II
S1609 Phase II
Coordinating Group: SWOG
DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors
Participants:
SWOG, CTSU
Study Chairs:
S Patel, Y Chae
Statisticians:
M Othus, M Plets, E Mayerson
Data Coordinators:
C McLeod, J Hayward
Date Activated:
01/13/2017
Objectives To evaluate the RECIST 1.1 overall response rate
(ORR) in subsets of patients with advanced rare
cancers treated with ipilimumab plus nivolumab
combination immunotherapy.
To evaluate toxicities in each cohort.
To estimate overall survival (OS), progression-free
survival (PFS), clinical benefit rate; and to estimate
immune-related ORR (irORR), and immune-related
PFS (irPFS) by unidimensional immune-related
response criteria.
To collect specimens for banking for use in future
correlative biomarker research studies.
Patient Population Patients must have histologically confirmed rare
cancer and/or cancer of unknown primary specified
on the list of eligible rare cancer histologic cohorts in
the S1609 protocol. Patients who do not qualify for
one of the histologic cohorts may be considered for
registration in the "Not Otherwise Categorized"
(NOC) cohort with confirmation by one of the study
chairs. As of September 11, 2017, patients are no
longer required to have been enrolled in EAY131
(NCI-MATCH) to be eligible for this study.
Patients must have measurable disease and have
progressed following at least one line of standard
systemic therapy and there must not be other
approved/standard therapy available that has been
shown to prolong overall survival. Patients are also
eligible if no standard treatment exists that has been
shown to prolong overall survival. Patients must not
have received either prior anti-CTLA4, anti-PD-1, or
anti-PD-L1 therapy. Other immunotherapy is
permitted, provided that it is completed at least seven
days prior to registration. Patients who had a prior
immune-related adverse event with prior
immunotherapy are not eligible. Patients with brain
metastases or primary brain tumors must have
completed treatment, surgery or radiation therapy ≥
28 days prior to registration and have stable disease
at time of registration. Patients with metastatic brain
parenchymal disease must have been treated and off
steroids for seven days prior to registration. Patients
must have been off all other systemic anti-cancer
therapy at least seven days prior to registration and
any therapy-induced toxicity must have recovered to
≤ Grade 1.
APRIL 24 - 27, 2019 SWOG MELANOMA 39
S1609/II
Patients must have a Zubrod performance status of 0-
2 and have adequate hematologic, hepatic, renal,
thyroid, and adrenal axis function. Patients must not
have active autoimmune disease that has required
systemic treatment in the past two years or any
uncontrolled intercurrent illness. Patients must not
have known active Hepatitis B Virus (HBV) or
Hepatitis C Virus (HCV) infection at time of
registration. Patients with HBV or HCV that have an
undetectable viral load, or in the opinion of the
treating investigator is well controlled, are eligible.
Patients who are known to be HIV-positive at
registration are eligible if they meet the conditions
outlined in the protocol.
Stratification/Descriptive Factors Patients will be described by histologic cohorts.
Accrual Goals The accrual goal for this study is 707 patients to
achieve 636 eligible patients. A two-stage design will
be used for all cohorts, with the exception of the
NOC and "Cancer of Unknown Primary" (CuP)
cohorts. Initially, six eligible patients will be
registered to each histologic cohort. If at least one
response is observed within a cohort, an additional 10
eligible patients will be registered to that cohort. Up
to 16 eligible patients will be registered to the CuP
cohort with no formal first stage response
assessment. Up to 60 eligible patients will be enrolled
to the NOC cohort, and data may be used to open
additional cohorts.
Summary Statement For the current status of this study, please refer to the
Early Therapeutics and Rare Cancers chapter.
APRIL 24 - 27, 2019 SWOG MELANOMA 40
S1614/III
S1614 Phase III
Coordinating Group: SWOG
A Phase III Randomized Trial of Prophylactic Antiviral Therapy in Patients
with Current or Past Hepatitis B Virus (HBV) Infection Receiving Anti-
Cancer Therapy for Solid Tumors
Participants:
SWOG, CTSU (Supported by ECOG-ACRIN)
Study Chairs:
J Hwang, A Lok, E Mitchell (ECOG-ACRIN)
Statisticians:
J Unger, E Mayerson
Data Coordinator:
K Carvalho
Date Activated:
02/21/2019
SCHEMA
Cohort 1:
Chronic HBV
Prophylactic
Antiviral Therapy
Upon Indication
Antiviral Therapy
Usual Care
Antiviral Therapy
Upon Indication
Antiviral Therapy
Cohort 2:
Past HBV
R
A
N
D
O
M
I
Z
A
T
I
O
N
R
A
N
D
O
M
I
Z
A
T
I
O
N
APRIL 24 - 27, 2019 SWOG MELANOMA 41
S1614/III
Objectives Co-primary objectives:
To compare the effect of prophylactic tenofovir
alafenamide (TAF) therapy versus upon indication
TAF therapy on time-to-adverse liver outcomes of
liver failure or liver-related death in patients with
chronic HBV infection (HBsAg+ and anti-HBc+)
receiving anti-cancer therapy for solid tumors.
To compare the effect of upon indication TAF
therapy versus usual care on time-to-adverse liver
outcomes of liver failure or liver-related death in
patients with past HBV infection (HBsAg- and anti-
HBc+) receiving anti-cancer therapy for solid tumors.
Secondary objectives:
Using time-to-event analysis, to compare the effect of
TAF therapy versus upon indication TAF therapy on
HBV reactivation, on the combined endpoint of
adverse liver outcomes (liver failure or liver-related
death) and HBV reactivation, and on HBV flare by
arm in patients with chronic HBV infection receiving
anti-cancer therapy for solid tumors.
Using time-to-event analysis, to compare the effect of
upon indication TAF therapy versus usual care on
HBV reactivation, on the combined endpoint of
adverse liver outcomes (liver failure or liver-related
death) and HBV reactivation, and on HBV flare by
arm in patients with past HBV infection receiving
anti-cancer therapy for solid tumors.
Patient Population Patients must be diagnosed with Stage I-III solid
tumor malignancy not involving the liver. Patients
must have HBV infection as indicated through
positive HBsAG or anti-HBc tests. Patients must not
have lymphoma, leukemia, or myeloma. Patients
must not have primary liver cancer or evidence of
any malignancy that involves the liver.
Patients must be planning to receive a new regimen
of systemic anti-cancer therapy for their solid tumor
malignancy and must have discontinued all previous
therapies. Patients must not have received anti-CD20
cancer therapy regimens nor had a hematopoietic
stem cell transplant. Patients must have discontinued
any antiviral medications active against HBV at least
90 days prior to registration, and discontinue any
contraindicated medications as identified in the
protocol at time of registration.
Patients must have a Zubrod performance status of 0-
2, and have adequate liver, renal, and coagulation
function. Patients must not have known cirrhosis,
known hepatitis-C infection, or history of human
immunodeficiency infection proven by an HIV test
within the past 365 days. Patients must have
complete results for HBsAg, anti-HBc, anti-HBs, and
HBV DNA lab tests as specified in the protocol.
Patients must be able to take oral medications.
Patients must be willing to submit specimens for
ongoing testing of HBV reactivation. Patients must
be offered the opportunity to participate in the
translational medicine studies.
Stratification/Descriptive Factors Patients with chronic HBV infection will be
randomized within Cohort 1, with randomization
stratified by planned cancer therapy type: any
cytotoxic therapy vs immunotherapy alone vs
targeted therapy alone vs immunotherapy and
targeted therapy.
Patients with past HBV infection will be randomized
within Cohort 2 with randomization stratified by the
following factors: (1) planned cancer therapy type:
any cytotoxic therapy vs immunotherapy alone vs
targeted therapy alone vs immunotherapy and
targeted therapy; and (2) anti-HBs status: positive vs
negative.
Accrual Goals The accrual goal for this study is 444 patients, 222
patients per cohort to achieve 200 eligible patients
per cohort. A single formal interim analysis for
efficacy for each cohort will be conducted when one
half of patients have reached one year of follow-up.
Summary Statement For the current status of this study, please refer to the
Symptom Control and QOL chapter.
APRIL 24 - 27, 2019 SWOG MELANOMA 42
S1616/II
S1616 Phase II
Coordinating Group: SWOG
A Phase II Randomized Study of Nivolumab (NSC-732442) with Ipilimumab
(NSC-748726) or Ipilimumab Alone in Advanced Melanoma Patients
Refractory to an Anti-PD-1 or Anti-PD-L1 Agent
Participants:
SWOG, CTSU
Study Chairs:
A VanderWalde, A Ribas
Statisticians:
M Wu, J Moon
Data Coordinator:
J Sanchez
Date Activated:
07/17/2017
SCHEMA
R
A
N
D
O
M
I
Z
A
T
I
O
N
Ipilimumab + Nivolumab
Note: For every one patient randomized to receive single agent ipilimumab,
three will be randomized to receive the combination of ipilimumab and
nivolumab
Ipilimumab
Nivolumab
APRIL 24 - 27, 2019 SWOG MELANOMA 43
S1616/II
Objectives To compare progression free survival (PFS) of
patients with advanced melanoma refractory to an
anti-PD-1 or anti-PD-L1 agent, treated with
combination therapy ipilimumab plus nivolumab
versus ipilimumab alone.
To estimate difference in T-cell infiltrate between on-
study biopsy samples of patients who respond to
combination therapy (including confirmed and
unconfirmed, complete and partial response per
RECIST 1.1) as compared to those who do not
respond.
To evaluate the objective response rate (ORR)
(confirmed and unconfirmed complete or partial
responses) in each treatment arm.
To evaluate overall survival in each treatment arm.
To evaluate the toxicity profile of patients in each
treatment arm.
Patient Population
Patients must have pathologically confirmed
melanoma that is either Stage IV or unresectable
Stage III. Patients may have primaries of cutaneous,
mucosal, or unknown origin. Patients with uveal
(ocular) primary are not eligible. Patients must have
measurable disease. If the only measurable disease is
cutaneous or subcutaneous, lesions must be at least
10 mm in greatest dimension and able to be serially
recorded using calipers and photographs. Patients
must not have central nervous system metastases
unless adequately treated and patient is asymptomatic
without requiring steroids for at least 14 days prior to
registration.
Patients must have had prior treatment with anti-PD-
1 or anti-PD-L1 agents and had documented disease
progression either while on these agents or after
stopping therapy with these agents without
intervening therapy. Patients must not have achieved
a confirmed partial or complete response to the anti-
PD-1 or anti-PD-L1 agents prior to progression.
Patients must not have had any systemic therapy
within 21 days prior to registration. Patients must not
have had prior radiation therapy within 14 days prior
to registration. Patients must not have had prior
treatment with ipilimumab or other CTLA-4
antagonists.
Patients must be at least 18 years of age and have a
Zubrod performance status of 0-2 with adequate
hepatic, renal, and hematologic function. Patients
with a known history of HIV must have an adequate
CD4 count. Patients must not have a known active
Hepatitis B, or Hepatitis C infection. Patients must
not have received systemic treatment with
corticosteroids or other immunosuppressive
medications within 14 days prior to registration.
Patients must not have organ allografts or a history of
immune-mediated pneumonitis or colitis that required
steroid treatment. Women of reproductive potential
must have a negative serum pregnancy test within
two days prior to registration.
Patients must be willing to undergo biopsies and
submit tissue and blood for the translational medicine
objectives.
Accrual Goals Patients will be randomized using a 3:1 ratio to
receive combination therapy ipilimumab and
nivolumab versus single therapy ipilimumab. In other
words, 63 patients will be randomized to receive the
combination regimen and 21 will be randomized to
receive the single agent regimen. Assuming an
ineligibility rate of 10% the total accrual goal is 94
patients to achieve 84 eligible patients.
Summary Statement As of December 31, 2018, 28 patients have been
registered. One patient is currently ineligible due to
not having received prior anti-PD1 or anti-PD-L1
therapy.
On the combination arm, 17 patients have been
assessed for adverse events. One patient has
experienced a treatment-related Grade 4 adverse
event, lymphopenia. On the single agent ipilimumab
arm, seven patients have been assessed for adverse
events. No treatment-related Grade 4 adverse events
have been reported on this arm.
APRIL 24 - 27, 2019 SWOG MELANOMA 44
S1616/II
Registration by Institution
Registrations ending December 31, 2018
Institutions
Total
Reg Institutions
Total
Reg
Los Angeles, U of CA 3 Kansas, U of 1
Ohio State Univ 3 Rochester, Univ of 1
Tennessee, U of 3 NRG 7
CRC West MI NCORP 2 ALLIANCE 4
New Mexico MU-NCORP 2 Total (10 Institutions) 28
Northwestern Univ 2
Registration, Eligibility, and Evaluability
Registrations ending December 31, 2018; Data as of January 16, 2019
TOTAL Ipilimumab
Nivolumab +
Ipilimumab
NUMBER REGISTERED 28 8 20
INELIGIBLE 1 1 0
ELIGIBLE 27 7 20
Analyzable, Pend. Elig. 4 0 4
RESPONSE ASSESSMENT
Determinable 19 6 13
Too Early 8 1 7
ADVERSE EVENT ASSESSMENT
Evaluable 24 7 17
Too Early 3 0 3
APRIL 24 - 27, 2019 SWOG MELANOMA 45
S1616/II
Patient Characteristics
Registrations ending December 31, 2018; Data as of January 16, 2019
Ipilimumab
(n=7)
Nivolumab +
Ipilimumab
(n=20)
AGE
Median 60.7 63.6
Minimum 50.7 46.0
Maximum 70.2 86.9
SEX
Males 3 43% 11 55%
Females 4 57% 9 45%
HISPANIC
Yes 1 14% 0 0%
No 6 86% 18 90%
Unknown 0 0% 2 10%
RACE
White 7 100% 16 80%
Asian 0 0% 2 10%
Unknown 0 0% 2 10%
PERFORMANCE STATUS
0 7 100% 11 55%
1 0 0% 7 35%
2 0 0% 1 5%
Data pending 0 0% 1 5%
Treatment Summary Registrations ending December 31, 2018; Data as of January 16, 2019
TOTAL
NUMBER ON PROTOCOL TREATMENT 11
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
16
Adverse Event or side effects 4
Refusal unrelated to adverse event 0
Other - not protocol specified 0
Reason under review 0
MAJOR PROTOCOL DEVIATIONS 0
LOST TO FOLLOW-UP 0
CONSENT WITHDRAWAL AFTER
TREATMENT INITIATION
0
APRIL 24 - 27, 2019 SWOG MELANOMA 46
S1616/II
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 2 to 5 Have Been Suppressed
Registrations ending December 31, 2018; Data as of January 16, 2019
Ipilimumab
(n=7)
Grade
Nivolumab + Ipilimumab
(n=17)
Grade
ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5
ALT increased 6 1 0 0 0 0 12 2 2 1 0 0
AST increased 6 1 0 0 0 0 14 2 0 1 0 0
Abdominal pain 6 0 1 0 0 0 15 2 0 0 0 0
Acute kidney injury 7 0 0 0 0 0 16 0 0 1 0 0
Adrenal insufficiency 6 0 1 0 0 0 16 0 0 1 0 0
Alkaline phosphatase increased 6 1 0 0 0 0 14 2 0 1 0 0
Anemia 7 0 0 0 0 0 16 0 0 1 0 0
Anorexia 6 0 1 0 0 0 13 1 2 1 0 0
Arthralgia 5 2 0 0 0 0 15 1 0 1 0 0
Autoimmune disorder 5 0 2 0 0 0 17 0 0 0 0 0
Dehydration 7 0 0 0 0 0 16 0 0 1 0 0
Diarrhea 6 1 0 0 0 0 12 2 1 2 0 0
Dyspnea 7 0 0 0 0 0 16 0 1 0 0 0
Endocrine disorders-Other 7 0 0 0 0 0 16 0 0 1 0 0
Fatigue 2 4 1 0 0 0 12 1 3 1 0 0
Fever 7 0 0 0 0 0 15 1 0 1 0 0
GERD 6 0 1 0 0 0 17 0 0 0 0 0
GI disorders-Other, specify 7 0 0 0 0 0 16 0 1 0 0 0
Headache 6 0 1 0 0 0 16 1 0 0 0 0
Hyperglycemia 6 1 0 0 0 0 14 2 1 0 0 0
Hypertension 7 0 0 0 0 0 15 0 2 0 0 0
Hypocalcemia 7 0 0 0 0 0 16 0 0 1 0 0
Hypokalemia 7 0 0 0 0 0 15 0 0 1 1 0
Hyponatremia 7 0 0 0 0 0 15 1 0 1 0 0
Hypotension 7 0 0 0 0 0 16 0 0 1 0 0
Hypothyroidism 6 0 1 0 0 0 16 1 0 0 0 0
Lung infection 7 0 0 0 0 0 16 0 0 1 0 0
Lymphocyte count decreased 7 0 0 0 0 0 15 0 1 0 1 0
Metab/nutrition disorders-Other 7 0 0 0 0 0 16 0 1 0 0 0
Nausea 5 2 0 0 0 0 16 0 0 1 0 0
Pruritus 6 1 0 0 0 0 9 5 2 1 0 0
Rash acneiform 7 0 0 0 0 0 15 1 1 0 0 0
Rash maculo-papular 5 1 0 1 0 0 11 3 2 1 0 0
Urinary incontinence 7 0 0 0 0 0 16 0 1 0 0 0
Weight loss 6 1 0 0 0 0 16 0 1 0 0 0
MAX. GRADE ANY ADVERSE EVENT 1 2 3 1 0 0 1 2 5 8 1 0
APRIL 24 - 27, 2019 SWOG MELANOMA 47
S1801/II
S1801 Phase II
Coordinating Group: SWOG
A Phase II Randomized Study of Adjuvant versus Neoadjuvant MK-3475
(Pembrolizumab) for Clinically Detectable Stage III-IV High Risk Melanoma
Participants:
SWOG, CTSU (Supported by ECOG-ACRIN)
Study Chairs:
S Patel, K Grossmann, E Buchbinder
Statisticians:
M Othus, J Moon
Data Coordinator:
V Kim
Date Activated:
12/06/2018
SCHEMA
Objectives To compare event-free survival (EFS) in patients
with high-risk resectable melanoma randomized to
neoadjuvant MK-3475 (pembrolizumab) with
patients randomized to adjuvant MK-3475
(pembrolizumab).
To assess the frequency and severity of toxicities on
each of the arms.
To compare between arms overall survival (OS),
disease control at 24 weeks, locoregional control in
the surgical site(s), and total number of MK-3475
(pembrolizumab) doses received.
On the neoadjuvant arm, to estimate the pathologic
response rate, the RECIST 1.1 response rate
(confirmed CR and PR), and the iRECIST response
rate (confirmed CR and PR), before surgical
resection.
To describe the proportion of patients on each arm
who received the surgery planned at randomization.
Patient Population Patients must have clinically detectable Stage III or
Stage IV resectable melanoma. Patients with
melanoma of mucosal or acral origin are eligible.
Patients with melanoma of uveal origin or with a
history of brain metastases documented by CT or
MRI within 42 days are not eligible. Patients are
eligible at initial presentation or at the time of the
Neoadjuvant
MK-3475
(Pembrolizumab)
R
A
N
D
O
M
I
Z
A
T
I
O
N
Adjuvant Arm
Neoadjuvant
Arm
Surgical
Resection
Adjuvant
MK-3475
(Pembrolizumab)
Adjuvant
MK-3475
(Pembrolizumab)
Surgical
Resection
R
E
G
I
S
T
R
A
T
I
O
N
R
E
G
I
S
T
R
A
T
I
O
N
APRIL 24 - 27, 2019 SWOG MELANOMA 48
S1801/II
first detected nodal, satellite/in-transit, distant
metastases, or recurrent disease in prior
lymphadenectomy basin or distant site. Patients with
multiple regional nodal basin involvement are
eligible. Gross or microscopic extracapsular nodal
extension is permitted.
Patients must not have received previous neoadjuvant
treatment for their melanoma. Patients may have
received prior non-immunotherapy adjuvant therapy.
Patients must not have had prior immunotherapy or
vaccine therapies. Patients must not be planning to
receive concomitant other biologic therapy, hormonal
therapy, other chemotherapy, or surgery. Patients
may have received prior radiation therapy, including
after prior surgical resection.
Patients must be at least 18 years of age and have a
Zubrod performance status of 0-2 and have adequate
bone marrow, hepatic, renal, and cardiac function.
Patients must not have a history of non-infectious
pneumonitis that required steroids or current
pneumonitis. Patients must not have an active
infection requiring systemic therapy. Patients must
not have active autoimmune disease that has required
systemic treatment in the past two years, and must
not have received live vaccines within 42 days prior
to randomization. Patients known to be HIV positive
are eligible if they have stable and adequate CD4
counts. Patients must not have known active
Hepatitis B Virus or Hepatitis C Virus infection.
Prior malignancy is allowed providing it does not
require concurrent therapy. Women of childbearing
potential must have a negative pregnancy test within
28 days prior to randomization.
Patients must be offered the opportunity to participate
in specimen banking. Patients randomized to
Neoadjuvant arm must be willing to submit tissue to
determine pathologic response.
Stratification/Descriptive Factors Randomization will be stratified by the following
factors: (1) LDH ≤ institutional upper limit of normal
vs > institutional upper limit of normal; (2) Nodal
involvement: 1 node vs 2-3 nodes vs other (including
4+ nodes, matted nodal mass, or metastatic disease)
at randomization.
Accrual Goals The accrual goal of this study is to randomize 556
patients with a goal of 500 eligible patients. A futility
analysis will be performed at 50% of expected
events.
Summary Statement This study was activated on December 6, 2018. As of
December 31, 2018, no patients have been registered.
ECOG-ACRIN Cancer Research Group EA6134 Study Progress and Safety Report Fall 2018
Page 1
EA6134 A RANDOMIZED PHASE III TRIAL OF DABRAFENIB + TRAMETINIB FOLLOWED BY IPILIMUMAB + NIVOLUMAB AT PROGRESSION VS. IPILIMUMAB + NIVOLUMAB FOLLOWED BY DABRAFENIB + TRAMETINIB AT PROGRESSION IN PATIENTS WITH ADVANCED BRAFV600 MUTANT MELANOMA
Sponsor(s)
Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Michael Atkins Statistician Dr. Sandra Lee Data Specialist Kerry Higgins Phase of Study III Type of Study Therapeutic Committee Melanoma Accrual Objective 300 Patients Participating Groups ECOG-ACRIN, CTSU NSC# 732442, 748726, 763093, 763760 Clinicaltrials.gov Study ID NCT02224781 Study Status Open to Accrual Date Proposed January 29, 2014 Date Activated July 13, 2015 Date Suspended February 2, 2016 Date Reactivated April 11, 2016 Schema
ECOG-ACRIN Cancer Research Group EA6134 Study Progress and Safety Report Fall 2018
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Purpose of Study The primary objective is to evaluate whether initial treatment with either combination ipilimumab-nivolumab (with subsequent dabrafenib in combination with trametinib) or dabrafenib in combination with trametinib (with subsequent ipilimumab-nivolumab) significantly improves 2 year overall survival (OS). Progression-free survival (PFS), response and adverse events (AE) data will also be evaluated. Study Population Patients with metastatic or progressive unresectable melanoma and BRAF mutation, less than 2 prior treatments for advanced disease and no prior treatment with a BRAF or MEK inhibitor or a CTLA4 or PD1 pathway blocker. Summary of Study Design In this randomized phase III study, patients with unresectable stage III or stage IV BRAFV600 mutant melanoma will be equally randomized to A: ipilimumab-nivolumab (with subsequent dabrafenib in combination with trametinib) or B: dabrafenib in combination with trametinib (with subsequent ipilimumab-nivolumab) using the stratification factors (ECOG PS, Serum LDH). The primary objective is to evaluate whether initial treatment with either combination ipilimumab-nivolumab (with subsequent dabrafenib in combination with trametinib) or dabrafenib in combination with trametinib (with subsequent ipilimumab-nivolumab) significantly improves 2 year overall survival. The primary endpoint for this study is the 2-year overall survival (OS) rate. Since the proportional hazard assumption is not appropriate for the proposed treatment arms, the most meaningful endpoint is the 2-year OS rate. The sample size calculation was conducted using the 2-year OS as a binary data. The primary analysis will be an ITT analysis based on the 2-year OS rate, using the Mantel-Haenszel test. The number of cases censored before two years is expected to be minimal in this study. The sample size for 2-year OS rate of 70% in arm A vs. 50% in arm will be 270 for 90% power. This is based on the two-sided type I error rate of 0.05 and allows for three interim analyses. An additional 10% (30 patients) have been added to cover for potential ineligibility or patient loss at the crossover time point. Assuming accrual rate of 16/month, accrual is estimated to take a maximum of 19 months. In addition, the follow-up time will be 2 years to assess the 2-year OS rate endpoint. Note that a clinically meaningful difference in 2-year OS rate is 70% vs. 50%. This assumption was used for the above power calculation of 90%. Formal interim analysis based on the difference of 2-year OS rate between the two arms will be conducted, starting at 33% information time (that is when first 100 patients enrolled are followed for 2 years). We expect this will be around 30 months after the study activates. After that, interim analysis will be repeated every 6 months. It is expected to at 64% and 100% information time. To preserve the overall type I error rate, critical values at the interim analyses will be determined using a truncated version of the Lan-DeMets spending function corresponding to the O'Brien-Fleming boundary. At each interim analysis, the difference in 2-year OS rates in arms A and B will be estimated. The repeated confidence interval (RCI) of Jennison-Turnbull will be provided. Strata will be taken into account for the RCI monitoring. As secondary clinical objectives, PFS, clinical response, toxicity profiles will be evaluated. This study also has extensive laboratory objectives and patient reported outcome objectives as outlined under the purpose of this study. For the laboratory correlatives, (i) the association of inherited variation with immune mediated adverse events (irAE) and response to ipilimumab + nivolumab will be evaluated and (ii) the utility of circulating BRAF levels in determining the response and resistance to either BRAF/MEK directed and/or combination immunotherapy will be evaluated.
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For the patient reported outcomes (PROs), the primary objective is to evaluate the overall clinical benefit between initial treatments (i.e., arm A: ipilimumab + nivolumab (with subsequent dabrafenib + trametinib). vs. arm B: dabrafenib + trametinib (with subsequent ipilimumab + nivolumab)), accounting for toxicities and overall survival. The quality-adjusted time without symptoms of disease progression or toxicity of treatment (Q-TWiST) analysis will be used to provide an integrated measure of quality and quantity of survival time. The Q-TWiST score based on overall survival at 2 years will be computed and compared. In addition, the differences in overall function over 2 years between initial treatment with dabrafenib + trametinib vs. ipilimumab + nivolumab will be assessed. Lastly, the effects of treatment crossover and treatment administration sequence on symptom burden and overall function will be evaluated. Progress to Date This study was activated on July 13, 2015 (Step 1 and Step 2). The study was suspended due to acute shortage in the supply of Dabrafenib and Trametinib capsules between February 2, 2016, and April 11, 2016. As of July 17, 2018, 150 patients enrolled to step 1, and 26 to step 2. Table 1a summarizes accrual by institution. Table 1b has accrual by group, and Table 1c shows projected accrual status as of July 17, 2018. Expected cumulative accrual and actual cumulative accrual are shown in Figure 1. This report is based on the data as of July 17, 2018. Patient status is displayed in Table 2 with patients accrued at that time. Demographics of patients by treatment arm are summarized in Table 3 for Steps 1 and 2. Record status on clinical report form is summarized in Table 4. The distribution of the reasons for treatment continuation of protocol treatment is summarized in Table 5. As of July 17, 2018 there were 110 cases (70 in arm A, 69in arm B in step 1) and 22 cases (9 in arm C and 13 in arm D in step 2) who reported treatment-related toxicities. Toxicity data is summarized in Table 6. Table 7 displays one case with treatment-related adverse events reported on ECOG-ACRIN CRFs. Based on CTEP-AERS reporting system, there were 11 cases with lethal adverse events: 46007 (arm A) respiratory failure, 46021 (arm A) neoplasms, 46028 (arm A) general disorder, 46052 (arm A) thromboembolic event, 46070 (arm A) nervous system disorder, 46102 (arm A) neoplasms, 46125 (arm A) neoplasms, 46003 (arm B) stroke, 46013 (arm B) neoplasms, 46018 (arm B) death NOS and 46012 (arm C) neoplasms. Cases 46003, 46007, 46012, 46018, 46021, 46052, 46102, 46125 have been reviewed using the data collected on ECOG-ACRIN CRFs and only the respiratory failure from case 46007 was considered treatment-related. Table 8 summarizes QOL data received.
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Table 1a. Accrual by ECOG-ACRIN Institution
Institution Name Step 1 Step 2 Cancer Research Consortium of West Michigan NCORP 1 0 Cancer Research for the Ozarks NCORP 3 0 Case Western Reserve University 3 0 Catholic Health Initiatives NCORP 1 0 Colorado Cancer Research Program NCORP 1 0 Dayton NCORP 4 2 Froedtert and the Medical College of Wisconsin 1 0 Georgia Cares Minority Underserved NCORP 1 0 Georgia NCORP 3 0 Hackensack University Medical Center 1 1 Heartland Cancer Research NCORP 4 0 Indiana Univ/Melvin and Bren Simon Cancer Center 3 1 Johns Hopkins Univ/Sidney Kimmel Cancer Center 3 1 Medical University of South Carolina MU NCORP 1 0 Metro Minnesota Community Oncology Res Consortium 5 2 Michigan Ca Res Consortium NCORP 3 1 Montana Cancer Consortium NCORP 1 0 Nevada Cancer Research Foundation NCORP 3 0 New Mexico MU NCORP 1 0 New York Oncology Hematology PC -Albany Med Center 1 0 NorthShore Univ HealthSystem-Evanston Hospital 1 0 Northwest NCI Community Oncology Research Program 1 0 Northwestern University 5 2 Ohio State University Comprehensive Cancer Center 3 0 Pacific Cancer Research Consortium NCORP 8 1 Saint Luke's University Hospital-Bethlehem Campus 1 0 Sanford NCORP of the North Central Plains 1 0 Stanford Cancer Institute Palo Alto 1 0 University of Alabama at Birmingham Cancer Center 4 1 University of Miami Miller Schl Med-SylvesterCaCtr 3 0 University of Michigan Comprehensive Cancer Center 2 0 University of Pittsburgh Cancer Institute (UPCI) 9 0 University of Wisconsin Hospital and Clinics 1 0 Vanderbilt University/Ingram Cancer Center 4 1 Wichita NCORP 1 0 Wisconsin NCORP 5 1 Total 94 14
Table 1b. Accrual by Group
Step 1 Step 2 ECOG-ACRIN 94 14 SWOG 27 7 ALLIANCE 9 2 NRG 20 3 Total 150 26
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Table 1c. Projected Accrual
Step 1 Step 2
Accrual goal 300 Planned accrual rate 192/yr Accrual to date 150 26 Annual accrual rate
Overall 53/yr 9/yr Last 6 months 56/yr 12/yr
Projected date of closure March 2021
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Table 2. Patient Status as of July 17, 2018
Step 1 Step 2 Cases Entered 150 26 Ineligible 1 0 Never Started Assigned Therapy 0 0
Reason for ineligibility (n=1): Surgery < 4 weeks from registration (46143).
Table 3. Demographics Step 1
Variable Level Arm A (n=75)
Arm B (n=75)
Total (n=150)
Sex Male 41 (54.7) 47 (62.7) 88 (58.7) Female 34 (45.3) 28 (37.3) 62 (41.3)
Race White 73 (98.6) 72 (98.6) 145 (98.6) Asian 1 (1.4) 1 (1.4) 2 (1.4) Unknown/Unreported 1 2 3
Ethnicity Hispanic 1 (1.4) 4 (5.6) 5 (3.4) Non-Hispanic 73 (98.6) 68 (94.4) 141 (96.6) Unknown/Missing 1 3 4
Age Median 59 56 59 Minimum 30 26 26 Maximum 81 83 83
Step 2
Variable Level Arm C (n=13)
Arm D (n=13)
Total (n=26)
Sex Male 7 (53.8) 8 (61.5) 15 (57.7) Female 6 (46.2) 5 (38.5) 11 (42.3)
Race White 12 (100.0) 13 (100.0) 25 (100.0) Unknown/Unreported 1 0 1
Ethnicity Non-Hispanic 12 (100.0) 12 (100.0) 24 (100.0) Unknown/Missing 1 1 2
Age Median 53 52 53 Minimum 31 34 31 Maximum 79 70 79
ECOG-ACRIN Cancer Research Group EA6134 Study Progress and Safety Report Fall 2018
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Table 4. Record Status
Form Name Forms
Due Forms
Received % Demography 146 146 100 Patient Characteristics 169 169 100 Treatment Agent: Dabrafenib 451 449 99.56 Treatment Agent: Ipilimumab - Induction 141 141 100 Treatment Agent: Nivolumab - Induction 141 141 100 Treatment Agent: Nivolumab - Maintenance 178 177 99.44 Treatment Agent: Trametinib 450 448 99.56 Adverse Event Form 774 752 97.16 Hematology/Chemistry 169 169 100 Late Adverse Event Form 2 2 100 Other Adverse Event Form 600 599 99.83 Disease Follow-Up Status Form (RECIST 1.1) 889 879 98.88 Off Treatment 14 14 100 Off-Treatment with Intent to Reg Next Step 90 90 100
Table 5. Reasons Off Treatment Step 1
For Patients Not Registered To Subsequent Steps (Includes all patients who started treatment and
for whom off-treatment data have been received)
Reasons N % Adverse event/side effects/complications 28 41.8 Death on study 6 9.0 Disease progression- relapse during active treatment 23 34.3 Other 3 4.5 Patient withdrawal/refusal after beginning protocol therapy 4 6.0 Treatment completed per protocol criteria 3 4.5 Total off treatment 67 100.0
Step 2 (Includes all patients who started treatment and
for whom off-treatment data have been received)
Reasons N % Adverse event/side effects/complications 1 6.7 Disease progression- relapse during active treatment 12 80.0 Treatment completed per protocol criteria 2 13.3 Total off treatment 15 100.0
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Table 6. Toxicity Incidence Step 1
Toxicity Type
Treatment Arm A (n=70) B (n=69)
Grade Grade 3 4 5 3 4 5
(%) (%) (%) (%) (%) (%) Anemia 1 - - 3 - - Disseminated intravascular coagulation - 1 - - - - Febrile neutropenia - - - 3 - - Leukocytosis 3 - - - - - Cardiac disorders - Other, specify - 1 - - - - Myocarditis 1 - - - - - Fatigue 7 - - 9 - - Fever - - - 9 - - Pain - - - 1 - - Edema limbs 1 - - - - - Infusion related reaction 1 - - - - - Rash acneiform - - - 1 - - Rash maculo-papular 9 - - 4 - - Endocrine disorders - Other, specify - 1 - - - - Abdominal pain 1 - - - - - Colitis 4 - - - - - Diarrhea 23 1 - - - - Enterocolitis 1 - - - - - Gastrointestinal disorders - Other, specify 1 - - - - - Ileus 1 - - - - - Nausea 10 - - - - - Vomiting 4 - - 1 - - Hepatic failure 1 - - - - - Autoimmune disorder 3 - - - - - Infections and infestations - Other, specify - - - 1 - - Sepsis - 1 - - 1 - Urinary tract infection 1 - - - - - Enterocolitis infectious 3 - - - - - Gallbladder infection - - - 1 - - Alanine aminotransferase increased 6 1 - - - - Aspartate aminotransferase increased 6 1 - - - - Blood bilirubin increased 1 3 - - - - Creatinine increased 4 - - 1 - - Lipase increased 4 9 - 4 - - Lymphocyte count decreased - - - 1 - - Neutrophil count decreased - - - 3 - - Serum amylase increased 3 1 - - 1 - Ejection fraction decreased - - - 3 - - Anorexia 3 - - - - - Dehydration 4 - - 1 - - Hypercalcemia 1 - - - - - Hyperglycemia 4 1 - - - - Hypoalbuminemia 6 - - - - - Hypokalemia 3 - - 1 - -
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Toxicity Type
Treatment Arm A (n=70) B (n=69)
Grade Grade 3 4 5 3 4 5
(%) (%) (%) (%) (%) (%) Hyponatremia 3 - - 6 1 - Hypophosphatemia 1 - - - - - Arthralgia 7 - - 1 - - Back pain 1 - - - - - Musculoskeletal and connective tissue disorder - Other, specify 1 - - - - - Myalgia 1 - - - - - Myositis 1 - - - - - Pain in extremity - - - 1 - - Generalized muscle weakness 3 - - - - - Headache 1 - - - - - Hypersomnia 1 - - - - - Peripheral sensory neuropathy 1 - - - - - Syncope - - - 4 - - Tremor 1 - - - - - Retinal detachment - - - 1 - - Adult respiratory distress syndrome - 1 - - - - Hypoxia 1 - - - - - Pneumonitis 1 - - - - - Respiratory failure - - 1 - - - Acute kidney injury 3 - - - - - Hypertension 3 - - - - - Hypotension 1 - - 1 - - Thromboembolic event - - - 1 - - WORST DEGREE 49 16 1 43 4 -
Step 2
Toxicity Type
Treatment Arm C (n=9) D (n=13) Grade Grade
3 4 5 3 4 5 (%) (%) (%) (%) (%) (%)
Anemia - - - 8 - - Fatigue - - - 15 - - Fever 11 - - 8 - - Rash maculo-papular 22 - - - - - Lipase increased - - - 8 - - Lymphocyte count decreased - - - 8 - - Dehydration - - - 8 - - Hypernatremia 11 - - - - - Hyponatremia 11 - - 8 - - Nervous system disorders - Other, specify - - - 8 - - Syncope 11 - - - - - Pneumonitis - - - 8 - - WORST DEGREE 44 - - 46 - -
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Table 7. Lethal Adverse Events that are Possibly Related to Treatment
Case Arm Description of Event 46007 A Respiratory failure
Table 8. QOL
QOL Timepoint
Patients Reaching
Timepoint % Forms
Completed Baseline Step 1 145 86.2 End of Cycle 1 in Step 1 - Arm A 70 51.4 End of Cycle 1 in Step 1 - Arm B 69 88.4 End of Cycle 2 in Step 1 - Arm A 65 38.5 End of Cycle 2 in Step 1 - Arm B 65 67.7 Disease stability or 6 Mos. Step 1-Arm A 53 20.8 Disease stability or 6 Mos. Step 1-Arm B 55 30.9 End of Step 1 Treatment 47 100.0 Baseline Step 2 25 72.0 End of Cycle 1 in Step 2 - Arm C 11 54.5 End of Cycle 1 in Step 2 - Arm D 13 53.8 End of Cycle 2 in Step 2 - Arm C 10 70.0 End of Cycle 2 in Step 2 - Arm D 12 41.7 Disease stability or 6 Mos. Step 2-Arm C 8 50.0 Disease stability or 6 Mos. Step 2-Arm D 11 36.4 End of Step 2 Treatment 9 100.0 12 Mos. from study entry - Arm A 36 22.2 12 Mos. from study entry - Arm B 36 0.0 18 Mos. from study entry - Arm A 22 13.6 18 Mos. from study entry - Arm B 23 4.3
ECOG-ACRIN Cancer Research Group EA6141 Study Progress and Safety Report Fall 2018
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EA6141 RANDOMIZED PHASE II/III STUDY OF NIVOLUMAB PLUS IPILIMUMAB PLUS SARGRAMOSTIM VERSUS NIVOLUMAB PLUS IPILIMUMAB IN PATIENTS WITH UNRESECTABLE STAGE III OR STAGE IV MELANOMA
Sponsor(s) Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Frank Hodi Statistician Dr. Sandra Lee Data Specialist Matthew Shimizu Phase of Study II/III Type of Study Therapeutic Committee Melanoma Accrual Objective 240 Patients Participating Groups ECOG-ACRIN, CTSU NSC# 732442, 748726 Clinicaltrials.gov Study ID NCT02339571 Study Status Open to Accrual Date Proposed July 9, 2014 Date Activated September 10, 2015 Date Suspended June 23, 2017 Schema
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Purpose of Study Primary Endpoint: To compare the overall survival (OS) of nivolumab/ipilimumab/sargramostin versus nivolumab/ipilumumab. Secondary Endpoints: (1) To compare Progression Free Survival (PFS) between nivolumab/ipilimumab/ sargramostim versus nivolumab/ipilimumab. (2) To assess for differences in tolerability, specifically rate of high grade events, between nivolumab/ipilimumab/ sargramostim versus nivolumab/ipilimumab. (3) To explore comparisons of immune-related response criteria to standard criteria as endpoint evaluations. (4) To explore PD-L1 and PD-L2 status by IHC of patient tumors and clinical activity and side effect profile. (5) To explore QOL of patients treated with nivolumab/ipilimumab/sargramostin versus nivolumab/ipilumumab. Study Population Patients with previously untreated unresectable stage III or IV melanoma. Summary of Study Design In this randomized phase II/III study, patients with advanced melanoma will be equally randomized to of Ipi-Nivo vs. Ipi-Nivo-GM using the stratification factors (BRAF mutation status, melanoma m stage). The stratified randomization will be based on the permuted block method. The primary objective is to compare overall survival between Nivo vs. Nivo-GM and Ipi-Nivo vs. Ipi-Nivo-GM. The secondary objectives are to evaluate the progression-free survival, response rate, safety and utility of immune related response criteria (irRC). The primary comparison will be overall survival (OS). It will be an ITT analysis in all patients. The median OS for Ipi+Nivo is assumed to be 2 years. By adding GM, there will be 50% improvement in the median OS. Accrual is anticipated to be 20 patients per month in general. After 40 patients have been randomized/treated and followed for at least 12 weeks, CTEP-AERS data will be reviewed carefully to ensure Ipi/Niovo containing regimen is safe to administer in the cooperative group setting. Although expected accrual rate is 40 patients/month, it will be slower at the beginning and this toxicity analysis is planned to be conducted while patients are accruing. If at least 20 patients have experienced grade 3 or higher treatment-related AEs (via CTEP-AERS reporting), accrual will be suspended and the AE data will be reviewed by ECOG-ACRIN DSMC. Otherwise accrual will continue. This study is mainly designed as a phase III study with an overall two-sided type I error rate of 0.05 and 83.5% power (after adjusting for the phase II comparison). For a phase III study with 5 interim analyses, it requires about 400 patients (with 265 deaths as a total number of deaths). To adjust for the phase II portion of the study, this design is slightly modified as shown below. Accrual will be suspended after 240 patients are randomized. The first interim analysis will be conducted when 113 deaths are observed. Accrual for 240 patients will take about one year, but it will take at least another 1.6 years to observe 113 deaths. This comparison will be considered as a phase II portion of the study. As a phase II study, OS will be compared using a one-sided type I error rate of 0.2. There will be approximately 90% power for the phase II part. Only if it is significant, we will proceed to the phase III part. In that case, the study will reopen for accrual and continue with accrual for another 160 patients. Since the phase II comparison will cost about 5.54% power, the power for phase III part is increased to 89%, to compensate for the loss of power for phase II comparison.
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For the logistical issues of reopening a phase III part, it is assumed it will begin 3 months after the phase II analysis is completed. For the phase III part, interim analyses of OS will be performed for all semi-annual DSMC meetings beginning when approximately 50% of the planned full information (133 deaths among all patients) has occurred, continuing until either criteria for early stopping are met or full information is reached. To preserve the overall type I error rate, critical values at the interim analyses will be determined using the Lan-DeMets spending function corresponding to the O'Brien-Fleming boundary. Under the accrual rate, follow up time, and failure rate assumptions above, interim analyses would be expected to occur at 0.25, 0.75, 1.3, 1.8, 2.3, 2.8 years after phase III accrual begins, at information times of 50%, 63%, 75%, 86%, 95%, and 100%. It will take approximately 2 years of additional follow up time after the last patient is randomized in phase III part. This study will also be monitored for early stopping for inefficacy. The approach of this monitoring will be based on the method proposed by Freidlin et al. (2010). Inefficacy monitoring will start around 50% information time. The study will be stopped if there is not at least a small trend in favor of the alternative hypothesis starting at this time. Specifically, an inefficacy monitoring boundary will begin at this time at a hazard ratio greater than 1 and will gradually increase to 20% of the targeted benefit at full information, subject to the requirement that two-sided 95% confidence interval for the log hazard ratio does not contain the design-alternative log hazard ratio of 0.67. The immune response will be assessed using the utility of Immune related response criteria (irRC). Standard response criteria (based on the RECIST) will be applied to assess clinical response. Immune response rate and clinical response rate will be compared between the two treatment arms. Progress to Date This study was activated on September 10, 2015 and suspended on June 23, 2017 as it reached the first stage accrual goal. As of June 23, 2017, 250 patients have enrolled. Table 1a summarizes accrual by institution. Table 1b has accrual by group and Table 1c shows projected accrual status as of July 17, 2018. Patient status as of July 17, 2018 is displayed in Table 2. Demographics of patients by treatment arm are summarized in Table 3. Record status as on clinical report form is summarized in Table 4. The distribution of the reasons for treatment discontinuation is summarized in Table 5. Toxicity data were reported for 123 cases in arm A and 120 cases in arm B as of July 17, 2018. Treatment-related toxicities are summarized in Table 6. The worst-degree grade 3 or higher toxicity rate was 53% in arm A and 69% in arm B. There were 3 grade 5 AEs in arm A and 1 in arm B. These cases with at least possibly treatment related grade 5 AEs are listed in Table 7. There are additional grade 5 AEs reported via CTEP-AERS system. They are: case 16010 (arm A) Dyspnea, 16011 (arm A) neoplasms progression, 16058 (arm A) GI disorder, 16064 (arm A) respiratory failure, 16078 (arm A) deaths NOS, 16121 (arm A) aspiration, 16196 (arm A) cardiac disorder, 16232 (arm B) multiorgan failure, 16233 (arm A) Deaths NOS and 16126 (arm B) neoplasms progression, 16242 (arm A), 16245 (arm A) deaths NOS. Of these, cases 16010, 16011, 16064, 16121, 16196, 16126, 16233 were reviewed at ECOG-ACRIN and considered as not treatment-related. Secondary primary tumor is listed in Table 8.
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Table 1a. Accrual by ECOG-ACRIN Institution
Institution Name Step 1 Aurora NCORP 2 Baystate Medical Center 2 Beth Israel Deaconess Medical Center 4 Cancer Research Consortium of West Michigan NCORP 6 Cancer Research for the Ozarks NCORP 1 Case Western Reserve University 10 Colorado Cancer Research Program NCORP 1 Columbus NCORP 3 Dana-Farber/Harvard Cancer Center 24 Dartmouth Hitchcock Medical Center 3 Dayton NCORP 3 Emory University/Winship Cancer Institute 8 Froedtert and the Medical College of Wisconsin 3 Georgia Cares Minority Underserved NCORP 1 Georgia NCORP 16 Hackensack University Medical Center 4 Indiana Univ/Melvin and Bren Simon Cancer Center 2 Johns Hopkins Univ/Sidney Kimmel Cancer Center 1 Mayo Clinic 1 Metro Minnesota Community Oncology Res Consortium 2 Michigan Ca Res Consortium NCORP 3 Montana Cancer Consortium NCORP 9 Nevada Cancer Research Foundation NCORP 9 New Mexico MU NCORP 5 NorthShore Univ HealthSystem-Evanston Hospital 1 Northwestern University 8 Ochsner NCORP 2 Sanford NCORP of the North Central Plains 2 Stanford Cancer Institute Palo Alto 2 UT Southwestern/Simmons Cancer Center-Dallas 1 University of Alabama at Birmingham Cancer Center 9 University of Miami Miller Schl Med-SylvesterCaCtr 4 University of Pittsburgh Cancer Institute (UPCI) 7 University of Wisconsin Hospital and Clinics 9 VCU Massey Cancer Center MU NCORP 6 Vanderbilt University/Ingram Cancer Center 11 Wichita NCORP 3 Total 188
Table 1b. Accrual by Group
ECOG-ACRIN 188 SWOG 36 ALLIANCE 18 NRG 8 Total 250
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Table 1c. Projected Accrual
Accrual goal 240 Planned accrual rate 240/yr Accrual to date 250 Annual accrual rate
Overall 140/yr Projected date of closure
Table 2. Patient Status as of July 17, 2018
Cases Entered 250 Ineligible 3 Never Started Assigned Therapy 2
Reason for ineligibility (n=3): No measurable disease (16242); Bilirubin > 1.5 X ULN (16226); No baseline PET-CT (16062). Reason for not starting therapy (n=2): Withdrawal/refusal before beginning protocol therapy (16014); Death before therapy (16143).
Table 3. Demographics
Variable Level Arm A
(n=126) Arm B
(n=124) Total
(n=250) Sex Male 85 (67.5) 66 (53.2) 151 (60.4)
Female 41 (32.5) 58 (46.8) 99 (39.6) Race White 119 (99.2) 113 (95.8) 232 (97.5)
African-American 0 (0.0) 2 (1.7) 2 (0.8) Asian 0 (0.0) 2 (1.7) 2 (0.8) Native American 1 (0.8) 1 (0.8) 2 (0.8) Unknown/Unreported 6 6 12
Ethnicity Hispanic 3 (2.6) 3 (2.6) 6 (2.6) Non-Hispanic 111 (97.4) 113 (97.4) 224 (97.4) Unknown/Missing 12 8 20
Age Median 62 61 62 Minimum 24 25 24 Maximum 86 82 86
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Table 4. Record Status
Form Name Forms
Due Forms
Received % Demography 250 250 100 Patient Characteristics 250 249 99.6 Treatment Agent: Ipilimumab 808 808 100 Treatment Agent: Nivolumab 2419 2417 99.92 Treatment Agent: Sargramostim 1463 1461 99.86 Adverse Events 2575 2575 100 Hematology/Chemistry 250 248 99.2 Late Adverse Events 14 14 100 Disease Follow-Up Status Form (RECIST 1.1) 2809 2805 99.86 Off Treatment 193 193 100
Table 5. Reasons Off Treatment
(Includes all patients who started treatment and for whom off-treatment data have been received)
Reasons N %
Adverse event/side effects/complications 97 50.0 Alternative therapy 5 2.6 Death on study 7 3.6 Disease progression- relapse during active treatment 51 26.3 Other 16 8.2 Patient off-treatment for other complicating disease 3 1.5 Patient withdrawal/refusal after beginning protocol therapy 10 5.2 Treatment completed per protocol criteria 5 2.6 Total off treatment 194 100.0
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Table 6. Toxicity Incidence
Toxicity Type
Treatment Arm A (n=123) B (n=120)
Grade Grade 3 4 5 3 4 5
(%) (%) (%) (%) (%) (%) Hearing impaired 1 - - - 1 - Anemia 1 - - 2 - - Blood and lymphatic system disorders - Other, specify 1 - - 1 - - Leukocytosis 1 - - - - - Atrioventricular block complete 1 - - - - - Myocarditis 1 - - - - - Death NOS - - 1 - - - Fatigue 5 - - 4 - - Fever - - - 1 - - Multi-organ failure - - - - - 1 Pain 1 - - - - - Non-cardiac chest pain 1 - - - - - Pruritus 2 - - 1 - - Rash maculo-papular 8 - - 9 - - Adrenal insufficiency 4 - - 3 - - Endocrine disorders - Other, specify 5 - - 3 - - Hyperthyroidism 1 - - - - - Hypothyroidism 1 - - 1 - - Abdominal pain 2 - - 2 - - Colitis 2 - - 10 - - Constipation 1 - - - - - Dental caries 1 - - - - - Diarrhea 7 2 1 15 - - Duodenal ulcer 1 - - - - - Dysphagia - - - 1 - - Enterocolitis 1 - - 1 - - Gastrointestinal disorders - Other, specify 1 - - - - - Mucositis oral - - - 2 - - Nausea 1 - - 3 - - Vomiting 2 - - 2 - - Lower gastrointestinal hemorrhage 1 - - - - - Hepatobiliary disorders - Other, specify - - - 1 1 - Allergic reaction 1 - - - - - Immune system disorders - Other, specify - - - 3 - - Autoimmune disorder 2 - - 1 - - Infections and infestations - Other, specify 1 - - 1 - - Skin infection 1 - - - - - Lung infection 1 - - 1 - - Fall 1 - - - - - Alanine aminotransferase increased 10 - - 11 - - Alkaline phosphatase increased 2 - - 2 - - Aspartate aminotransferase increased 3 1 - 10 - - Blood bilirubin increased 1 - - - - - Cardiac troponin I increased - - - 1 - - CPK increased - - - 1 1 - Creatinine increased - - - 2 - - Investigations - Other, specify - - - 1 - -
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Toxicity Type
Treatment Arm A (n=123) B (n=120)
Grade Grade 3 4 5 3 4 5
(%) (%) (%) (%) (%) (%) Lipase increased 7 4 - 11 6 - Lymphocyte count decreased 1 1 - 1 - - Platelet count decreased 1 1 - - - - Serum amylase increased 5 - - 3 1 - Urine output decreased - 1 - - - - Acidosis - - - 1 1 - Anorexia 4 - - - - - Dehydration 2 - - 4 - - Hypercalcemia - - - - 2 - Hyperglycemia 1 - - 3 3 - Hyperkalemia 1 - - - - - Hyperuricemia - 2 - 1 2 - Hypokalemia - 2 - 2 - - Hyponatremia 2 - - 4 - - Hypophosphatemia - - - 1 - - Metabolism and nutrition disorders - Other, specify - - - 1 - - Back pain - - - 1 - - Bone pain 1 - - - - - Joint effusion - - - 1 - - Pain in extremity - - - 1 - - Generalized muscle weakness 2 - - - - - Muscle weakness lower limb 2 - - - - - Muscle weakness right-sided - - - 1 - - Dizziness 1 - - - - - Dysphasia - - - 1 - - Headache 3 - - 1 - - Nervous system disorders - Other, specify 1 - - - - - Peripheral motor neuropathy - - - 1 - - Peripheral sensory neuropathy - 1 - 1 - - Seizure 1 - - 1 - - Syncope 1 - - 1 - - Uveitis 1 - - - - - Anxiety - - - 1 - - Confusion - - - 1 - - Aspiration - - 1 - - - Dyspnea 1 - - 5 2 - Hypoxia 1 - - 1 - - Pneumonitis 2 - - 3 - - Respiratory, thoracic and mediastinal disorders - Other, specify - - - - 1 - Renal and urinary disorders - Other, specify 1 - - - - - Chronic kidney disease - 1 - - - - Acute kidney injury - - - 2 - - Hypertension - - - 1 - - Hypotension 2 1 - 1 - - Thromboembolic event - - - 1 - - WORST DEGREE 38 13 2 53 15 1
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Table 7. Lethal Adverse Events that are Possibly Related to Treatment
Case Arm Description of Event 16058 A Diarrhea 16242 A Aspiration 16245 A Death NOS 16232 B Multi-organ failure
Table 8. Second Primary Cancers
Site Arm A Liver, Gall Bladder, Bile Duct 1
ECOG-ACRIN Cancer Research Group E3612 Study Progress and Safety Report Fall 2018
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E3612 A RANDOMIZED PHASE II TRIAL OF IPILIMUMAB WITH OR WITHOUT BEVACIZUMAB IN PATIENTS WITH UNRESECTABLE STAGE III OR STAGE IV MELANOMA
Sponsor(s) Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Frank Hodi Statistician Dr. Sandra Lee Data Specialist Matthew Shimizu Phase of Study II Type of Study Therapeutic Committee Melanoma Accrual Objective 168 Patients Participating Groups ECOG-ACRIN, CTSU DCP Treatment Credit 1.0 NSC# 704865, 732442 Clinicaltrials.gov Study ID NCT01950390 Study Status Closed to Accrual Date Proposed October 4, 2012 Date Activated December 13, 2013 Date Terminated September 25, 2017 Final Accrual 169 Patients Schema
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Purpose of Study Primary Endpoint (1) To compare overall survival for patients receiving ipilimumab plus bevacizumab versus ipilimumab alone. Secondary Endpoints (1) To evaluate the progression free survival, response rate and safety in patients receiving ipilimumab plus bevacizumab versus ipilimumab alone. (2) To evaluate the utility of immune related response criteria (irRC) in patients receiving ipilimumab plus bevacizumab versus ipilimumab alone. Study Population Patients with measurable metastatic melanoma, no more than one prior therapy for metastatic disease, no prior therapy with bevacizumab or ipilimumab. Summary of Study Design In this randomized phase II study, patients with advanced melanoma will be equally randomized to Arm A: Iplimumab (Ipi) or Arm B: Ipi + Bevacizumab using the stratification factors (Prior Therapy and BRAF mutation status). The stratified randomization will be based on the permuted block method. The primary objective is to compare overall survival between Arms A vs. B. The secondary objectives are to evaluate the progression-free survival, response rate, safety and utility of immune related response criteria (irRC) in patients in Arms A vs. B. The primary comparison will be OS in arms A vs. B. It will be an ITT analysis in all eligible patients. It is assumed that the median OS in patients treated in arm A will be around 11 months and the median OS will be improved to 16.5 months (50% improvement) in arm B. If the OS follows an exponential distribution, this difference corresponds to an improvement of one-year OS rate from 47% (in arm A) to 60% (in arm B). A comparison of arms A vs. B will be made using a stratified logrank test with one-sided type I error of 10%. One interim analysis will be performed at 50% information time (57 deaths), with the final analysis at 114 deaths. To preserve the overall type I error rate, critical values at the analyses will be determined using the O'Brien and Fleming boundary. Under the accrual and failure rate assumptions below, one interim and final analyses are expected to occur at 12 and 28 months after activation. The repeated confidence interval (RCI) of Jennison-Turnbull will also be evaluated at the interim analysis. This design will provide power of 80%. Progress to Date This study was open between December 13, 2013 and September 25, 2017. Final accrual was 169 patients. Table 1a summarizes accrual by institution and Table 1b has accrual by group. Patient status as of July17, 2018 is displayed in Table 2. Demographics of patients by treatment arm are summarized in Table 3. Record status on clinical report form is summarized in Table 4. The distribution of the reasons for treatment discontinuation of protocol treatment is summarized in Table 5. One hundred and sixty-four patients have reported toxicity (82 in each arm) as of July 17, 2018. Treatment-related grade 3 or higher toxicities are summarized in Table 6. Table 7 summarizes 2 cases with (treatment-related) lethal toxicities reported via ECOG-ACRIN CRFs. Based on CTEP AERS reporting, there were 13 additional cases with lethal adverse events: 36005 (arm A) cardiac arrest, 36122 (arm A) death NOS, 36131 (arm A) neoplasms, 36143 (arm A) cardiac arrest, 36148 (arm A) heart failure, 36160 (arm A) neoplasms, 36169 (arm A) death NOS, 36017 (arm B) aspiration, 36113 (arm B) death, 36142 (arm B) neoplasms, 36155 (arm B) neoplasms, 36158 (arm B) cardiac arrest and 36163 (arm B) sepsis. All these cases have been reviewed using the data collected on ECOG-ACRIN CRFs. All of them were considered having lethal adverse events unrelated to the treatment. Table 8 summaries second primary cancers.
ECOG-ACRIN Cancer Research Group E3612 Study Progress and Safety Report Fall 2018
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Table 1a. Accrual by ECOG-ACRIN Institution
Institution Name Step 1
Baystate Medical Center 2 Beth Israel Deaconess Medical Center 4 Cancer Alliance of Nebraska 2 Cancer Research Consortium of West Michigan NCORP 2 Cancer Research for the Ozarks NCORP 3 Case Western Reserve University 10 Columbus NCORP 6 Dana-Farber/Harvard Cancer Center 8 Dayton NCORP 1 Delaware/Christiana Care NCORP 1 Eastern Connecticut Hematology and Oncology Assoc 3 Emory University/Winship Cancer Institute 3 Fox Chase Cancer Center 2 Froedtert and the Medical College of Wisconsin 3 Geisinger Cancer Institute NCORP 2 Georgia NCORP 2 Hackensack University Medical Center 4 Heartland Cancer Research NCORP 9 Indiana Univ/Melvin and Bren Simon Cancer Center 7 Iowa-Wide Oncology Research Coalition NCORP 1 Mayo Clinic 1 MedStar Georgetown University Hospital 2 Michigan Ca Res Consortium NCORP 4 Montefiore MU NCORP 5 Nevada Cancer Research Foundation NCORP 9 NorthShore Univ HealthSystem-Evanston Hospital 1 Northwestern University 6 Ohio State University Comprehensive Cancer Center 2 Thomas Jefferson University Hospital 3 University of Alabama at Birmingham Cancer Center 6 University of Michigan Comprehensive Cancer Center 3 University of Pittsburgh Cancer Institute (UPCI) 13 University of Wisconsin Hospital and Clinics 7 Wichita NCORP 3 Wisconsin NCORP 2 Total 142
Table 1b. Accrual by Group
ECOG-ACRIN 142 SWOG 6 ALLIANCE 12 NRG 9 Total 169
ECOG-ACRIN Cancer Research Group E3612 Study Progress and Safety Report Fall 2018
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Table 2. Patient Status as of July 17, 2018
Cases Entered 169 Ineligible 7 Never Started Assigned Therapy 4
Reason for ineligibility (n=7): Brain mets (36021); Baseline AE (36096); Issues with baseline imaging (35057, 36119, 36156, 36163); High AST level (36145). Reason for not starting therapy (n=4): Ineligibility (36021, 36145); Withdrawal (36053); Adverse events (36123). Duplicate registration: 36038
Table 3. Demographics
Variable Level Arm A (n=85)
Arm B (n=84)
Total (n=169)
Sex Male 57 (67.1) 41 (48.8) 98 (58.0) Female 28 (32.9) 43 (51.2) 71 (42.0)
Race White 81 (97.6) 80 (100.0) 161 (98.8) African-American 1 (1.2) 0 (0.0) 1 (0.6) Asian 1 (1.2) 0 (0.0) 1 (0.6) Unknown/Unreported 2 4 6
Ethnicity Hispanic 2 (2.4) 3 (3.7) 5 (3.0) Non-Hispanic 80 (97.6) 79 (96.3) 159 (97.0) Unknown/Missing 3 2 5
Age Median 65 65 65 Minimum 26 36 26 Maximum 91 87 91
ECOG-ACRIN Cancer Research Group E3612 Study Progress and Safety Report Fall 2018
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Table 4. Record Status
Form Name Forms
Due Forms
Received % Demography 169 169 100 Patient Characteristics 169 169 100 Treatment Agent: Bevacizumab 823 821 99.76 Treatment Agent: Ipilimumab 741 739 99.73 Adverse Event Form 1567 1543 98.47 Hematology/Chemistry 1425 1422 99.79 Late Adverse Event Form 2 1 50 Other Adverse Event Form 1159 1158 99.91 Disease Follow-Up Status Form (RECIST 1.1) 1578 1574 99.75 Off Treatment 158 158 100
Table 5. Reasons Off Treatment
(Includes all patients who started treatment and for whom off-treatment data have been received)
Reasons N %
Adverse event/side effects/complications 38 24.1 Alternative therapy 1 0.6 Death on study 8 5.1 Disease progression- relapse during active treatment 95 60.1 Other 9 5.7 Patient withdrawal/refusal after beginning protocol therapy 6 3.8 Treatment completed per protocol criteria 1 0.6 Total off treatment 158 100.0
ECOG-ACRIN Cancer Research Group E3612 Study Progress and Safety Report Fall 2018
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Table 6. Toxicity
Step 1
Toxicity Type
Treatment Arm A (n=82) B (n=82)
Grade Grade 3 4 5 3 4 5
(%) (%) (%) (%) (%) (%) Anemia 1 - - 4 - - Atrial fibrillation - - - 1 - - Fatigue 5 - - 10 - - Fever 1 - - - - - Gait disturbance - - - 1 - - Sudden death NOS - - - - - 1 Erythema multiforme - - - 1 - - Pruritus - - - 2 - - Rash maculo-papular 9 - - 6 - - Skin ulceration - - - - 1 - Adrenal insufficiency 2 1 - 2 - - Endocrine disorders - Other, specify 1 - - 1 - - Hypothyroidism - - - 1 - - Abdominal pain 4 - - - - - Colitis 6 - - 6 - - Colonic perforation 1 - - 1 - - Diarrhea 17 - - 7 - - Gastrointestinal disorders - Other, specify - - - 1 - - Mucositis oral - - - 1 - - Nausea - - - 2 - - Pancreatitis - - - 1 - - Proctitis - - - 1 - - Rectal fistula - - - 1 - - Vomiting - - - 1 - - Cholecystitis - - - 1 - - Autoimmune disorder 4 - - - - - Infections and infestations - Other, specify - - - 1 - - Sepsis - 1 - - - - Sinusitis - - - 1 - - Wound infection - - - 1 - - Alanine aminotransferase increased 5 1 - 2 - - Aspartate aminotransferase increased 4 - - 2 - - Blood bilirubin increased 1 - - - - - Investigations - Other, specify - - - 1 - - Lipase increased 4 1 - 2 1 - Lymphocyte count decreased - 1 - - - - Platelet count decreased - 1 - - - - Serum amylase increased 1 - - - 1 - Anorexia - - - 2 - - Dehydration 1 - - 9 - - Hyperuricemia - - - - 1 -
ECOG-ACRIN Cancer Research Group E3612 Study Progress and Safety Report Fall 2018
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Toxicity Type
Treatment Arm A (n=82) B (n=82)
Grade Grade 3 4 5 3 4 5
(%) (%) (%) (%) (%) (%) Hypoglycemia - 1 - - - - Hypokalemia 2 - - 1 - - Hyponatremia 5 - - 1 2 - Hypophosphatemia - - - 1 - - Metabolism and nutrition disorders - Other, specify - - - 1 - - Arthralgia - - - 1 - - Myalgia - - - 1 - - Generalized muscle weakness 1 - - 4 - - Headache 1 - - 2 - - Peripheral motor neuropathy 1 - - - - - Reversible posterior leukoencephalopathy syndrome - - - 1 - - Confusion - - - 1 - - Cough - - - 1 - - Dyspnea 2 - - - - - Proteinuria - - - 1 - - Acute kidney injury - - 1 - - - Hypertension 1 - - 35 - - Thromboembolic event - - - 1 - - WORST DEGREE 32 7 1 50 7 1
Table 7. Lethal Adverse Events that are Possibly Related to Treatment
Case Arm Description of Event 36064 36086
A B
Acute kidney injury Sudden death NOS
Table 8. Second Primary Cancers
Site Arm A Arm B Head And Neck - 1 Renal Cell 1 - Skin Cancer Not Melanoma 1 -