OCTOBER 2 - 5, 2019 SWOG MELANOMA 1
MELANOMA COMMITTEE
PRIVILEGED COMMUNICATION NOT FOR PUBLICATION OR REFERENCE
OCTOBER 2 - 5, 2019 SWOG MELANOMA 2
CONTENTS
S1320 Phase II ............................................................................................................................................................... 6
S1404 Phase III ............................................................................................................................................................ 16
S1512 Phase II ............................................................................................................................................................. 27
S1607 Phase II ............................................................................................................................................................. 32
S1609 Phase II ............................................................................................................................................................. 38
S1614 Phase III ............................................................................................................................................................ 40
S1616 Phase II ............................................................................................................................................................. 42
S1801 Phase II ............................................................................................................................................................. 48
OCTOBER 2 - 5, 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
193
89
277
1040
308
136
0
100
200
300
400
500
600
700
800
900
1000
1100
Time of Registration
Jul 2013Jun 2014
Jul 2014Jun 2015
Jul 2015Jun 2016
Jul 2016Jun 2017
Jul 2017Jun 2018
Jul 2018Jun 2019
56
96
67
107
161
178
224
477
63
150
OCTOBER 2 - 5, 2019 SWOG MELANOMA 4
Patient Registrations by Study and Arm MELANOMA COMMITTEE
Jan 2019
Jun 2019
Jul 2018
Dec 2018
Jan 2018
Jun 2018
All
Patients
S1320 Adv, BRAF mut, Intermittent vs Continuous Dabrafenib + Trametinib
Lead In Registration
Lead-in Continuous Dosing 12 18 28 249
Randomization
Continuous Dosing 11 6 15 108
Intermittent Dosing 10 6 13 103
21 12 28 211
S1512 Melan, Adv, Desmoplastic, MK-3475 (Pembrolizumab)
Registration
MK-3475 (Pembrolizumab) 8 7 6 26
S1607 MELAN, Adv, T-VEC, MK-3475
Registration
T-VEC + MK-3475 (Pembrolizumab) 11 7 1 19
S1616 MELAN, Adv, Ipilimumab ± Nivolumab
Randomization
Ipilimumab 4 3 4 12
Nivolumab + Ipilimumab 13 10 7 33
17 13 11 45
S1801 Melan, Adv, Adjuvant vs Neoadjuvant MK-3475 (Pembrolizumab)
Randomization
Adjuvant Arm (Pre-surgery) 15 0 0 15
Neoadjuvant MK-3475 (Pembrolizumab) 14 0 0 14
29 0 0 29
Surgery
Surgery 14 0 0 14
Adjuvant Therapy
Post-Surgery MK-3475 (Pembrolizumab) 3 0 0 3
OCTOBER 2 - 5, 2019 SWOG MELANOMA 5
Non-SWOG Studies with SWOG-Credited Registrations MELANOMA COMMITTEE
Studies with Accrual from January 2018 - June 2019
SWOG Accrual
SWOG
Champion
Jan 2019
Jun 2019
Jul 2018
Dec 2018
Jan 2018
Jun 2018
SWOG
Total
Total
Accrued
EA6134 Adv, BRAF mut, Dabrafenib + Trametinib/Ipilimumab +
Nivolumab vs Ipilimumab + Nivolumab/Dabrafenib + Trametinib
B Chmielowski 9 4 2 39 198
Date Activated: 12/15/15
Most Recent Progress Report
EA6141 Melan, Avd, Nivolumab + Ipilimumab ± Sargmostim K Kim 0 0 0 36 250
Date Activated: 03/01/16 Date Temporarily Closed: 06/23/17
Most Recent Progress Report
EA6174 Merkel, Adjuvant Pembrolizumab vs Standard of Care
Observation
C Hsu 1 0 0 1 11
Date Activated: 07/23/18
Most Recent Progress Report
OCTOBER 2 - 5, 2019 SWOG MELANOMA 6
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, L Qian
Data Coordinator:
J Sanchez
Date Activated:
07/22/2014
Date Closed:
04/19/2019
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
OCTOBER 2 - 5, 2019 SWOG MELANOMA 7
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 Having met its accrual goal, this study was
permanently closed on April 19, 2019. The final
accrual was 249 patients participating in lead-in
continuous treatment. Four patients were ineligible
for the following reasons: inadequate baseline disease
assessment (1), inadequate cardiac function (1), not
having a V600E or V600K BRAF mutation (1), and
inadequate hematologic function (1). In addition,
three eligible patients who never received protocol
treatment were never randomized and are not
evaluable for any of the study endpoints. 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 242 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
OCTOBER 2 - 5, 2019 SWOG MELANOMA 8
S1320/II
six patients experienced treatment-related Grade 4
adverse events due to the following: CPK increased
and MS/connective tissue disorder, sepsis,
hypocalcemia, neutrophil count decreased,
hyponatremia, and the other due to hypocalcemia and
pneumonitis (1 patient each).
Two hundred and eleven patients were randomized
between intermittent and continuous dosing. Five
patients were ineligible for the following reasons:
ineligible for the trial at the initial registration (3),
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).
On the continuous dosing arm, 103 patients have
been assessed for adverse events. Six patients have
experienced Grade 4 treatment-related adverse events
due to the following reasons: sepsis (2), anemia and
increases in ALT and AST, dyspnea, lipase increase
and creatinine increase (1 patient each). On the
intermittent dosing arm, 100 patients have been
assessed for adverse events. Three patients have
experienced Grade 4 treatment-related adverse events
due to the following reasons: fever, lipase increase,
and acute kidney injury (1 patient each).
Registration by Institution
Lead-In Continuous Dosing
Institutions
Total
Reg Institutions
Total
Reg
Kaiser Perm NCORP 30 Colorado, U of 2
Kansas, U of 17 CRC West MI NCORP 2
Ohio State Univ 17 Ozarks NCORP 2
Utah, U of 12 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
Wichita NCORP 8 Dayton NCORP 1
Michigan, U of 7 Hawaii MU-NCORP 1
Arkansas, U of 6 Lahey Hosp & Med Ctr 1
Heartland NCORP 6 UF Cancer Center/Arkansas, U of 1
Los Angeles, U of CA 4 Wisconsin NCORP 1
Nevada CRF NCORP 4 ECOG-ACRIN 49
Rochester, Univ of 4 NRG 22
Columbus NCORP 3 ALLIANCE 15
KaiserPermanenteSCAL/Kaiser Perm NCORP 3 Total (32 Institutions) 249
Arizona CC, Univ of 2
OCTOBER 2 - 5, 2019 SWOG MELANOMA 9
S1320/II
Registration, Eligibility, and Evaluability
Lead-In Continuous Dosing
Data as of August 9, 2019
Lead-in
Continuous
Dosing
NUMBER REGISTERED 249
INELIGIBLE 4
ELIGIBLE 245
Not Analyzable 3
ADVERSE EVENT ASSESSMENT
Evaluable 242
Treatment Summary
Lead-In Continuous Dosing
Data as of August 9, 2019
Lead-in
Continuous
Dosing
NUMBER ON PROTOCOL TREATMENT 0
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
242
Treatment completed as planned 207
Adverse Event or side effects 18
Refusal unrelated to adverse event 1
Progression/relapse 13
Death 2
Other - not protocol specified 1
Reason under review 0
MAJOR PROTOCOL DEVIATIONS 0
LOST TO FOLLOW-UP 0
CONSENT WITHDRAWAL AFTER
TREATMENT INITIATION
16
OCTOBER 2 - 5, 2019 SWOG MELANOMA 10
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
Data as of August 9, 2019
Lead-in Continuous Dosing
(n=242)
Grade
ADVERSE EVENTS <=2 3 4 5
AST increased 236 6 0 0
Abdominal pain 241 1 0 0
Acute kidney injury 241 0 1 0
Anemia 238 4 0 0
Anorexia 240 2 0 0
Arthralgia 241 1 0 0
Blood bilirubin increased 241 1 0 0
Blood/lymph disorder-Other 241 1 0 0
CPK increased 241 0 1 0
Cardiac troponin T increased 241 1 0 0
Chills 239 3 0 0
Constipation 241 1 0 0
Dehydration 235 7 0 0
Diarrhea 239 3 0 0
Dyspnea 241 1 0 0
ECG QT corrected int prolong 241 1 0 0
Ejection fraction decreased 241 0 1 0
Epistaxis 241 1 0 0
Erythema multiforme 241 1 0 0
Fatigue 237 5 0 0
Febrile neutropenia 239 3 0 0
Fever 237 5 0 0
Fracture 241 1 0 0
Gastric hemorrhage 241 1 0 0
Generalized muscle weakness 240 2 0 0
Headache 240 2 0 0
Hyperglycemia 240 2 0 0
Hypertension 238 4 0 0
Hypoalbuminemia 241 1 0 0
Hypocalcemia 240 0 2 0
Hypokalemia 241 1 0 0
Hyponatremia 231 10 1 0
Hypophosphatemia 241 1 0 0
Hypotension 238 4 0 0
Hypoxia 241 1 0 0
Leukocytosis 241 1 0 0
Lipase increased 240 2 0 0
Lung infection 241 1 0 0
Lymphocyte count decreased 236 6 0 0
MS/connective tissue disorder 240 1 1 0
Metab/nutrition disorders-Other 241 1 0 0
Mucositis oral 241 1 0 0
Nausea 240 2 0 0
OCTOBER 2 - 5, 2019 SWOG MELANOMA 11
S1320/II
Lead-in Continuous Dosing
(n=242)
Grade
ADVERSE EVENTS <=2 3 4 5
Neutrophil count decreased 233 8 1 0
Platelet count decreased 241 1 0 0
Pneumonitis 241 0 1 0
Proteinuria 241 1 0 0
Rash acneiform 239 3 0 0
Rash maculo-papular 238 4 0 0
Retinopathy 241 1 0 0
Sepsis 239 0 2 1
Skin infection 240 2 0 0
Skin/subq tissue ds-Other 241 1 0 0
Thromboembolic event 239 3 0 0
Tx related secondary malig 240 2 0 0
Upper GI hemorrhage 241 1 0 0
Urinary tract infection 240 2 0 0
Vasc disorders-Other, spec 241 1 0 0
Vomiting 240 2 0 0
White blood cell decreased 238 4 0 0
MAX. GRADE ANY ADVERSE EVENT 172 62 7 1
OCTOBER 2 - 5, 2019 SWOG MELANOMA 12
S1320/II
Randomization by 6 Month IntervalsDivisions by ARM
Randomization
Continuous Dosing Intermittent Dosing
0
10
20
30
40
50
Time of Registration
JulDec2014
JanJun
2015
JulDec2015
JanJun
2016
JulDec2016
JanJun
2017
JulDec2017
JanJun
2018
JulDec2018
JanJun
2019
13
5
12
15
11
23
10
13
6
13
7
12
13
10
1
20
1110
6
Registration, Eligibility, and Evaluability
Randomization
Data as of August 9, 2019
TOTAL
Continuous
Dosing
Intermittent
Dosing
NUMBER REGISTERED 211 108 103
INELIGIBLE 5 3 2
ELIGIBLE 206 105 101
Analyzable, Pend. Elig. 2 2 0
RESPONSE ASSESSMENT
Determinable 186 96 90
Not Determinable 4 3 1
Too Early 16 6 10
ADVERSE EVENT ASSESSMENT
Evaluable 203 103 100
Too Early 3 2 1
OCTOBER 2 - 5, 2019 SWOG MELANOMA 13
S1320/II
Patient Characteristics
Randomization
Data as of August 9, 2019
Continuous
Dosing
(n=105)
Intermittent
Dosing
(n=101)
AGE
Median 58.7 62.5
Minimum 22.7 20.9
Maximum 88.6 88.8
SEX
Males 62 59% 70 69%
Females 43 41% 31 31%
HISPANIC
Yes 2 2% 4 4%
No 100 95% 97 96%
Unknown 3 3% 0 0%
RACE
White 103 98% 98 97%
Native American 1 1% 0 0%
Multi-Racial 0 0% 1 1%
Unknown 1 1% 2 2%
LDH
Elevated (>IULN) 39 37% 38 38%
Normal 66 63% 63 62%
PRIOR IMMUNE CHECKPOINT INHIBITOR
Yes 31 30% 30 30%
No 74 70% 71 70%
PRIOR IMMUNOTHERAPY
Yes 36 34% 40 40%
No 67 64% 61 60%
Data pending 2 2% 0 0%
PERFORMANCE STATUS
0 59 56% 58 57%
1 43 41% 41 41%
2 1 1% 2 2%
Data pending 2 2% 0 0%
STAGE
III 13 12% 12 12%
IV 92 88% 89 88%
OCTOBER 2 - 5, 2019 SWOG MELANOMA 14
S1320/II
Treatment Summary
Randomization
Data as of August 9, 2019
Total
NUMBER ON PROTOCOL TREATMENT 41
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
165
Treatment completed as planned 0
Adverse Event or side effects 33
Refusal unrelated to adverse event 7
Progression/relapse 113
Death 4
Other - not protocol specified 8
Reason under review 0
MAJOR PROTOCOL DEVIATIONS 0
LOST TO FOLLOW-UP 0
CONSENT WITHDRAWAL AFTER
TREATMENT INITIATION
10
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 August 9, 2019
Continuous Dosing
(n=103)
Grade
Intermittent Dosing
(n=100)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
ALT increased 101 1 1 0 99 1 0 0
AST increased 98 4 1 0 98 2 0 0
Acute kidney injury 103 0 0 0 99 0 1 0
Alkaline phosphatase increased 102 1 0 0 97 3 0 0
Anemia 100 2 1 0 98 2 0 0
Anorexia 103 0 0 0 99 1 0 0
Arthralgia 101 2 0 0 99 1 0 0
Back pain 102 1 0 0 100 0 0 0
Blood bilirubin increased 102 1 0 0 100 0 0 0
Chills 102 1 0 0 99 1 0 0
Confusion 103 0 0 0 99 1 0 0
Creatinine increased 102 0 1 0 100 0 0 0
Dehydration 102 1 0 0 100 0 0 0
Diarrhea 101 2 0 0 99 1 0 0
Dry skin 102 1 0 0 100 0 0 0
Dyspnea 102 0 1 0 100 0 0 0
ECG QT corrected int prolong 102 1 0 0 99 1 0 0
Ejection fraction decreased 99 4 0 0 96 4 0 0
OCTOBER 2 - 5, 2019 SWOG MELANOMA 15
S1320/II
Continuous Dosing
(n=103)
Grade
Intermittent Dosing
(n=100)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
Eye disorders - Other, specify 103 0 0 0 99 1 0 0
Fatigue 95 8 0 0 97 3 0 0
Fever 97 6 0 0 99 0 1 0
Flu like symptoms 101 2 0 0 100 0 0 0
Gastric hemorrhage 102 1 0 0 100 0 0 0
Generalized muscle weakness 101 2 0 0 98 2 0 0
Glucose intolerance 102 1 0 0 100 0 0 0
Hand-Foot syndrome 102 1 0 0 100 0 0 0
Hypercalcemia 103 0 0 0 99 1 0 0
Hyperglycemia 100 3 0 0 98 2 0 0
Hypertension 96 7 0 0 97 3 0 0
Hypoalbuminemia 102 1 0 0 100 0 0 0
Hyponatremia 99 4 0 0 98 2 0 0
Hypophosphatemia 103 0 0 0 99 1 0 0
Hypotension 101 2 0 0 99 1 0 0
Hypothyroidism 102 1 0 0 100 0 0 0
Infections/infestations-Other 103 0 0 0 99 1 0 0
Investigations-Other, specify 103 0 0 0 99 1 0 0
LV systolic dysfunction 102 1 0 0 99 1 0 0
Lipase increased 100 2 1 0 97 2 1 0
Localized edema 102 1 0 0 100 0 0 0
Lung infection 102 1 0 0 100 0 0 0
Lymphocyte count decreased 99 4 0 0 99 1 0 0
Mucositis oral 102 1 0 0 100 0 0 0
Myalgia 103 0 0 0 99 1 0 0
Nausea 103 0 0 0 99 1 0 0
Neutrophil count decreased 100 3 0 0 100 0 0 0
Pain in extremity 102 1 0 0 100 0 0 0
Platelet count decreased 102 1 0 0 100 0 0 0
Rash acneiform 101 2 0 0 100 0 0 0
Rash maculo-papular 101 2 0 0 99 1 0 0
Resp/thoracic/mediastinal ds 102 1 0 0 100 0 0 0
Retinal detachment 103 0 0 0 98 2 0 0
Sepsis 101 0 2 0 100 0 0 0
Serum amylase increased 103 0 0 0 98 2 0 0
Skin/subq tissue ds-Other 102 1 0 0 100 0 0 0
Syncope 102 1 0 0 100 0 0 0
Thromboembolic event 100 2 1 0 100 0 0 0
Tx related secondary malig 103 0 0 0 98 2 0 0
Urinary tract infection 103 0 0 0 99 1 0 0
Urinary tract obstruction 102 1 0 0 100 0 0 0
White blood cell decreased 100 3 0 0 99 1 0 0
MAX. GRADE ANY ADVERSE
EVENT
59 38 6 0 66 31 3 0
OCTOBER 2 - 5, 2019 SWOG MELANOMA 16
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, ECOG-ACRIN)
Study Chairs:
K Grossmann, S Patel, A Tarhini (ECOG-ACRIN),
T Petrella (CCTG)
Statisticians:
M Othus, J Moon, H Li, L Qian
Data Coordinators:
L Kingsbury, J Sanchez
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
OCTOBER 2 - 5, 2019 SWOG MELANOMA 17
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 analysis 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-six patients
are currently ineligible for the following reasons:
incorrect stage of disease (20), inadequate/incomplete
OCTOBER 2 - 5, 2019 SWOG MELANOMA 18
S1404/III
resection of disease (22), radiologic or clinical
evidence that patient was not disease free (10) , lack
of adequate tissue for PD-L1 testing (10) , inadequate
renal function , concurrent radiation therapy ,
recurrent satellite metastases , recurrent distant
metastases (1 patient each) .
A total of 1,345 patients were randomized. Thirty-
eight are currently ineligible, 37 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 37 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 acute inflammatory
demyelinating polyneuropathy (coded as "Nervous
system disorders - Other).
On the pembrolizumab arm, 641 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 13 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").
Initial Registrations by 3 Month IntervalsInitial Registration
Total
0
50
100
150
200
250
300
Time of Registration
OctDec2015
JanMar
2016
AprJun
2016
JulSep2016
OctDec2016
JanMar
2017
AprJun
2017
JulSep2017
164
259
73
268
207
185
8
262
OCTOBER 2 - 5, 2019 SWOG MELANOMA 19
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 CC, Univ 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 August 8, 2019
Tissue for PD
-L1 testing
NUMBER REGISTERED 1426
INELIGIBLE 66
ELIGIBLE 1360
Analyzable, Pend. Elig. 15
OCTOBER 2 - 5, 2019 SWOG MELANOMA 20
S1404/III
Randomization by 3 Month IntervalsDivisions by ARM
Randomization
FDA approved regimen MK-3475 (Pembrolizumab)
0
50
100
150
200
250
300
Time of Registration
OctDec2015
JanMar
2016
AprJun
2016
JulSep2016
OctDec2016
JanMar
2017
AprJun
2017
JulSep2017
68
118
29
147
99110
2
105
65
127
30
133
96
102
2
112
OCTOBER 2 - 5, 2019 SWOG MELANOMA 21
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 CC, Univ 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 August 8, 2019
TOTAL
FDA approved
regimen
MK-3475
(Pembrolizumab)
NUMBER REGISTERED 1345 678 667
INELIGIBLE 38 20 18
ELIGIBLE 1307 658 649
ADVERSE EVENT ASSESSMENT
Evaluable 1210 569 641
Not Evaluable 97 89 8
OCTOBER 2 - 5, 2019 SWOG MELANOMA 22
S1404/III
Patient Characteristics
Randomization
Data as of August 8, 2019
FDA approved
regimen
(n=658)
MK-3475
(Pembrolizumab)
(n=649)
AGE
Median 57.0 56.3
Minimum 18.3 20.0
Maximum 86.0 82.6
SEX
Males 398 60% 382 59%
Females 260 40% 267 41%
HISPANIC
Yes 18 3% 26 4%
No 621 94% 606 93%
Unknown 19 3% 17 3%
RACE
White 625 95% 622 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% 220 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% 543 84%
1 108 16% 106 16%
OCTOBER 2 - 5, 2019 SWOG MELANOMA 23
S1404/III
Treatment Summary
Randomization
Data as of August 8, 2019
Total
NUMBER ON PROTOCOL TREATMENT 24
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
1283
Treatment completed as planned 403
Adverse Event or side effects 473
Refusal unrelated to adverse event 142
Other - not protocol specified 36
Reason under review 0
MAJOR PROTOCOL DEVIATIONS 97
LOST TO FOLLOW-UP 4
CONSENT WITHDRAWAL AFTER
TREATMENT INITIATION
136
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 August 8, 2019
FDA approved regimen
(n=569)
Grade
MK-3475 (Pembrolizumab)
(n=641)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
ALT increased 523 39 7 0 622 19 0 0
AST increased 535 30 4 0 628 13 0 0
Abdominal pain 563 6 0 0 639 2 0 0
Acidosis 568 1 0 0 639 1 1 0
Acute kidney injury 567 2 0 0 639 2 0 0
Adrenal insufficiency 560 8 1 0 637 4 0 0
Alkaline phosphatase increased 566 3 0 0 641 0 0 0
Anemia 569 0 0 0 640 1 0 0
Anorexia 565 4 0 0 640 1 0 0
Anxiety 567 2 0 0 641 0 0 0
Arthralgia 566 3 0 0 638 3 0 0
Arthritis 568 1 0 0 641 0 0 0
Atelectasis 568 1 0 0 641 0 0 0
Atrial fibrillation 568 1 0 0 641 0 0 0
Atrial flutter 569 0 0 0 640 1 0 0
Autoimmune disorder 567 0 2 0 640 1 0 0
Back pain 566 3 0 0 641 0 0 0
Blood bilirubin increased 567 2 0 0 639 1 1 0
Blood/lymph disorder-Other 568 1 0 0 641 0 0 0
Blurred vision 568 1 0 0 641 0 0 0
OCTOBER 2 - 5, 2019 SWOG MELANOMA 24
S1404/III
FDA approved regimen
(n=569)
Grade
MK-3475 (Pembrolizumab)
(n=641)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
Bone pain 568 1 0 0 641 0 0 0
Bronchospasm 569 0 0 0 640 0 1 0
CPK increased 564 3 2 0 639 1 1 0
Cardiac disorder-Other, spec 568 1 0 0 641 0 0 0
Cardiac troponin T increased 568 1 0 0 641 0 0 0
Colitis 535 32 2 0 628 13 0 0
Colonic perforation 568 0 1 0 641 0 0 0
Confusion 567 2 0 0 640 1 0 0
Cough 568 1 0 0 640 1 0 0
Creatinine increased 567 1 1 0 641 0 0 0
Cystitis noninfective 568 1 0 0 641 0 0 0
Dehydration 566 3 0 0 640 1 0 0
Delirium 568 1 0 0 641 0 0 0
Depression 565 4 0 0 641 0 0 0
Diarrhea 515 53 1 0 623 18 0 0
Dizziness 568 1 0 0 641 0 0 0
Duodenal ulcer 568 1 0 0 641 0 0 0
Dyspepsia 568 1 0 0 641 0 0 0
Dyspnea 557 11 1 0 637 3 1 0
Encephalitis infection 567 1 1 0 641 0 0 0
Encephalopathy 568 1 0 0 641 0 0 0
Endocrine disorders-Other 565 4 0 0 638 2 1 0
Enterocolitis 563 5 0 1 640 1 0 0
Enterocolitis infectious 567 2 0 0 640 1 0 0
Erectile dysfunction 568 1 0 0 641 0 0 0
Esophagitis 568 1 0 0 641 0 0 0
Eye disorders - Other, specify 568 1 0 0 640 0 1 0
Eye pain 569 0 0 0 640 1 0 0
FEV1 decreased 569 0 0 0 640 1 0 0
Facial nerve disorder 569 0 0 0 640 1 0 0
Fall 568 1 0 0 641 0 0 0
Fatigue 540 29 0 0 638 3 0 0
Febrile neutropenia 567 1 1 0 641 0 0 0
Flu like symptoms 568 1 0 0 640 1 0 0
GI disorders-Other, specify 566 3 0 0 641 0 0 0
Gastritis 567 2 0 0 641 0 0 0
Gen disorders/admin site cond 567 2 0 0 640 1 0 0
Generalized muscle weakness 566 3 0 0 640 1 0 0
Headache 556 13 0 0 638 3 0 0
Hepatic pain 569 0 0 0 640 1 0 0
Hepatitis viral 567 2 0 0 641 0 0 0
Hepatobil disorders-Other 568 1 0 0 641 0 0 0
Hiccups 569 0 0 0 640 1 0 0
Hyperglycemia 565 4 0 0 634 3 4 0
Hypersomnia 568 1 0 0 641 0 0 0
Hypertension 562 7 0 0 639 2 0 0
Hyperthyroidism 568 0 1 0 640 1 0 0
Hypertriglyceridemia 561 6 2 0 640 1 0 0
Hypoalbuminemia 568 1 0 0 641 0 0 0
Hypokalemia 566 3 0 0 641 0 0 0
Hyponatremia 554 11 4 0 632 9 0 0
OCTOBER 2 - 5, 2019 SWOG MELANOMA 25
S1404/III
FDA approved regimen
(n=569)
Grade
MK-3475 (Pembrolizumab)
(n=641)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
Hypophosphatemia 566 3 0 0 638 3 0 0
Hypotension 566 3 0 0 641 0 0 0
Hypothyroidism 566 3 0 0 641 0 0 0
Hypoxia 566 3 0 0 639 2 0 0
Immune sys disorders-Other 568 1 0 0 639 2 0 0
Infections/infestations-Other 568 1 0 0 641 0 0 0
Infusion related reaction 568 1 0 0 640 1 0 0
Insomnia 568 1 0 0 641 0 0 0
Joint effusion 569 0 0 0 640 1 0 0
Leukocytosis 567 2 0 0 641 0 0 0
Lipase increased 564 4 1 0 640 1 0 0
Lower GI hemorrhage 568 1 0 0 641 0 0 0
Lung infection 568 1 0 0 637 4 0 0
Lymphocyte count decreased 557 11 1 0 638 3 0 0
MS/connective tissue disorder 568 1 0 0 639 2 0 0
Meningitis 566 3 0 0 641 0 0 0
Metab/nutrition disorders-Other 567 2 0 0 640 0 1 0
Mucositis oral 569 0 0 0 639 2 0 0
Muscle weakness lower limb 568 1 0 0 641 0 0 0
Myalgia 565 4 0 0 640 1 0 0
Myocardial infarction 569 0 0 0 640 1 0 0
Myocarditis 569 0 0 0 640 0 0 1
Myositis 568 1 0 0 640 1 0 0
Nausea 559 10 0 0 640 1 0 0
Neoplasms, all 569 0 0 0 640 0 0 1
Nervous sys disorders-Other 565 3 1 0 639 1 1 0
Neuralgia 567 2 0 0 641 0 0 0
Neutrophil count decreased 519 43 7 0 639 2 0 0
Pain 568 1 0 0 641 0 0 0
Pain in extremity 567 2 0 0 641 0 0 0
Pain of skin 569 0 0 0 640 1 0 0
Pancreatitis 566 2 1 0 636 5 0 0
Papulopustular rash 568 1 0 0 641 0 0 0
Peripheral motor neuropathy 568 1 0 0 641 0 0 0
Peripheral sensory neuropathy 568 0 1 0 641 0 0 0
Pharyngitis 568 1 0 0 641 0 0 0
Pleural effusion 568 1 0 0 641 0 0 0
Pneumonitis 563 6 0 0 636 5 0 0
Proctitis 569 0 0 0 640 1 0 0
Pruritus 562 7 0 0 641 0 0 0
Rash acneiform 569 0 0 0 639 2 0 0
Rash maculo-papular 538 31 0 0 632 9 0 0
Rash pustular 568 1 0 0 641 0 0 0
Resp/thoracic/mediastinal ds 569 0 0 0 640 1 0 0
Respiratory failure 567 0 1 1 641 0 0 0
Restrictive cardiomyopathy 568 1 0 0 641 0 0 0
Retinal detachment 569 0 0 0 640 0 1 0
Retinal tear 569 0 0 0 640 1 0 0
Secondary Leukemia 569 0 0 0 640 0 0 1
Seizure 569 0 0 0 640 1 0 0
Sepsis 567 0 2 0 640 0 1 0
OCTOBER 2 - 5, 2019 SWOG MELANOMA 26
S1404/III
FDA approved regimen
(n=569)
Grade
MK-3475 (Pembrolizumab)
(n=641)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
Serum amylase increased 568 1 0 0 640 1 0 0
Sinus tachycardia 567 2 0 0 641 0 0 0
Sinusitis 569 0 0 0 640 1 0 0
Skin infection 568 1 0 0 640 1 0 0
Skin/subq tissue ds-Other 567 2 0 0 639 2 0 0
Syncope 563 6 0 0 640 1 0 0
Tremor 569 0 0 0 640 1 0 0
Vitreous hemorrhage 569 0 0 0 640 1 0 0
Vomiting 561 8 0 0 640 1 0 0
Weight loss 567 2 0 0 641 0 0 0
Wheezing 569 0 0 0 640 0 1 0
White blood cell decreased 550 17 2 0 641 0 0 0
MAX. GRADE ANY ADVERSE
EVENT
255 275 37 2 517 109 13 2
OCTOBER 2 - 5, 2019 SWOG MELANOMA 27
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, L Qian
Data Coordinator:
M Shi
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
with unresectable disease are eligible for Cohort B.
OCTOBER 2 - 5, 2019 SWOG MELANOMA 28
S1512/II
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 30 patients to
achieve 25 eligible patients.
Cohort B will accrue approximately 26 patients to
achieve 21 eligible patients.
Summary Statement On July 2, 2019, the trial design for Cohort A was
modified, reducing the accrual goal to 25 eligible
patients.
As of June 30, 2019, 26 patients have been
registered, 12 to Cohort A and 14 to Cohort B. One
patient withdrew consent prior to receiving any
protocol treatment and is not analyzable for any of
the study endpoints.
Twenty-three patients have been assessed for adverse
events. One patient in Cohort B has experienced
treatment-related Grade 4 lung infection and sepsis.
Registration by Institution
Registrations ending June 30, 2019
Institutions
Total
Reg Institutions
Total
Reg
H Lee Moffitt CC 10 Utah, U of 2
Ohio State Univ 4 Georgia NCORP 1
Los Angeles, U of CA 3 Northwestern Univ 1
Kansas, U of 2 Southeast COR NCORP 1
So Calif, U of 2 Total (9 Institutions) 26
OCTOBER 2 - 5, 2019 SWOG MELANOMA 29
S1512/II
Registration, Eligibility, and Evaluability
Classified by Cohort
Registrations ending June 30, 2019; Data as of August 8, 2019
TOTAL
Resectable
(Cohort A)
Unresectable
(Cohort B)
NUMBER REGISTERED 26 12 14
ELIGIBLE 26 12 14
Analyzable, Pend. Elig. 11 4 7
Not Analyzable 1 1 0
BASELINE DISEASE STATUS
Measurable 15 7 8
Non Measurable 1 1 0
Too Early 9 3 6
RESPONSE ASSESSMENT
Determinable 11 5 6
Not Determinable 1 0 1
Too Early 12 5 7
Not Applicable 1 1 0
ADVERSE EVENT ASSESSMENT
Evaluable 23 10 13
Too Early 2 1 1
Patient Characteristics
Classified by Cohort
Registrations ending June 30, 2019; Data as of August 8, 2019
Resectable
(Cohort A)
(n=11)
Unresectable
(Cohort B)
(n=14)
AGE
Median 80.8 80.4
Minimum 49.2 58.7
Maximum 91.1 89.6
SEX
Males 8 73% 13 93%
Females 3 27% 1 7%
HISPANIC
No 11 100% 14 100%
RACE
White 11 100% 14 100%
PERFORMANCE STATUS
0 8 73% 9 64%
1 3 27% 5 36%
OCTOBER 2 - 5, 2019 SWOG MELANOMA 30
S1512/II
Treatment Summary
Classified by Cohort
Registrations ending June 30, 2019; Data as of August 8, 2019
TOTAL
Resectable
(Cohort A)
Unresectable
(Cohort B)
NUMBER ON PROTOCOL TREATMENT 10 2 8
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
15 9 6
Treatment completed as planned 7 7 0
Adverse Event or side effects 0 0 0
Refusal unrelated to adverse event 1 0 1
Progression/relapse 1 0 1
Death 0 0 0
Other - not protocol specified 0 0 0
Reason under review 6 2 4
MAJOR PROTOCOL DEVIATIONS 0 0 0
LOST TO FOLLOW-UP 0 0 0
CONSENT WITHDRAWAL AFTER
TREATMENT INITIATION
1 1 0
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 June 30, 2019; Data as of August 8, 2019
Resectable (Cohort A)
(n=10)
Grade
Unresectable (Cohort B)
(n=13)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
ALT increased 10 0 0 0 13 0 0 0
Abdominal distension 10 0 0 0 13 0 0 0
Alkaline phosphatase increased 10 0 0 0 13 0 0 0
Anemia 10 0 0 0 13 0 0 0
Anorexia 10 0 0 0 13 0 0 0
Arthralgia 10 0 0 0 13 0 0 0
Blood bilirubin increased 10 0 0 0 13 0 0 0
Bullous dermatitis 10 0 0 0 13 0 0 0
CPK increased 10 0 0 0 12 1 0 0
Cardiac troponin I increased 10 0 0 0 13 0 0 0
Confusion 10 0 0 0 13 0 0 0
Constipation 10 0 0 0 13 0 0 0
Diarrhea 10 0 0 0 13 0 0 0
Dizziness 10 0 0 0 13 0 0 0
Dysphagia 10 0 0 0 13 0 0 0
Dyspnea 10 0 0 0 12 1 0 0
Edema limbs 10 0 0 0 13 0 0 0
Endocrine disorders-Other 10 0 0 0 13 0 0 0
OCTOBER 2 - 5, 2019 SWOG MELANOMA 31
S1512/II
Resectable (Cohort A)
(n=10)
Grade
Unresectable (Cohort B)
(n=13)
Grade
ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5
Eye disorders - Other, specify 10 0 0 0 13 0 0 0
Fall 10 0 0 0 13 0 0 0
Fatigue 10 0 0 0 13 0 0 0
Fever 10 0 0 0 13 0 0 0
Flu like symptoms 10 0 0 0 13 0 0 0
Generalized muscle weakness 10 0 0 0 13 0 0 0
Headache 10 0 0 0 13 0 0 0
Hypercalcemia 10 0 0 0 13 0 0 0
Hyperkalemia 10 0 0 0 13 0 0 0
Hypernatremia 10 0 0 0 13 0 0 0
Hypertension 10 0 0 0 13 0 0 0
Hyperthyroidism 10 0 0 0 13 0 0 0
Hypoalbuminemia 10 0 0 0 13 0 0 0
Hypokalemia 10 0 0 0 13 0 0 0
Hyponatremia 10 0 0 0 13 0 0 0
Hypothyroidism 10 0 0 0 13 0 0 0
Hypoxia 10 0 0 0 12 1 0 0
Insomnia 10 0 0 0 13 0 0 0
Lung infection 10 0 0 0 12 0 1 0
Lymphocyte count decreased 10 0 0 0 13 0 0 0
MS/connective tissue disorder 10 0 0 0 12 1 0 0
Myalgia 10 0 0 0 13 0 0 0
Myositis 10 0 0 0 12 1 0 0
Nausea 10 0 0 0 13 0 0 0
Neoplasms, all 10 0 0 0 13 0 0 0
Pain 10 0 0 0 13 0 0 0
Pain in extremity 10 0 0 0 13 0 0 0
Paresthesia 10 0 0 0 13 0 0 0
Platelet count decreased 10 0 0 0 13 0 0 0
Pneumonitis 10 0 0 0 13 0 0 0
Pruritus 10 0 0 0 13 0 0 0
Rash maculo-papular 10 0 0 0 12 1 0 0
Sepsis 10 0 0 0 12 0 1 0
Skin/subq tissue ds-Other 10 0 0 0 12 1 0 0
Tremor 10 0 0 0 13 0 0 0
Urinary incontinence 10 0 0 0 13 0 0 0
Vomiting 10 0 0 0 13 0 0 0
MAX. GRADE ANY ADVERSE
EVENT
10 0 0 0 9 3 1 0
OCTOBER 2 - 5, 2019 SWOG MELANOMA 32
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
Study Chairs:
S Hu-Lieskovan, A Ribas
Statisticians:
M Wu, J Moon, L Qian
Data Coordinator:
M Shi
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
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
OCTOBER 2 - 5, 2019 SWOG MELANOMA 33
S1607/II
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
anti-hepatic drug, and must not have active hepatic
skin lesions or prior complications of hepatic
infection which require treatment with an anti-hepatic
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 June 30, 2019, 19 patients have been
registered, 5 to the cohort with at least one visceral
lesion and 14 to the cohort with non-visceral disease
only.
Eighteen patients have been assessed for adverse
events. No treatment-related adverse events greater
than Grade 3 have been reported.
OCTOBER 2 - 5, 2019 SWOG MELANOMA 34
S1607/II
Registration by Institution
Registrations ending June 30, 2019
Institutions Total Reg
Los Angeles, U of CA 8
So Calif, U of 3
Ohio State Univ 2
Utah, U of 2
ECOG-ACRIN 3
NRG 1
Total (6 Institutions) 19
Registration, Eligibility, and Evaluability
Classified by Cohort
Registrations ending June 30, 2019; Data as of August 14, 2019
TOTAL
Visceral
(Cohort A)
Non-Visceral
(Cohort B)
NUMBER REGISTERED 19 5 14
ELIGIBLE 19 5 14
Analyzable, Pend. Elig. 8 1 7
RESPONSE ASSESSMENT
Determinable 9 3 6
Too Early 10 2 8
ADVERSE EVENT ASSESSMENT
Evaluable 18 5 13
Too Early 1 0 1
OCTOBER 2 - 5, 2019 SWOG MELANOMA 35
S1607/II
Patient Characteristics
Classified by Cohort
Registrations ending June 30, 2019; Data as of August 14, 2019
Visceral
(Cohort A)
(n=5)
Non-Visceral
(Cohort B)
(n=14)
AGE
Median 51.5 60.9
Minimum 35.4 37.8
Maximum 76.0 93.7
SEX
Males 3 60% 6 43%
Females 2 40% 8 57%
HISPANIC
Yes 2 40% 1 7%
No 3 60% 13 93%
RACE
White 3 60% 13 93%
Pacific Islander 0 0% 1 7%
Unknown 2 40% 0 0%
PERFORMANCE STATUS
0 1 20% 11 79%
1 4 80% 2 14%
2 0 0% 1 7%
OCTOBER 2 - 5, 2019 SWOG MELANOMA 36
S1607/II
Treatment Summary
Classified by Cohort
Registrations ending June 30, 2019; Data as of August 14, 2019
TOTAL
Visceral
(Cohort A)
Non-Visceral
(Cohort B)
NUMBER ON PROTOCOL TREATMENT 13 2 11
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
6 3 3
Treatment completed as planned 0 0 0
Adverse Event or side effects 0 0 0
Refusal unrelated to adverse event 0 0 0
Progression/relapse 6 3 3
Death 0 0 0
Other - not protocol specified 0 0 0
Reason under review 0 0 0
MAJOR PROTOCOL DEVIATIONS 0 0 0
LOST TO FOLLOW-UP 0 0 0
CONSENT WITHDRAWAL AFTER
TREATMENT INITIATION
0 0 0
OCTOBER 2 - 5, 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 June 30, 2019; Data as of August 14, 2019
Visceral (Cohort A)
(n=5)
Grade
Non-Visceral (Cohort B)
(n=13)
Grade
ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5
Abdominal pain 5 0 0 0 0 0 12 1 0 0 0 0
Anemia 5 0 0 0 0 0 12 0 1 0 0 0
Anorexia 5 0 0 0 0 0 12 0 1 0 0 0
Blood bilirubin increased 5 0 0 0 0 0 12 1 0 0 0 0
Chills 5 0 0 0 0 0 10 2 1 0 0 0
Dyspnea 5 0 0 0 0 0 12 0 0 1 0 0
Fatigue 5 0 0 0 0 0 9 2 0 2 0 0
Fever 4 1 0 0 0 0 12 0 1 0 0 0
Flu like symptoms 4 0 0 1 0 0 9 1 3 0 0 0
Headache 5 0 0 0 0 0 12 0 1 0 0 0
Hot flashes 4 1 0 0 0 0 13 0 0 0 0 0
Hyponatremia 5 0 0 0 0 0 12 0 0 1 0 0
Hypothyroidism 5 0 0 0 0 0 12 0 1 0 0 0
Hypoxia 5 0 0 0 0 0 12 0 0 1 0 0
Injection site reaction 4 0 1 0 0 0 11 1 1 0 0 0
Lymphocyte count decreased 5 0 0 0 0 0 12 1 0 0 0 0
MS/connective tissue disorder 5 0 0 0 0 0 12 1 0 0 0 0
Malaise 5 0 0 0 0 0 12 1 0 0 0 0
Nausea 5 0 0 0 0 0 10 1 2 0 0 0
Neutrophil count decreased 5 0 0 0 0 0 12 1 0 0 0 0
Non-cardiac chest pain 5 0 0 0 0 0 12 1 0 0 0 0
Platelet count decreased 5 0 0 0 0 0 12 1 0 0 0 0
Pruritus 5 0 0 0 0 0 12 0 1 0 0 0
Rash maculo-papular 5 0 0 0 0 0 12 1 0 0 0 0
Sinus tachycardia 5 0 0 0 0 0 12 0 1 0 0 0
Skin infection 5 0 0 0 0 0 12 0 1 0 0 0
Tumor pain 5 0 0 0 0 0 12 0 0 1 0 0
Vomiting 5 0 0 0 0 0 12 1 0 0 0 0
White blood cell decreased 5 0 0 0 0 0 12 1 0 0 0 0
MAX. GRADE ANY ADVERSE
EVENT
3 1 0 1 0 0 3 3 5 2 0 0
OCTOBER 2 - 5, 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 Magner, S Gurung
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 the overall response rate (ORR) in
patients with gestational trophoblastic tumors treated
with ipilimumab plus nivolumab combination
immunotherapy.
To evaluate the RECIST 1.1 overall response rate
(ORR) in patients PD-L1 amplified cancers treated
with nivolumab 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 or with PD-L1 amplification only.
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 in one of
the histologically defined rare cancer cohorts maybe
have received either prior anti-CTLA-4 or other prior
anti-PD-1/anti-PD-L1 therapy, but not both, provided
that it is completed at least 4 weeks prior to
registration. Patients in the PD-L1 amplification
cohort must not have received anti-PD-1/anti-PD-L1
therapy; prior anti-CTLA-4 is allowed provided that
it is completed at least 4 weeks prior to registration.
Patients who had a prior immune-related adverse
event with prior immunotherapy are not eligible.
OCTOBER 2 - 5, 2019 SWOG MELANOMA 39
S1609/II
Patients with brain metastases or primary brain
tumors must have completed treatment, surgery or
radiation therapy at least 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 or less.
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, with
the exception of PD-L1 amplification patients.
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.
OCTOBER 2 - 5, 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 Coordinators:
S Dzingle, R Topacio
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
OCTOBER 2 - 5, 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
balanced 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 balanced 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.
OCTOBER 2 - 5, 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
Study Chairs:
A VanderWalde, A Ribas
Statisticians:
M Wu, L Qian, 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
OCTOBER 2 - 5, 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. 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.
Patient 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 June 30, 2019, 45 patients have been
registered. Two patients are currently ineligible: one
due to not having received prior anti-PD-1 or anti-
PD-L1 therapy, the other due to not having
documented progression while on anti-PD-1 or anti-
PD-LI therapy.
On the combination arm, 31 patients have been
assessed for adverse events. One patient has
experienced treatment-related Grade 4 adverse
events, lymphopenia and hypokalemia. On the single
agent arm, 11 patients have been assessed for adverse
events. No treatment-related adverse events greater
than Grade 3 have been reported on this arm.
OCTOBER 2 - 5, 2019 SWOG MELANOMA 44
S1616/II
Registration by Institution
Registrations ending June 30, 2019
Institutions
Total
Reg Institutions
Total
Reg
Los Angeles, U of CA 5 Eisenhower Med Ctr/San Diego, U of CA 1
Northwestern Univ 5 Kaiser Perm NCORP 1
Tennessee, U of 5 Kansas, U of 1
CRC West MI NCORP 3 Rochester, Univ of 1
Ohio State Univ 3 NRG 8
H Lee Moffitt CC 2 ALLIANCE 4
New Mexico MU-NCORP 2 ECOG-ACRIN 3
Dayton NCORP 1 Total (15 Institutions) 45
Registration, Eligibility, and Evaluability
Registrations ending June 30, 2019; Data as of August 8, 2019
TOTAL Ipilimumab
Nivolumab +
Ipilimumab
NUMBER REGISTERED 45 12 33
INELIGIBLE 2 1 1
ELIGIBLE 43 11 32
Analyzable, Pend. Elig. 6 2 4
RESPONSE ASSESSMENT
Determinable 34 9 25
Too Early 9 2 7
ADVERSE EVENT ASSESSMENT
Evaluable 42 11 31
Too Early 1 0 1
OCTOBER 2 - 5, 2019 SWOG MELANOMA 45
S1616/II
Patient Characteristics
Registrations ending June 30, 2019; Data as of August 8, 2019
Ipilimumab
(n=11)
Nivolumab +
Ipilimumab
(n=32)
AGE
Median 61.7 63.0
Minimum 50.7 34.4
Maximum 75.2 86.9
SEX
Males 7 64% 20 63%
Females 4 36% 12 38%
HISPANIC
Yes 2 18% 0 0%
No 8 73% 30 94%
Unknown 1 9% 2 6%
RACE
White 11 100% 27 84%
Asian 0 0% 3 9%
Unknown 0 0% 2 6%
PERFORMANCE STATUS
0 8 73% 18 56%
1 2 18% 9 28%
2 0 0% 3 9%
Data pending 1 9% 2 6%
Treatment Summary
Registrations ending June 30, 2019; Data as of August 8, 2019
TOTAL
NUMBER ON PROTOCOL TREATMENT 12
NUMBER OFF PROTOCOL TREATMENT
REASON OFF TREATMENT
31
Adverse Event or side effects 5
Refusal unrelated to adverse event 2
Other - not protocol specified 0
Reason under review 0
MAJOR PROTOCOL DEVIATIONS 0
LOST TO FOLLOW-UP 0
CONSENT WITHDRAWAL AFTER
TREATMENT INITIATION
0
OCTOBER 2 - 5, 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 June 30, 2019; Data as of August 8, 2019
Ipilimumab
(n=11)
Grade
Nivolumab + Ipilimumab
(n=31)
Grade
ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5
ALT increased 10 1 0 0 0 0 21 5 3 2 0 0
AST increased 10 1 0 0 0 0 20 8 1 2 0 0
Abdominal pain 10 0 1 0 0 0 28 2 1 0 0 0
Adrenal insufficiency 10 0 1 0 0 0 30 0 0 1 0 0
Alkaline phosphatase increased 10 1 0 0 0 0 27 3 0 1 0 0
Anemia 11 0 0 0 0 0 27 2 0 2 0 0
Anorexia 10 1 0 0 0 0 25 1 4 1 0 0
Arthralgia 8 3 0 0 0 0 27 3 0 1 0 0
Autoimmune disorder 9 0 2 0 0 0 31 0 0 0 0 0
Back pain 11 0 0 0 0 0 30 0 1 0 0 0
Bloating 11 0 0 0 0 0 30 0 1 0 0 0
Blurred vision 10 1 0 0 0 0 30 0 1 0 0 0
Colitis 11 0 0 0 0 0 29 1 0 1 0 0
Creatinine increased 11 0 0 0 0 0 30 0 1 0 0 0
Dehydration 11 0 0 0 0 0 29 0 1 1 0 0
Diarrhea 9 2 0 0 0 0 20 4 3 4 0 0
Dyspnea 11 0 0 0 0 0 29 1 1 0 0 0
Endocrine disorders-Other 11 0 0 0 0 0 30 0 0 1 0 0
Enterocolitis 11 0 0 0 0 0 30 0 0 1 0 0
Fatigue 4 4 3 0 0 0 20 4 6 1 0 0
Fever 10 1 0 0 0 0 27 3 0 1 0 0
GERD 10 0 1 0 0 0 31 0 0 0 0 0
GI disorders-Other, specify 11 0 0 0 0 0 29 1 1 0 0 0
Generalized muscle weakness 10 0 1 0 0 0 30 0 1 0 0 0
Genital edema 11 0 0 0 0 0 30 0 1 0 0 0
Headache 10 0 1 0 0 0 27 3 1 0 0 0
Hyperglycemia 10 1 0 0 0 0 27 3 1 0 0 0
Hypertension 11 0 0 0 0 0 30 0 1 0 0 0
Hyperthyroidism 11 0 0 0 0 0 29 1 1 0 0 0
Hypocalcemia 11 0 0 0 0 0 30 0 0 1 0 0
Hypokalemia 11 0 0 0 0 0 28 1 0 1 1 0
Hyponatremia 11 0 0 0 0 0 26 3 0 2 0 0
Hypotension 11 0 0 0 0 0 29 0 1 1 0 0
Hypothyroidism 10 0 1 0 0 0 30 1 0 0 0 0
Laryngeal edema 11 0 0 0 0 0 30 0 1 0 0 0
Lung infection 11 0 0 0 0 0 30 0 0 1 0 0
Lymphocyte count decreased 10 1 0 0 0 0 27 1 2 0 1 0
MS/connective tissue disorder 11 0 0 0 0 0 30 0 1 0 0 0
Metab/nutrition disorders-Oth 11 0 0 0 0 0 30 0 1 0 0 0
Mucositis oral 11 0 0 0 0 0 27 2 2 0 0 0
Myalgia 11 0 0 0 0 0 29 1 1 0 0 0
Nausea 7 4 0 0 0 0 28 1 1 1 0 0
Neck pain 11 0 0 0 0 0 30 0 1 0 0 0
Neuralgia 11 0 0 0 0 0 30 0 1 0 0 0
OCTOBER 2 - 5, 2019 SWOG MELANOMA 47
S1616/II
Ipilimumab
(n=11)
Grade
Nivolumab + Ipilimumab
(n=31)
Grade
ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5
Pain in extremity 11 0 0 0 0 0 27 3 1 0 0 0
Pruritus 9 2 0 0 0 0 19 7 4 1 0 0
Rash acneiform 10 1 0 0 0 0 29 1 1 0 0 0
Rash maculo-papular 8 2 0 1 0 0 18 8 4 1 0 0
Skin ulceration 11 0 0 0 0 0 30 0 1 0 0 0
Skin/subq tissue ds-Other 11 0 0 0 0 0 29 1 1 0 0 0
Syncope 11 0 0 0 0 0 30 0 0 1 0 0
Urinary incontinence 11 0 0 0 0 0 30 0 1 0 0 0
Uveitis 11 0 0 0 0 0 30 0 0 1 0 0
Vomiting 10 1 0 0 0 0 29 1 0 1 0 0
Weight loss 10 1 0 0 0 0 28 2 1 0 0 0
MAX. GRADE ANY ADVERSE
EVENT
1 6 3 1 0 0 4 3 9 14 1 0
OCTOBER 2 - 5, 2019 SWOG MELANOMA 48
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 (ECOG-ACRIN)
Statisticians:
M Othus, J Moon, L Qian
Data Coordinator:
M Shi
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.
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
OCTOBER 2 - 5, 2019 SWOG MELANOMA 49
S1801/II
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
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) stage of
disease at randomization: IIIB vs IIIC vs IIID/IV.
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 As of June 30, 2019, 29 patients have been
registered, 15 on the adjuvant arm, 14 on the
neoadjuvant arm.
Ten patients have been assessed for adverse events
related to neoadjuvant pembrolizumab. No treatment-
related adverse events greater than Grade 3 have been
reported on this arm.
As of June 30, 2019, 14 patients have been registered
to the surgery step. One patient is currently ineligible
due to having disease progression which rendered the
patient unable to receive the planned surgery. There
are no adverse event data to report at this time. Sites
are reminded to submit data on the post-surgical
adverse event assessment in a timely manner. One
patient on the adjuvant arm refused to continue on the
clinical trial after receiving surgery. Another patient
was removed from protocol therapy after a post-
surgical disease assessment revealed evidence of
distant metastases.
As of June 30, 2019, three patients have enrolled for
adjuvant therapy following surgery, including one
patient on the neoadjuvant arm. One patient is
currently ineligible due to disease progression
following surgery. No adverse events have been
reported.
OCTOBER 2 - 5, 2019 SWOG MELANOMA 50
S1801/II
Randomization by 1 Month IntervalsDivisions by ARM
Adjuvant Arm Neoadjuvant Pembrolizumab
0
10
20
Time of Registration
Feb2019
Mar2019
Apr2019
May2019
Jun2019
22
6
1
42
6
6
Registration by Institution
Randomization
Registrations ending June 30, 2019
Institutions
Total
Reg Institutions
Total
Reg
CRC West MI NCORP 4 Montana NCORP 1
Kaiser Perm NCORP 3 So Calif, U of 1
Northwestern Univ 3 Utah, U of 1
Wisconsin NCORP 3 ALLIANCE 3
Arizona CC, Univ of 2 ECOG-ACRIN 3
Heartland NCORP 2 NRG 1
Harrington CC 1 Total (14 Institutions) 29
Michigan CRC NCORP 1
OCTOBER 2 - 5, 2019 SWOG MELANOMA 51
S1801/II
Registration, Eligibility, and Evaluability
Randomization
Registrations ending June 30, 2019; Data as of August 14, 2019
TOTAL Adjuvant Arm
Neoadjuvant
Pembrolizumab
NUMBER REGISTERED 29 15 14
ELIGIBLE 29 15 14
Analyzable, Pend. Elig. 21 10 11
RESPONSE ASSESSMENT
Determinable 1 0 1
Too Early 13 0 13
Not Applicable 15 15 0
ADVERSE EVENT ASSESSMENT
Evaluable 10 0 10
Too Early 4 0 4
Not Applicable 15 15 0
OCTOBER 2 - 5, 2019 SWOG MELANOMA 52
S1801/II
Patient Characteristics
Registrations ending June 30, 2019; Data as of August 14, 2019
Adjuvant Arm
(n=15)
Neoadjuvant
Pembrolizumab
(n=14)
AGE
Median 61.9 60.6
Minimum 30.5 25.6
Maximum 88.6 84.5
SEX
Males 11 73% 7 50%
Females 4 27% 7 50%
HISPANIC
Yes 1 7% 1 7%
No 14 93% 10 71%
Unknown 0 0% 3 21%
RACE
White 14 93% 13 93%
Asian 1 7% 0 0%
Unknown 0 0% 1 7%
LDH
Low/Normal 12 80% 12 86%
High 3 20% 2 14%
STAGE
IIIB 5 33% 6 43%
IIIC 7 47% 6 43%
IIID/IV 3 20% 2 14%
OCTOBER 2 - 5, 2019 SWOG MELANOMA 53
S1801/II
Number of Patients with a Given Type and Grade of Adverse Event
Randomization
Adverse Events Unlikely or Not Related to Treatment Excluded
Registrations ending June 30, 2019; Data as of August 14, 2019
Neoadjuvant Pembrolizumab
(n=10)
Grade
ADVERSE EVENTS 0 1 2 3 4 5
ALT increased 7 1 2 0 0 0
AST increased 8 1 1 0 0 0
Abdominal pain 9 1 0 0 0 0
Arthralgia 8 1 1 0 0 0
CPK increased 9 0 1 0 0 0
Colitis 9 0 1 0 0 0
Creatinine increased 9 1 0 0 0 0
Diarrhea 9 0 0 1 0 0
Fatigue 5 3 2 0 0 0
Generalized muscle weakness 9 0 1 0 0 0
Hyperglycemia 9 0 0 1 0 0
Mucositis oral 9 1 0 0 0 0
Myalgia 9 0 1 0 0 0
Myositis 9 0 1 0 0 0
Nausea 8 2 0 0 0 0
Pruritus 9 1 0 0 0 0
Rash maculo-papular 9 1 0 0 0 0
Vomiting 9 1 0 0 0 0
MAX. GRADE ANY ADVERSE
EVENT
3 4 2 1 0 0
OCTOBER 2 - 5, 2019 SWOG MELANOMA 54
S1801/II
Registration, Eligibility, and Evaluability
Classified by Randomization Arm
Surgery
Registrations ending June 30, 2019; Data as of August 14, 2019
TOTAL Adjuvant Arm
Neoadjuvant
Pembrolizumab
NUMBER REGISTERED 14 12 2
INELIGIBLE 1 0 1
ELIGIBLE 13 12 1
Analyzable, Pend. Elig. 8 7 1
RESPONSE ASSESSMENT
Not Applicable 13 12 1
ADVERSE EVENT ASSESSMENT
Too Early 13 12 1
ECOG-ACRIN Cancer Research Group EA6174 Study Progress and Safety Report Spring 2019
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EA6174 A PHASE III RANDOMIZED TRIAL COMPARING ADJUVANT PEMBROLIZUMAB TO STANDARD OF CARE OBSERVATION IN COMPLETELY RESECTED MERKEL CELL CARCINOMA
Sponsor(s) Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Brian Gastman Statistician Dr. Sandra Lee Data Specialist Matthew Talbot Phase of Study III Type of Study Therapeutic Committee Accrual Objective
Melanoma 500 Patients
Participating Groups ECOG-ACRIN, ECOG-ACRIN, SWOG, ALLIANCE, NRG
NSC# 776864 Clinicaltrials.gov Study ID NCT03712605 Study Status Open to Accrual Date Activated October 1, 2018 Schema
ECOG-ACRIN Cancer Research Group EA6174 Study Progress and Safety Report Spring 2019
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Purpose of Study Primary Objective: To compare OS and RFS as co-primary endpoints within the two arms Secondary Objectives: To evaluate adverse events, evaluate distant metastasis free survival (DMFS), evaluate the impact of radiation on clinical outcomes (OS, RFS, DMFS). Study Population Patients with Merkel cell carcinoma with pathologic stages (AJCC version 8) I-IIIb. Interim analysis for OS will begin when OS endpoint reaches approximately 50% information time. For the OS endpoint, it is expected to have 4 interim analyses (at information times of .50, .65, .78, and .88) and a final analysis. Full information for OS corresponds to 112 deaths. For the efficacy analysis, critical values for interim analyses will be determined using the O’Brien-Fleming boundary to preserve the overall one-sided type I error rate of 0.020. For the futility analysis, conditional power and hazard ratio for OS will be computed at each interim analysis. If the conditional power is less than 10% and estimated hazard ratio is greater than 0.89, the OS analysis will be considered in favor of the null hypothesis. The hazard ratio of 0.89 is based on 20% of the alternative effect size, i.e. exp(log(0.56)X.2)).
Summary of Study Design The co-primary endpoint will be RFS and OS. RFS is defined as the time from randomization until disease recurrence of death from any cause. OS is defined as the time from randomization until death. Since moderate percentage of ling-term cures have been observed in this patient population, we used a model proposed by Berkson and Gage (1952) and Goldman (1984). This model specifies that the target population is a mixture, with proportion p who will be cured, and (1 – p) who will fail according to an exponential distribution with rate β. The OS or RFS function D(t) for the arm with pembrolizumab (A) and without pembrolizumab (B) is expressed as:
DB(t) = p + (1 - p) exp(- β t) DA(t) = {p + (1 - p) exp(- β t)}ө
where ө represents a hazard ratio under the proportional hazards alternative.
Based on the Merkelcell.org OS data for Merkel cell patients stage I- IIIB, the estimated cure rate is 62% and median OS for those not cured is 1.8 years. This corresponds to 1-yr, 2-yr, 3-yr, 4-yr, 5-yr, 6-yr, 7-yr, and 8-yr OS rates of .88, .80, .74, .70, .68, .66, .65 and .64, respectively in the control arm. For RFS, the estimated cure rate is 56% and median RFS for those not cured is 1 year. This corresponds to 1-yr, 2-yr, 3-yr, 4-yr, 5-yr, 6-yr, 7-yr, and 8-yr RFS rates of .78, .67, .62, .59, .57, .57, .56 and .56, respectively in the control arm. An ITT analysis using the stratified log-rank test will be performed to compare OS and RFS between the two arms.
Accrual of 500 patients will take approximately 2 years and additional follow up time will be 2.5 years. Thus, total study duration will be in the range of 4.5 years. Accrual rate of 250 patients/year is based on a survey conducted at ECOG-ACRIN and SWOG institutes.
Under the proportional hazards alternative, we hypothesize that pembrolizumab will reduce the hazard for death by 44% (hazard ratio ө =0.56). The full information is 112 deaths for the OS endpoint. This design provides approximately 80% power with one-sided type I error rate of 0.020 for the OS endpoint. Under the proportional hazards alternative, we hypothesize that pembrolizumab will reduce the hazard for relapse by 44% (hazard ratio ө =0.56). The full information is 154 events for RFS endpoint. This design provides approximately 80% power with one-sided type I error rate of 0.005 for the RFS endpoint. An
ECOG-ACRIN Cancer Research Group EA6174 Study Progress and Safety Report Spring 2019
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ITT analysis using the stratified log-rank test will be performed. For the co-primary endpoint of OS and RFS, overall one-sided type I error rate of 0.025 was divided such that the full information for OS is reached at 4.5 years and for RFS is reached at year 4.3. The study will be considered positive if the either endpoint demonstrates significant effects of pembrolizumab.
Interim analysis for OS will begin when the OS endpoint reaches approximately 50% information time. For the OS endpoint, it is expected to have 4 interim analyses (at information times of .50, .65, .78, and .88) and a final analysis. Full information for OS corresponds to 112 deaths. For the efficacy analysis, critical values for interim analyses will be determined using the O’Brien-Fleming boundary to preserve the overall one-sided type I error rate of 0.020. For the futility analysis, conditional power and hazard ratio for OS will be computed at each interim analysis. If the conditional power is less than 10% and estimated hazard ratio is greater than 0.89, the OS analysis will be considered in favor of the null hypothesis. The hazard ratio of 0.89 is based on 20% of the alternative effect size, i.e. exp(log(0.56)X.2)).
For the RFS endpoint, the first interim analysis will begin when accrual is closed and all patients are off randomized treatment. It is expected to occur at year 3.3. Subsequently interim analyses will be repeated every 6 months. It is expected to have 2 interim analyses (at information time of .87 and .95) and a final analysis. Full information for RFS corresponds to 154 RFS events. For the efficacy analysis, O’Brien and Fleming boundary will be used with an overall one-sided type I error rate of 0.005. For the futility analysis, conditional power and hazard ratio for RFS will be computed at each interim analysis. If the conditional power is less than 10% and estimated hazard ratio is greater than .89, then, the RFS analysis will be considered in favor of the null hypothesis. Progress to Date This study was activated on October 1, 2018. As of February 7, 2019, three patients have enrolled. Table 1a summarizes accrual by institution and Table 1b has accrual by group. Patient status as of February 7, 2019 is displayed in Table 2. Demographics of patients by treatment arm are summarized in Table 3.
Table 1a. Accrual by ECOG-ACRIN Institution
Institution Name Step 1 Georgia NCORP 1 Heartland Cancer Research NCORP 1 Total 2
Table 1b. Accrual by Group
ECOG-ACRIN 2 ALLIANCE 1 Total 3
Table 2. Patient Status as of February 7, 2019
Cases Entered 3 Ineligible 0 Never Started Assigned Therapy 0
ECOG-ACRIN Cancer Research Group EA6174 Study Progress and Safety Report Spring 2019
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Table 3. Demographics
Variable Level Arm A
(n=1) Arm B
(n=2) Total (n=3)
Sex Male 1 (100.0) 1 (50.0) 2 (66.7) Female 0 (0.0) 1 (50.0) 1 (33.3)
Race White 1 (100.0) 2 (100.0) 3 (100.0) Ethnicity Non-Hispanic 1 (100.0) 2 (100.0) 3 (100.0) Age Median 55 65 57
Minimum 55 57 55 Maximum 55 73 73
ECOG-ACRIN Cancer Research Group EA6134 Study Progress and Safety Report Spring 2019
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EA6134 DREAMSEQ (DOUBLET, RANDOMIZED EVALUATION IN ADVANCED MELANOMA SEQUENCING) A PHASE III TRIAL
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 Spring 2019
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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.
ECOG-ACRIN Cancer Research Group EA6134 Study Progress and Safety Report Spring 2019
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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 February 7, 2019, 170 patients enrolled to step 1, and 38 to step 2. Table 1a summarizes accrual by institution. Table 1b has accrual by group, and Table 1c shows projected accrual status as of February 7, 2019. Expected cumulative accrual and actual cumulative accrual are shown in Figure 1. This report is based on the data as of February 7, 2019. 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 February 7, 2019 there were 159 cases (81 in arm A, 78 in arm B in step 1) and 33 cases (14 in arm C and 19 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.
ECOG-ACRIN Cancer Research Group EA6134 Study Progress and Safety Report Spring 2019
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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 4 1 Case Western Reserve University 4 0 Catholic Health Initiatives NCORP 2 0 Colorado Cancer Research Program NCORP 1 0 Dayton NCORP 4 2 Emory University/Winship Cancer Institute 1 0 Froedtert and the Medical College of Wisconsin 1 0 Georgia Cares Minority Underserved NCORP 1 0 Georgia NCORP 3 0 Hackensack University Medical Center 2 1 Heartland Cancer Research NCORP 4 0 Indiana Univ/Melvin and Bren Simon Cancer Center 4 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 6 2 Michigan Ca Res Consortium NCORP 3 1 Montana Cancer Consortium NCORP 1 0 Nevada Cancer Research Foundation NCORP 3 1 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 1 Northwestern University 5 2 Ohio State University Comprehensive Cancer Center 3 0 Pacific Cancer Research Consortium NCORP 9 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 1 University of Michigan Comprehensive Cancer Center 2 0 University of Pittsburgh Cancer Institute (UPCI) 9 0 University of Wisconsin Hospital and Clinics 2 1 Vanderbilt University/Ingram Cancer Center 4 1 Wichita NCORP 2 0 Wisconsin NCORP 7 1 Total 106 19
Table 1b. Accrual by Group
Step 1 Step 2 ECOG-ACRIN 106 19 SWOG 32 12 ALLIANCE 9 2 NRG 23 5 Total 170 38
ECOG-ACRIN Cancer Research Group EA6134 Study Progress and Safety Report Spring 2019
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Table 1c. Projected Accrual
Step 1 Step 2 Accrual goal 300 Planned accrual rate 192/yr Accrual to date 170 38 Annual accrual rate Overall 50/yr 11/yr Last 6 months 40/yr 20/yr
Projected date of closure May 2022
Table 2. Patient Status as of February 7, 2019
Step 1 Step 2 Cases Entered 170 38 Ineligible 1 0 Never Started Assigned Therapy 0 0
Reason for ineligibility (n=1): Surgery < 4 weeks from registration (46143).
ECOG-ACRIN Cancer Research Group EA6134 Study Progress and Safety Report Spring 2019
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Table 3. Demographics Step 1
Variable Level Arm A (n=88)
Arm B (n=82)
Total (n=170)
Sex Male 49 (55.7) 53 (64.6) 102 (60.0) Female 39 (44.3) 29 (35.4) 68 (40.0)
Race White 85 (98.8) 79 (98.8) 164 (98.8) Asian 1 (1.2) 1 (1.3) 2 (1.2) Unknown/Unreported 2 2 4
Ethnicity Hispanic 1 (1.2) 5 (6.3) 6 (3.6) Non-Hispanic 85 (98.8) 74 (93.7) 159 (96.4) Unknown/Missing 2 3 5
Age Median 59 57 59 Minimum 30 26 26 Maximum 81 84 84
Step 2
Variable Level Arm C (n=17)
Arm D (n=21)
Total (n=38)
Sex Male 10 (58.8) 12 (57.1) 22 (57.9) Female 7 (41.2) 9 (42.9) 16 (42.1)
Race White 16 (100.0) 21 (100.0) 37 (100.0) Unknown/Unreported 1 0 1
Ethnicity Non-Hispanic 16 (100.0) 19 (100.0) 35 (100.0) Unknown/Missing 1 2 3
Age Median 58 54 55 Minimum 31 28 28 Maximum 82 77 82
Table 4. Record Status
Form Name Forms
Due Forms
Received % Demography 167 167 100.0 Patient Characteristics 202 202 100.0 Treatment Agent: Dabrafenib 618 610 98.7 Treatment Agent: Ipilimumab - Induction 171 171 100.0 Treatment Agent: Nivolumab - Induction 172 172 100.0 Treatment Agent: Nivolumab - Maintenance 253 253 100.0 Treatment Agent: Trametinib 618 610 98.7 Adverse Event Form 1043 1024 98.2 Hematology/Chemistry 202 202 100.0 Late Adverse Event Form 6 6 100.0 Other Adverse Event Form 820 820 100.0 Disease Follow-Up Status Form (RECIST 1.1) 1219 1208 99.1 Off Treatment 20 20 100.0 Off-Treatment with Intent to Reg Next Step 114 114 100.0
ECOG-ACRIN Cancer Research Group EA6134 Study Progress and Safety Report Spring 2019
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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 30 38.5 Death on study 6 7.7 Disease progression- relapse during active treatment 24 30.8 Other 5 6.4 Patient off-treatment for other complicating disease 1 1.3 Patient withdrawal/refusal after beginning protocol therapy 4 5.1 Treatment completed per protocol criteria 8 10.3 Total off treatment 78 100.0
Step 2 (Includes all patients who started treatment and
for whom off-treatment data have been received)
Reasons N % Adverse event/side effects/complications 2 10.0 Death on study 1 5.0 Disease progression- relapse during active treatment 14 70.0 Other 1 5.0 Treatment completed per protocol criteria 2 10.0 Total off treatment 20 100.0
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Table 6. Toxicity Incidence
Step 1
Toxicity Type
Treatment Arm A (n=81) B (n=78)
Grade Grade 3 4 5 3 4 5
(%) (%) (%) (%) (%) (%) Anemia 1 - - 3 - - Disseminated intravascular coagulation - 1 - - - - Febrile neutropenia - - - 3 - - Leukocytosis 2 - - - - - Cardiac disorders - Other, specify - 1 - - - - Myocarditis 1 - - - - - Adrenal insufficiency 1 - - - - - Endocrine disorders - Other, specify 2 1 - - - - Retinal detachment - - - 1 - - Abdominal pain 2 - - - - - Colitis 5 - - - - - Diarrhea 22 1 - 1 - - Enterocolitis 1 - - - - - Gastrointestinal disorders - Other, specify 1 - - - - - Ileus 1 - - - - - Nausea 10 - - - - - Pancreatitis 1 - - - - - Vomiting 6 - - 1 - - Fatigue 7 - - 8 - - Fever - - - 8 - - Flu like symptoms 1 - - - - - Pain - - - 1 - - Edema limbs 1 - - - - - Infusion related reaction 1 - - - - - Hepatic failure 1 - - - - - Cytokine release syndrome 1 - - - - - Autoimmune disorder 2 - - - - - Infections and infestations - Other, specify - - - 1 - - Meningitis 1 - - - - - Sepsis - 1 - - 1 - Urinary tract infection 2 - - - - - Enterocolitis infectious 2 - - - - - Lung infection 1 - - - - - Gallbladder infection - - - 1 - - Fall 1 - - - - - Alanine aminotransferase increased 5 2 - - - - Aspartate aminotransferase increased 6 1 - - - - Blood bilirubin increased 1 2 - - - - Creatinine increased 4 - - 1 - - Lipase increased 6 9 - 5 3 - Lymphocyte count decreased - - - 3 - - Neutrophil count decreased - - - 3 - - Serum amylase increased 5 1 - - 1 -
ECOG-ACRIN Cancer Research Group EA6134 Study Progress and Safety Report Spring 2019
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Toxicity Type
Treatment Arm A (n=81) B (n=78)
Grade Grade 3 4 5 3 4 5
(%) (%) (%) (%) (%) (%) Ejection fraction decreased - - - 5 - - Anorexia 4 - - - - - Dehydration 6 - - 1 - - Hypercalcemia 1 - - - - - Hyperglycemia 4 1 - - - - Hypoalbuminemia 5 - - - - - Hypokalemia 2 - - 1 - - Hyponatremia 5 - - 5 1 - Hypophosphatemia 1 - - - - - Arthralgia 6 - - 1 - - Back pain 1 - - - - - Musculoskeletal and connective tissue disorder - Other, specify 1 - - - - - Myalgia 1 - - - - - Myositis 2 - - - - - Pain in extremity - - - 1 - - Generalized muscle weakness 2 - - - - - Treatment related secondary malignancy - - - 1 - - Headache 4 - - - - - Hypersomnia 1 - - - - - Peripheral sensory neuropathy 1 - - - - - Syncope - - - 4 - - Tremor 1 - - - - - Proteinuria 1 - - - - - Acute kidney injury 2 - - - - - Adult respiratory distress syndrome - 1 - - - - Hypoxia 1 - - - - - Pneumonitis 1 - - - - - Respiratory failure - - 1 - - - Rash acneiform - - - 1 - - Rash maculo-papular 9 - - 5 - - Hypertension 2 - - 1 - - Hypotension 2 - - 1 - - Thromboembolic event - - - 1 - - WORST DEGREE 51 16 1 46 6 -
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Step 2
Toxicity Type Treatment Arm
C (n=14) D (n=19)
Grade Grade 3 4 5 3 4 5
(%) (%) (%) (%) (%) (%) Anemia - - - 5 - - Adrenal insufficiency - - - 5 - - Endocrine disorders - Other, specify - - - 5 - - Diarrhea 7 - - - - - Nausea 7 - - - - - Pancreatitis - - - 5 - - Fatigue 7 - - 11 - - Fever 7 - - 5 - - Infections and infestations - Other, specify - - - 5 - - Alanine aminotransferase increased - - - 5 - - Aspartate aminotransferase increased - - - 5 - - Lipase increased - - - 5 5 - Lymphocyte count decreased - - - 5 - - Serum amylase increased - - - 5 - - Dehydration - - - 5 - - Hypernatremia 7 - - - - - Hyponatremia 7 - - 5 - - Nervous system disorders - Other, specify - - - 5 - - Syncope 7 - - - - - Pneumonitis - - - 5 - - Pruritus - - - 5 - - Rash maculo-papular 14 - - - - - Hypotension - - - 5 - - WORST DEGREE 29 - - 47 5 -
Table 7. Lethal Adverse Events that are Possibly Related to Treatment
Case Arm Description of Event 46007 A Respiratory failure
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Table 8. Second Primary Cancers (By arm during which event was reported)
Site Arm A
Thyroid 1
Table 9. QOL Table
QOL Timepoint
Patients Reaching
Timepoint % Forms
Completed Baseline Step 1 166 84.3 End of Cycle 1 in Step 1 - Arm A 80 52.5 End of Cycle 1 in Step 1 - Arm B 78 89.7 End of Cycle 2 in Step 1 - Arm A 77 36.4 End of Cycle 2 in Step 1 - Arm B 76 68.4 Disease stability or 6 Mos. Step 1-Arm A 71 21.1 Disease stability or 6 Mos. Step 1-Arm B 71 36.6 End of Step 1 Treatment 57 100.0 Baseline Step 2 36 72.2 End of Cycle 1 in Step 2 - Arm C 15 66.7 End of Cycle 1 in Step 2 - Arm D 17 64.7 End of Cycle 2 in Step 2 - Arm C 15 73.3 End of Cycle 2 in Step 2 - Arm D 15 40.0 Disease stability or 6 Mos. Step 2-Arm C 13 53.8 Disease stability or 6 Mos. Step 2-Arm D 14 35.7 End of Step 2 Treatment 11 100.0 12 Mos. from study entry - Arm A 56 23.2 12 Mos. from study entry - Arm B 55 0.0 18 Mos. from study entry - Arm A 40 20.0 18 Mos. from study entry - Arm B 38 5.3
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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. 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
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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 June 23, 2017. Patient status as of February 7, 2019 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 124 cases in arm A and 120 cases in arm B as of February 7, 2019. Treatment-related toxicities are summarized in Table 6. The worst-degree grade 3 or higher toxicity rate was 56% in arm A and 69% in arm B. There were 4 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 12 grade 5 AEs reported via CTEP-AERS system. They include: 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, 16216 (arm B) Neoplasm, 16196 (arm A) cardiac disorder, 16232 (arm B) multiorgan failure, 16233 (arm A) Deaths NOS, 16242 (arm A), 16245 (arm A) deaths NOS. Of these, cases 16010, 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 February 7, 2018
Cases Entered 250 Ineligible 4 Never Started Assigned Therapy 3
Reason for ineligibility (n=4): High Bilirubin (16226); No measurable disease (16242, 16062); Use of Immunosuppressant (16710). Reason for not starting therapy (n=3): Withdrawal/refusal before beginning protocol therapy (16014); Death before therapy (16143); Ineligible (16170).
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 - Phase II
Form Name Forms
Due Forms
Received % Demography 250 250 100.0 Patient Characteristics 250 249 99.6 Treatment Agent: Ipilimumab 810 810 100.0 Treatment Agent: Nivolumab 2722 2721 100.0 Treatment Agent: Sargramostim 1677 1675 99.9 Adverse Events 2902 2902 100.0 Hematology/Chemistry 250 248 99.2 Late Adverse Events 15 15 100.0 Disease Follow-Up Status Form 2 2 100.0 Disease Follow-Up Status Form (RECIST 1.1) 3238 3232 99.8 Off Treatment 210 210 100.0
Table 5. Reasons Off Treatment - Phase II
(Includes all patients who started treatment and for whom off-treatment data have been received)
Reasons N %
Adverse event/side effects/complications 100 46.7 Alternative therapy 5 2.3 Death on study 7 3.3 Disease progression- relapse during active treatment 51 23.8 Other 17 7.9 Patient off-treatment for other complicating disease 3 1.4 Patient withdrawal/refusal after beginning protocol therapy 13 6.1 Treatment completed per protocol criteria 18 8.4 Total off treatment 214 100.0
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Table 6. Toxicity Incidence - Phase II
Step 1
Toxicity Type
Treatment Arm A (n=124) B (n=120)
Grade Grade 3 4 5 3 4 5
(%) (%) (%) (%) (%) (%) Anemia 1 - - 2 - - Blood and lymphatic system disorders - Other, specify 1 - - 1 - - Leukocytosis 1 - - - - - Atrioventricular block complete 1 - - - - - Myocarditis 1 - - - - - Hearing impaired 1 - - - 1 - Adrenal insufficiency 4 - - 3 - - Endocrine disorders - Other, specify 5 - - 3 - - Hyperthyroidism 1 - - - - - Hypothyroidism 1 - - - - - Uveitis 1 - - - - - Abdominal pain 2 - - 2 - - Colitis 2 - - 10 - - Constipation 1 - - - - - Dental caries 1 - - - - - Diarrhea 6 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 - - - - - Death NOS - - 1 - - - Fatigue 5 - - 4 - - Fever - - - 1 - - Multi-organ failure - - - - - 1 Pain 1 - - - - - Non-cardiac chest pain 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 - - - - - Skin infection 1 - - - - - Lung infection 1 - - 1 - - Fall 1 - - - - - Alanine aminotransferase increased 10 - - 11 - - Alkaline phosphatase increased 2 - - 2 - - Aspartate aminotransferase increased 4 1 - 10 - - Blood bilirubin increased 1 - - - - - Cardiac troponin I increased - - - 1 - -
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Toxicity Type
Treatment Arm A (n=124) B (n=120)
Grade Grade 3 4 5 3 4 5
(%) (%) (%) (%) (%) (%) CPK increased - - - 1 1 - Creatinine increased - - - 2 - - Investigations - Other, specify - - - 1 - - Lipase increased 8 4 - 11 6 - Lymphocyte count decreased 1 1 - 2 - - Neutrophil count decreased - - - 1 - - Platelet count decreased 1 1 - - - - Serum amylase increased 5 - - 3 1 - Urine output decreased - 1 - - - - Acidosis - - - 1 1 - Anorexia 4 - - - - - Dehydration 2 - - 3 - - Hypercalcemia - - - - 1 - Hyperglycemia 1 1 - 3 3 - Hyperkalemia 1 - - - - - Hyperuricemia - 2 - 1 2 - Hypokalemia - 2 - 2 - - Hyponatremia 2 1 - 4 - - Hypophosphatemia - - - 1 - - Metabolism and nutrition disorders - Other, specify - - - 1 - - Back pain - - - 1 - - Bone pain 1 - - - - - Joint effusion - - - 1 - - Myalgia 1 - - - - - Pain in extremity - - - 1 - - Generalized muscle weakness 4 - - - - - Muscle weakness lower limb 2 - - - - - Muscle weakness right-sided - - - 1 - - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify - - 1 - - - Dizziness 1 - - - - - Dysphasia - - - 1 - - Headache 3 - - 1 - - Nervous system disorders - Other, specify 1 - - - - - Peripheral motor neuropathy - - - 1 - - Peripheral sensory neuropathy - - - 1 - - Seizure 1 - - 1 - - Syncope 2 - - 1 - - Anxiety - - - 1 - - Confusion - - - 1 - - Renal and urinary disorders - Other, specify 1 - - - - - Chronic kidney disease - 1 - - - - Acute kidney injury - - - 2 - - Aspiration - - 1 - - - Dyspnea 1 - - 5 2 - Hypoxia 1 - - 1 - -
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Toxicity Type
Treatment Arm A (n=124) B (n=120)
Grade Grade 3 4 5 3 4 5
(%) (%) (%) (%) (%) (%) Pneumonitis 2 - - 4 - - Respiratory failure - - - - 1 - Respiratory, thoracic and mediastinal disorders - Other, specify - - - - 1 - Pruritus 2 - - 1 - - Rash maculo-papular 8 - - 9 - - Hypertension - - - 1 - - Hypotension 2 1 - 1 - - Thromboembolic event - - - 1 - - WORST DEGREE 39 14 3 53 15 1
Table 7. Lethal Adverse Events that are Possibly Related to Treatment
Case Arm Description of Event 16058 A Diarrhea 16242 A Aspiration 16245 16078
A A
Neoplasms Death NOS
16232 B Multi-organ failure
Table 8. Second Primary Cancers
Site Arm A Arm B
Breast 1 - Liver, Gall Bladder, Bile Duct 1 -