MELANOMA COMMITTEE - SWOG 2019... · metastatic BRAFV600E/K mutant melanoma. To compare the...

APRIL 24 - 27, 2019 SWOG MELANOMA 1

MELANOMA COMMITTEE


CONTENTS

S1204 Surveillance ........................................................................................................................................................ 6

S1320 Phase II ............................................................................................................................................................... 8

S1404 Phase III ............................................................................................................................................................ 19

S1512 Phase II ............................................................................................................................................................. 29

S1607 Phase II ............................................................................................................................................................. 33

S1609 Phase II ............................................................................................................................................................. 38

S1614 Phase III ............................................................................................................................................................ 40

S1616 Phase II ............................................................................................................................................................. 42

S1801 Phase II ............................................................................................................................................................. 47


Patient Registrations to Studies

by 12 Month Intervals

MELANOMA COMMITTEE

Screening registrations and registrations to Biologic only studies are excluded.

SWOG LAPS MEMBER NCORP NON-SWOG

187145

104

674

845

97

0

100

200

300

400

500

600

700

800

900

Time of Registration

Jan 2013Dec 2013

Jan 2014Dec 2014

Jan 2015Dec 2015

Jan 2016Dec 2016

Jan 2017Dec 2017

Jan 2018Dec 2018

101

51

76 108

129

126

311

116

152

185

392


Patient Registrations by Study and Arm MELANOMA COMMITTEE

Jul 2018

Dec 2018

Jan 2018

Jun 2018

Jul 2017

Dec 2017

All

Patients

S1320 Adv, BRAF mut, Intermittent vs Continuous Dabrafenib + Trametinib

Lead In Registration

Lead-in Continuous Dosing 18 28 31 237

Randomization

Continuous Dosing 6 15 13 97

Intermittent Dosing 6 13 10 93

12 28 23 190

S1404 Adv, HD-IFN/Ipilimumab vs MK-3475

Tissue Submission

Tissue for PD-L1 testing 0 0 185 1,426

Randomization

FDA approved regimen 0 0 110 678

MK-3475 (Pembrolizumab) 0 0 102 667

0 0 212 1,345

S1512 Melan, Adv, Desmoplastic, MK-3475 (Pembrolizumab)

Registration

MK-3475 (pembrolizumab) 7 6 4 18

S1607 Adv, T-VEC, MK-3475 (Pembrolizumab)

Registration

T-VEC + MK-3475(Pembrolizumab) 7 1 0 8

S1616 Adv, Ipilimumab ± Nivolumab

Randomization

Ipilimumab 3 4 1 8

Nivolumab + Ipilimumab 10 7 3 20

13 11 4 28


Non-SWOG Studies with SWOG-Credited Registrations MELANOMA COMMITTEE

Studies with Accrual from July 2017 - December 2018

SWOG Accrual

SWOG

Champion

Jul 2018

Dec 2018

Jan 2018

Jun 2018

Jul 2017

Dec 2017

SWOG

Total

Total

Accrued

E3612 Adv, Ipilimumab ± Bevacizumab 0 0 1 6 169

Date Activated: 12/13/13 Date Closed: 09/25/17

Most Recent Progress Report

EA6134 Adv, BRAF mut, Dabrafenib + Trametinib/Ipilimumab +

Nivolumab vs Ipilimumab + Nivolumab /Dabrafenib + Trametinib

B Chmielowski 4 2 8 30 166

Date Activated: 12/15/15


EA6141 Adv, Nivolumab + Ipilimumab ± Sargmostim K Kim 0 0 0 36 250

Date Activated: 03/01/16



S1204

S1204 Surveillance

A Sero-Epidemiologic Survey and Cost-Effectiveness Study of Screening for

Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) and

Hepatitis C Virus (HCV) Among Newly Diagnosed Cancer Patients

Study Chairs:

S Ramsey, D Hershman

Statisticians:

J Unger, K Arnold

Data Coordinator:

M Yee

Date Activated:

08/29/2013

Date Closed:

02/15/2017

Objectives Among newly diagnosed cancer patients presenting

to SWOG-affiliated community and academic

oncology clinics, estimate the prevalence of human

immunodeficiency virus (HIV), hepatitis B (HBV),

and hepatitis C (HCV) infection.

Evaluate known sociodemographic, clinical, and

behavioral factors that are significantly associated

with previously undiagnosed HIV, HBV, and/or

HCV infection in a population of people with newly

diagnosed cancer

Among patients who are identified as having HIV,

HBV, and/or HCV, describe the timing and type of

treatments received (if any), both for the viral

infections and the cancers.

Describe the type of adverse events possibly

attributable to the patient's viral status in patients

with HIV, HBV, and/or HCV infection.

Using simulation modeling that is directly informed

by the data obtained from this study, determine the

cost-effectiveness (expressed as cost per infection

detected and cost per year of life gained) of (1)

routine, universal screening and (2) risk factor-

directed screening of newly diagnosed cancer

patients for HIV, HBV and/or HCV versus current

care.

Patient Population Patients must be presenting for evaluation or

treatment for the first diagnosis of a new solid or

hematologic cancer malignancy. Confirmed diagnosis

date must be within 120 days prior to first clinic visit

as a newly diagnosed cancer patient at the registering

clinic. Patients presenting for "second opinions" of

confirmed malignancies are eligible, including those

who have started cancer treatment at other facilities.

Patients must be registered within 90 days after their

first clinic visit. Patients must not have been

diagnosed with a malignancy other than the current

malignancy within the past five years, with the

exception of basal cell or squamous cell skin cancer,

in situ cervical cancer, or in situ breast cancer.

Patients must have no evidence of disease for a prior

malignancy for at least five years prior to

randomization except as noted above.


S1204

Patients must be 18 years of age or older. Patients

must have had their blood drawn for viral status

testing for HIV, HBV and HCV or provide

acceptable viral status documentation prior to

registration, as defined in the protocol. Note that

patients must have blood drawn for testing prior to

registration for any of the three viruses not covered

by the documentation. Patients are allowed to

participate in other clinical trials.

Accrual Goals A total of 3,061 patients will be accrued to achieve

3,000 eligible patients.

Summary Statement For the current status of this study, please refer to the

Cancer Care Delivery chapter.


S1320/II

S1320 Phase II

Coordinating Group: SWOG

A Randomized Phase II Trial of Intermittent versus Continuous Dosing of

Dabrafenib (NSC-763760) and Trametinib (NSC-763093) in BRAFV600E/K

Mutant Melanoma

Participants:

SWOG, CTSU (Supported by ECOG-ACRIN)

Study Chairs:

A Algazi, A Daud, R Lo, J Mehnert (ECOG-ACRIN)

Statisticians:

M Othus, J Moon

Data Coordinator:

J Sanchez

Date Activated:

07/22/2014

SCHEMA

Objectives To compare progression-free survival with

intermittent dosing versus continuous dosing of

dabrafenib and trametinib among patients with

metastatic BRAFV600E/K mutant melanoma.

To compare the response rate (complete and partial

response, confirmed and unconfirmed), overall

survival, and survival after progression between the

two dosing schedules.

R

A

N

D

O

M

I

Z

A

T

I

O

N

Continuous Treatment

Intermittent Treatment

R

E

G

I

S

T

R

A

T

I

O

N

Continuous Treatment Lead-in


S1320/II

To compare the frequency and severity of fever

greater than Grade 1 per CTCAE 4.0 of the two

dosing schedules.

To estimate the frequency and severity of toxicities

of the two dosing schedules.

To bank tissue and whole blood in anticipation of

future studies to evaluate molecular events associated

with clinical benefit and disease progression in

patients treated with continuous versus intermittent

dabrafenib and trametinib.

Patient Population Patients must have histologically or cytologically

confirmed Stage IV or unresectable Stage III

melanoma. Patients must have BRAF mutation-

positive melanoma (i.e., V600E or V600K).

BRAFV600

mutant status must be documented by a

CLIA-certified laboratory. Patients must have

measurable disease as defined by RECIST 1.1.

Contrast-enhanced CT scans of the neck, chest,

abdomen and pelvis are required. A whole body

PET/CT scan with diagnostic quality images and

intravenous iodinated contrast may be used in lieu of

a contrast enhanced CT of the neck, chest, abdomen

and pelvis. Contrast may be omitted if the treating

investigator believes that exposure to contrast poses

an excessive risk to the patient. Patients with a

history of brain metastases are eligible if the patient

is asymptomatic with no residual neurological

dysfunction and has not received enzyme-reducing

anti-epileptic drugs or corticosteroids for at least

seven days prior to registration. Patients must have

serum LDH obtained prior to registration for

treatment randomization stratification and accurate

staging.

Patients must not have received a prior BRAF or

MEK inhibitor. Prior surgery, radiotherapy,

immunotherapy, or chemotherapy are allowed.

Patients must have adequate hematologic, hepatic,

cardiac, and renal function and a Zubrod performance

status of 0-2. Patients must not have a known history

or current evidence of retinal vein occlusion (RVO)

or central serous retinopathy (CSR). Patients must

not have any predisposing factors for RVO or CSR

such as uncontrolled glaucoma, ocular hypertension,

uncontrolled systemic hypertension, diabetes

mellitus, or a history of hyperviscosity or

hypercoagulability syndromes. An ophthalmic exam

is required for all patients. Patients must not have

evidence of optic disc cupping, visual field defects,

or an intraocular pressure greater than 21 mmHg.

Patients must be able to take oral medications and

must not have any impairment of gastrointestinal

disease that may significantly alter the absorption of

protocol treatment. Patients must discontinue

treatment with therapeutic warfarin prior to

registration. Patients must not have a history of

pneumonitis or interstitial lung disease. Patients with

known hepatitis B, or hepatitis C are not eligible.

Patients known to be HIV positive must have CD4

cells ≥ 500 uL, a serum HIV viral load < 25,000

IU/ml, and must be able to discontinue antiretroviral

therapy. Patients must have a dermatology exam

within 28 days prior to registration.

Patients must be offered the opportunity to participate

in specimen banking.

Stratification/Descriptive Factors Treatment randomization will be stratified by the

following: (1) prestudy serum LDH: elevated (>

IULN) vs normal; (2) known prior exposure to

immune checkpoint inhibitors targeting CTLA-4,

PD-1, or PD-L1: yes vs no.

Accrual Goals The accrual goal is 206 eligible randomized patients.

An interim analysis testing for harm will be

performed when 78 progression events have

occurred.

Summary Statement

Because accrual to this study has been slower than

anticipated, it is expected that 100% of the events

needed to perform the final analysis will be reached

before the original accrual goal could be reached. To

account for the slower than anticipated accrual rate,

the study was amended to reduce the sample size

from 236 eligible randomized patients to 206 eligible

randomized patients. This new design will have the

same power as the original design using the same

alpha level. In addition, in an effort to increase

accrual, a protocol amendment was also amended to

allow patients with a history of untreated brain

metastases as long as the patient is asymptomatic.

As of December 31, 2018, 237 patients have been

registered to lead-in continuous dosing. Seven

patients are currently ineligible for the following

reasons: inadequate baseline disease assessment (3),

inadequate cardiac function (2), not having a V600E

or V600K BRAF mutation (1), inadequate

hematologic function (1). In addition, three eligible

patients never received protocol treatment and were

never randomized are not evaluable for any of the

study endpoints. One additional patient is excluded


S1320/II

from the analysis. At the time of registration,

documentation was provided of histologic

confirmation of melanoma. However, after the

patient progressed on study, the pathology report

from the patient's resected disease revealed that it

was myxofibrosarcoma rather than melanoma. Most

patients who were unable to complete the one cycle

of lead-in continuous dosing came off protocol

treatment either due to adverse events or disease

progression. One patient was never randomized and

remained on continuous dosing off protocol (coded as

Reason Off Treatment = “Other – not protocol

specified”).

A total of 217 patients have been assessed for adverse

events related to lead-in continuous dosing. There has

been one treatment-related death due to sepsis. This

patient also experienced Grade 4 acute kidney injury

and Grade 4 ejection fraction decrease. An additional

six patients experienced treatment-related Grade 4

adverse events due to the following: CPK increased

and MS/connective tissue disorder (1), sepsis (1),

hypocalcaemia (1), neutrophil count decreased (1),

hyponatremia (1), and hypocalcaemia and

pneumonitis (1).

A total of 190 patients have been randomized

between intermittent and continuous dosing. Seven


reasons: ineligible for the trial at the initial

registration (5), and disease progression during the

lead-in continuous dosing phase (2). Seven patients

have discontinued protocol treatment for reasons

coded as “other – not protocol specified”: treatment

delay longer than 14 days, not due to toxicity (2),

other primary cancer (1), and a change in treatment

plan by the medical team (4). In addition, one eligible

patient who was found to have myxofibrosarcoma is

excluded from the analysis, for reasons described

above.

On the continuous dosing arm, 89 patients have been

assessed for adverse events. Five patients have

experienced Grade 4 treatment-related adverse events

due to the following reasons: anemia and increases in

ALT and AST (1), dyspnea (1), lipase increase (1),

sepsis (1) and creatinine increase (1). On the

intermittent dosing arm, 88 patients have been

assessed for adverse events. Three patients have

experienced Grade 4 treatment-related adverse events

due to the following reasons: fever (1), lipase

increase (1), and acute kidney injury (1).


S1320/II

Registration by Institution

Lead-In Continuous Dosing

Registrations ending December 31, 2018

Institutions

Total

Reg Institutions

Total

Reg

Kaiser Perm NCORP 28 Colorado, U of 2

Kansas, U of 17 CRC West MI NCORP 2

Ohio State Univ 17 Ozarks NCORP 2

Utah, U of 11 PCRC NCORP 2

Loyola University 8 Bay Area NCORP 1

San Francisco, U-CA 8 Boston Medical Ctr 1

Southeast COR NCORP 8 CORA NCORP 1

Arkansas, U of 6 Dayton NCORP 1

Heartland NCORP 6 Hawaii MU-NCORP 1

Wichita NCORP 6 Lahey Hosp & Med Ctr 1

Michigan, U of 5 UF Cancer Center/Arkansas, U of 1

Los Angeles, U of CA 4 Wisconsin NCORP 1

Nevada CRF NCORP 4 ECOG-ACRIN 48

Rochester, Univ of 4 NRG 20

Columbus NCORP 3 ALLIANCE 13

KaiserPermanenteSCAL/Kaiser Perm NCORP 3 Total (32 Institutions) 237

Arizona MC, U of 2

Registration, Eligibility, and Evaluability


Registrations ending December 31, 2018; Data as of January 18, 2019

Lead-in

Continuous

Dosing

NUMBER REGISTERED 237

INELIGIBLE 7

ELIGIBLE 230

Analyzable, Pend. Elig. 9

Not Analyzable 4

ADVERSE EVENT ASSESSMENT

Evaluable 217

Too Early 9


S1320/II

Treatment Summary



Lead-in

Continuous

Dosing

NUMBER ON PROTOCOL TREATMENT 10

NUMBER OFF PROTOCOL TREATMENT

REASON OFF TREATMENT

216

Treatment completed as planned 184

Adverse Event or side effects 17

Refusal unrelated to adverse event 1

Progression/relapse 11

Death 2

Other - not protocol specified 1

Reason under review 0

MAJOR PROTOCOL DEVIATIONS 0


S1320/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 3 to 5 or Unknown Have Been Suppressed


Lead-in Continuous

Dosing

(n=217)

Grade

ADVERSE EVENTS <=2 3 4 5

AST increased 211 6 0 0

Abdominal pain 216 1 0 0

Acute kidney injury 216 0 1 0

Anemia 213 4 0 0

Anorexia 215 2 0 0

Arthralgia 216 1 0 0

Blood bilirubin increased 216 1 0 0

Blood/lymph disorder-Other 216 1 0 0

CPK increased 216 0 1 0

Cardiac troponin T increased 216 1 0 0

Chills 216 1 0 0

Constipation 216 1 0 0

Dehydration 210 7 0 0

Diarrhea 214 3 0 0

Dyspnea 216 1 0 0

ECG QT corrected int prolong 216 1 0 0

Ejection fraction decreased 216 0 1 0

Epistaxis 216 1 0 0

Erythema multiforme 216 1 0 0

Fatigue 212 5 0 0

Febrile neutropenia 214 3 0 0

Fever 213 4 0 0

Fracture 216 1 0 0

Gastric hemorrhage 216 1 0 0

Generalized muscle weakness 215 2 0 0

Headache 215 2 0 0

Hyperglycemia 216 1 0 0

Hypertension 213 4 0 0

Hypoalbuminemia 216 1 0 0

Hypocalcemia 215 0 2 0

Hypokalemia 216 1 0 0

Hyponatremia 206 10 1 0

Hypophosphatemia 216 1 0 0

Hypotension 213 4 0 0

Hypoxia 216 1 0 0

Leukocytosis 216 1 0 0

Lipase increased 215 2 0 0

Lung infection 216 1 0 0

Lymphocyte count decreased 211 6 0 0

MS/connective tissue disorder 215 1 1 0


S1320/II

Lead-in Continuous

Dosing

(n=217)

Grade

ADVERSE EVENTS <=2 3 4 5

Metab/nutrition disorders-Other 216 1 0 0

Mucositis oral 216 1 0 0

Nausea 215 2 0 0

Neutrophil count decreased 208 8 1 0

Platelet count decreased 216 1 0 0

Pneumonitis 216 0 1 0

Proteinuria 216 1 0 0

Rash acneiform 214 3 0 0

Rash maculo-papular 213 4 0 0

Retinopathy 216 1 0 0

Sepsis 215 0 1 1

Skin infection 215 2 0 0

Skin/subq tissue ds-Other 216 1 0 0

Thromboembolic event 216 1 0 0

Tx related secondary malig 215 2 0 0

Upper GI hemorrhage 216 1 0 0

Urinary tract infection 215 2 0 0

Vasc disorders-Other, spec 216 1 0 0

Vomiting 215 2 0 0

White blood cell decreased 213 4 0 0

MAX. GRADE ANY ADVERSE EVENT 152 58 6 1


S1320/II


Randomization


TOTAL

Continuous

Dosing

Intermittent

Dosing

NUMBER REGISTERED 190 97 93

INELIGIBLE 7 5 2

ELIGIBLE 183 92 91

Analyzable, Pend. Elig. 5 2 3

Not Analyzable 1 1 0

RESPONSE ASSESSMENT

Determinable 161 83 78

Not Determinable 3 2 1

Too Early 18 6 12


Evaluable 177 89 88

Too Early 5 2 3


S1320/II

Patient Characteristics

Randomization


Continuous

Dosing

(n=91)

Intermittent

Dosing

(n=91)

AGE

Median 59.2 62.8

Minimum 22.7 20.9

Maximum 88.6 88.8

SEX

Males 55 60% 60 66%

Females 36 40% 31 34%

HISPANIC

Yes 2 2% 4 4%

No 87 96% 87 96%

Unknown 2 2% 0 0%

RACE

White 89 98% 88 97%

Native American 1 1% 0 0%

Multi-Racial 0 0% 1 1%

Unknown 1 1% 2 2%

LDH

Elevated (>IULN) 36 40% 33 36%

Normal 55 60% 58 64%

PRIOR IMMUNE CHECKPOINT INHIBITOR

Yes 26 29% 26 29%

No 65 71% 65 71%

PRIOR IMMUNOTHERAPY

Yes 28 31% 35 38%

No 54 59% 49 54%

Unknown 9 10% 7 8%

PERFORMANCE STATUS

0 50 55% 54 59%

1 38 42% 36 40%

2 1 1% 1 1%

Data pending 2 2% 0 0%

STAGE

III 11 12% 11 12%

IV 80 88% 80 88%


S1320/II

Treatment Summary

Randomization


Total




144




Progression/relapse 101

Death 3





Randomization




Continuous Dosing

(n=89)

Grade

Intermittent Dosing

(n=88)

Grade

ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5

ALT increased 87 1 1 0 88 0 0 0

AST increased 84 4 1 0 87 1 0 0

Acute kidney injury 89 0 0 0 87 0 1 0

Alkaline phosphatase increased 88 1 0 0 87 1 0 0

Anemia 86 2 1 0 86 2 0 0

Arthralgia 88 1 0 0 87 1 0 0

Back pain 88 1 0 0 88 0 0 0

Blood bilirubin increased 88 1 0 0 88 0 0 0

Chills 88 1 0 0 87 1 0 0

Confusion 89 0 0 0 87 1 0 0

Creatinine increased 88 0 1 0 88 0 0 0

Dehydration 88 1 0 0 88 0 0 0

Diarrhea 87 2 0 0 87 1 0 0

Dry skin 88 1 0 0 88 0 0 0

Dyspnea 88 0 1 0 88 0 0 0

ECG QT corrected int prolong 88 1 0 0 87 1 0 0

Ejection fraction decreased 85 4 0 0 84 4 0 0

Eye disorders - Other, specify 89 0 0 0 87 1 0 0

Fatigue 82 7 0 0 86 2 0 0

Fever 83 6 0 0 87 0 1 0


S1320/II

Continuous Dosing

(n=89)

Grade

Intermittent Dosing

(n=88)

Grade

ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5

Flu like symptoms 87 2 0 0 88 0 0 0

Gastric hemorrhage 88 1 0 0 88 0 0 0

Generalized muscle weakness 87 2 0 0 86 2 0 0

Glucose intolerance 88 1 0 0 88 0 0 0

Hand-Foot syndrome 88 1 0 0 88 0 0 0

Hypercalcemia 89 0 0 0 87 1 0 0

Hyperglycemia 86 3 0 0 86 2 0 0

Hypertension 83 6 0 0 85 3 0 0

Hypoalbuminemia 88 1 0 0 88 0 0 0

Hyponatremia 85 4 0 0 86 2 0 0

Hypotension 88 1 0 0 87 1 0 0

Infections/infestations-Other 89 0 0 0 87 1 0 0

Investigations-Other, specify 89 0 0 0 87 1 0 0

LV systolic dysfunction 88 1 0 0 87 1 0 0

Lipase increased 86 2 1 0 85 2 1 0

Localized edema 88 1 0 0 88 0 0 0

Lung infection 88 1 0 0 88 0 0 0

Lymphocyte count decreased 85 4 0 0 87 1 0 0

Mucositis oral 88 1 0 0 88 0 0 0

Myalgia 89 0 0 0 87 1 0 0

Neutrophil count decreased 86 3 0 0 88 0 0 0

Pain in extremity 88 1 0 0 88 0 0 0

Platelet count decreased 88 1 0 0 88 0 0 0

Rash acneiform 87 2 0 0 88 0 0 0

Rash maculo-papular 88 1 0 0 88 0 0 0

Resp/thoracic/mediastinal ds 88 1 0 0 88 0 0 0

Retinal detachment 89 0 0 0 86 2 0 0

Sepsis 88 0 1 0 88 0 0 0

Serum amylase increased 89 0 0 0 86 2 0 0

Skin/subq tissue ds-Other 88 1 0 0 88 0 0 0

Syncope 88 1 0 0 88 0 0 0

Thromboembolic event 87 2 0 0 88 0 0 0

Tx related secondary malig 89 0 0 0 86 2 0 0

Urinary tract infection 89 0 0 0 87 1 0 0

Urinary tract obstruction 88 1 0 0 88 0 0 0

White blood cell decreased 86 3 0 0 87 1 0 0

MAX. GRADE ANY ADVERSE EVENT 50 34 5 0 59 26 3 0


S1404/III

S1404 Phase III


A Phase III Randomized Trial Comparing Physician/Patient Choice of Either

High Dose Interferon or Ipilimumab to MK-3475 (Pembrolizumab) in

Patients with High Risk Resected Melanoma

Participants:

SWOG, CTSU (Supported by CCTG and ECOG-

ACRIN)

Study Chairs:

K Grossmann, S Patel, A Tarhini (ECOG-ACRIN),

T Petrella (CCTG)

Statisticians:

M Othus, J Moon, H Li

Data Coordinators:

V Kim, L Kingsbury

Date Activated:

10/15/2015

Date Closed:

08/15/2017

SCHEMA

R

A

N

D

O

M

I

Z

A

T

I

O

N

FDA approved regimen:

Physician/Patient choice of

Interferon alfa-2b/Ipilimumab

MK-3475 (Pembrolizumab)

R

E

G

I

S

T

R

A

T

I

O

N

Tissue Submission*

*PD-L1 status determined by central laboratory

and blinded to the investigator and patient


S1404/III

Objectives

Co-Primary Objectives:

To compare overall survival (OS) of patients with

resected Stage III and IV melanoma treated with

physician/patient choice of either high dose

interferon alfa-2b or ipilimumab versus MK-3475

(pembrolizumab).

To compare OS of patients with resected Stage III

and IV melanoma treated with physician/patient

choice of either high dose interferon alfa-2b or

ipilimumab versus MK-3475 (pembrolizumab)

among patients who are PD-L1 positive.

To compare relapse-free survival (RFS) of patients

with resected Stage III and IV melanoma treated with

physician/patient choice of either high dose

interferon alfa-2b or ipilimumab versus MK-3475

(pembrolizumab).

Secondary Objectives:

To estimate OS and RFS for patients who are PD-L1

negative or PD-L1 indeterminate in this population.

To compare OS and RFS between the two arms

within the PD-L1 positive and PD-L1 negative

subgroups and to investigate the interaction between

PD-L1 status (positive versus negative) and treatment

arm.

To assess the safety and tolerability of the regimens.

Patient Population

Patients must have histologically confirmed selected

Stage III (IIIA/N2a, IIIB, IIIC) or Stage IV

melanoma of cutaneous or mucosal origin or

unknown primary. Patients must not have melanoma

of ocular origin. Patients are eligible for this trial

either at initial presentation of their melanoma, at

time of first detected nodal, satellite/in-transit, distant

metastases, or recurrent disease in prior

lymphadenectomy basin or distant site. Patients must

not have a history of brain metastases. Patients who

have multiple regional nodal basin involvement are

eligible. Gross or microscopic extracapsular nodal

extension is permitted. All disease must have been

completely resected with negative pathologic margins

and no clinical, radiologic, or pathologic evidence of

any incompletely resected melanoma. Patients must

have available and be willing to submit adequate

tissue for PD-L1 testing.

Patients may have received prior radiotherapy,

including after the surgical resection that rendered the

patient disease-free. Patients must not have received

neoadjuvant treatment for their melanoma. Patients

must not have received prior immunotherapy,

including but not limited to ipilimumab, interferon

alfa-2b, pegylated interferon, high dose IL-2, anti-

PD-1, anti-PD-L1, intra-tumoral, or vaccine

therapies. Patients must be registered within 98 days

of the last surgery performed to render the patient

free of disease.

Patients must have a Zubrod performance status of 0-

1, and have adequate renal, hepatic, hematologic, and

cardiac function. Patients must not have active

autoimmune disease that has required systemic

treatment in the past two years.Patients must not have

an active infection requiring systemic therapy.

Patients must not have pneumonitis or a history of

non-infectious pneumonitis that required steroids.

Patients known to be HIV positive must have

adequate CD4 counts and low viral load. Patients

must not have known active hepatitis B or C

infections. Patients must not have received live

vaccines within 42 days prior to enrollment. Women

of childbearing potential must have a negative

pregnancy test within 28 days prior to randomization.

Stratification/Descriptive Factors Treatment randomization will be stratified by the

following: (1) surgically resected AJCC stage:

IIIA(N2a) vs IIIB vs IIIC vs IV; (2) PD-L1 status:

positive vs negative vs indeterminate; (3) planned

control arm regimen: high dose interferon vs

ipilimumab.

Accrual Goals The accrual goal of this study is to randomize 1,240

eligible patients. Up to two interim analyses of

overall survival will be performed when 55% and

80% of the expected deaths across both arms

combined have been observed. An interim analyses

of relapse-free survival (RFS) will be performed

when 75% of the expected RFS events have been

observed.

Summary Statement This study was permanently closed after reaching its

accrual goal. A total of 1,426 patients were registered

to the PD-L1 status screening step. Sixty-three


reasons: incorrect stage of disease (20),

inadequate/incomplete resection of disease (21),

radiologic or clinical evidence that patient was not

disease free (10), lack of adequate tissue for PD-L1


S1404/III

testing (8), inadequate renal function (1), concurrent

radiation therapy (1), recurrent satellite metastases

(1), recurrent distant metastases (1).

A total of 1,345 patients were randomized. Thirty-

seven are currently ineligible, including 36 who were

ineligible at the screening step and one patient due to

a positive pregnancy test. Ninety-seven patients, 89

of them randomized to the control arm, did not

receive any protocol treatment, coded as a major

protocol deviation, and are not evaluable for adverse

events.

On the control arm, 569 patients have been assessed

for adverse events. There have been two treatment

related deaths, one due to enterocolitis, the other due

to respiratory failure (with a prior Grade 4 sepsis);

both patients were receiving ipilimumab. An

additional 36 patients have experienced treatment-

related Grade 4 adverse events. These have been

primarily hematologic among patients who received

high-dose interferon and immune-related among

patients who received ipilimumab. One patient

experienced Grade 4 AIDP (coded as "Nervous

system disorders - Other).

On the pembrolizumab arm, 642 patients have been

assessed for adverse events. There have been two

treatment related deaths, one due to myocarditis, the

other due to a secondary leukemia (AML, also coded

as "Neoplasms, all"). An additional 12 patients have

experienced treatment-related Grade 4 adverse

events. Notable Grade 4 adverse events include four

cases of hyperglycemia, one case of acidosis, one

case of diabetic ketoacidosis (coded as

Metabolic/nutrition disorders - Other), one case of

Type 1 diabetes (coded as "Endocrine disorders-

Other"). In addition, one patient experienced Grade 4

myasthenia gravis (coded as "Nervous system

disorders, Other") and another experienced Grade 4

episcleritis (coded as "Eye disorders, other").


S1404/III


Initial Registration

Institutions

Total

Reg Institutions

Total

Reg

Kaiser Perm NCORP 77 Cedars-Sinai Med Ctr 8

H Lee Moffitt CC 53 City of Hope Med Ctr 8

MD Anderson CC 48 Dayton NCORP 8

Colorado, U of 34 Michigan CRC NCORP 8

Utah, U of 34 TX Oncology-Central/San Antonio, U of TX 8

Ohio State Univ 33 Wisconsin NCORP 8

Heartland NCORP 29 Yale University 7

Kansas, U of 26 Columbus NCORP 6

Cleveland Clinic OH 25 Rochester, Univ of 6

Los Angeles, U of CA 24 San Diego, U of CA 6

Georgia NCORP 21 Tennessee, U of 6

Northwestern Univ 19 Arkansas, U of 5

PCRC NCORP 17 Sutter Cancer RC 5

CRC West MI NCORP 15 UF Cancer Center/Arkansas, U of 5

Michigan, U of 13 Cincinnati MC, U of 4

Wichita NCORP 13 Gulf South MU-NCORP 4

Baylor Univ Med Ctr 12 Montana NCORP 4

Oregon Hlth Sci Univ 12 Ozarks NCORP 4

Arizona MC, U of 11 All Other SWOG Institutions 22

Mt Sinai Med Ctr 11 ECOG-ACRIN 323

Northwest NCORP 11 ALLIANCE 150

CORA NCORP 10 CCTG 130

New Mexico MU-NCORP 10 NRG 113

Southeast COR NCORP 10 Total (61 Institutions) 1426

Wayne State Univ 10


Initial Registration

Data as of January 24, 2019

Tissue for PD-L1

testing

NUMBER REGISTERED 1426

INELIGIBLE 63

ELIGIBLE 1363

Analyzable, Pend. Elig. 18


S1404/III


Randomization

Institutions

Total

Reg Institutions

Total

Reg

Kaiser Perm NCORP 74 Wayne State Univ 9

H Lee Moffitt CC 52 Cedars-Sinai Med Ctr 8

MD Anderson CC 43 City of Hope Med Ctr 8

Ohio State Univ 33 Michigan CRC NCORP 8

Utah, U of 31 Wisconsin NCORP 8

Colorado, U of 29 Dayton NCORP 7

Heartland NCORP 27 TX Oncology-Central/San Antonio, U of TX 7

Cleveland Clinic OH 25 Rochester, Univ of 6

Kansas, U of 25 San Diego, U of CA 6

Los Angeles, U of CA 23 Tennessee, U of 6

Georgia NCORP 20 Yale University 6

PCRC NCORP 17 Arkansas, U of 5

Northwestern Univ 16 Sutter Cancer RC 5

CRC West MI NCORP 13 UF Cancer Center/Arkansas, U of 5

Wichita NCORP 13 Columbus NCORP 4

Baylor Univ Med Ctr 12 Gulf South MU-NCORP 4

Michigan, U of 12 Montana NCORP 4

Oregon Hlth Sci Univ 12 Ozarks NCORP 4

Arizona MC, U of 11 All Other SWOG Institutions 24

Northwest NCORP 11 ECOG-ACRIN 302

Mt Sinai Med Ctr 10 ALLIANCE 144

Southeast COR NCORP 10 CCTG 122

CORA NCORP 9 NRG 106

New Mexico MU-NCORP 9 Total (60 Institutions) 1345


Randomization


TOTAL

FDA approved

regimen

MK-3475

(Pembrolizumab)


INELIGIBLE 37 20 17

ELIGIBLE 1308 658 650


Evaluable 1211 569 642

Not Evaluable 97 89 8


S1404/III


Randomization


FDA approved

regimen

(n=658)

MK-3475

(Pembrolizumab)

(n=650)

AGE

Median 57.0 56.1

Minimum 18.3 20.0

Maximum 86.0 82.6

SEX

Males 398 60% 383 59%

Females 260 40% 267 41%

HISPANIC

Yes 18 3% 26 4%

No 621 94% 607 93%

Unknown 19 3% 17 3%

RACE

White 625 95% 623 96%

Black 5 1% 2 0%

Asian 6 1% 4 1%

Pacific Islander 1 0% 0 0%

Native American 0 0% 2 0%

Multi-Racial 3 0% 0 0%

Unknown 18 3% 19 3%

STAGE

IIIA 68 10% 76 12%

IIIB 327 50% 312 48%

IIIC 223 34% 221 34%

IV 40 6% 41 6%

PLANNED CONTROL-ARM REGIMEN

High Dose Interferon 157 25% 153 25%

Ipilimumab 466 75% 457 75%

PERFORMANCE STATUS

0 550 84% 544 84%

1 108 16% 106 16%


S1404/III

Treatment Summary

Randomization


Total




1272








Randomization




FDA approved

regimen

(n=569)

Grade


(n=642)

Grade

ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5

ALT increased 524 39 6 0 623 19 0 0

AST increased 535 30 4 0 629 13 0 0

Abdominal pain 563 6 0 0 640 2 0 0

Acidosis 568 1 0 0 640 1 1 0

Acute kidney injury 567 2 0 0 640 2 0 0

Adrenal insufficiency 560 8 1 0 638 4 0 0


Anemia 568 1 0 0 641 1 0 0

Anorexia 565 4 0 0 641 1 0 0

Anxiety 567 2 0 0 642 0 0 0

Arthralgia 567 2 0 0 639 3 0 0

Arthritis 568 1 0 0 642 0 0 0

Atelectasis 568 1 0 0 642 0 0 0

Atrial fibrillation 568 1 0 0 642 0 0 0

Atrial flutter 569 0 0 0 641 1 0 0

Autoimmune disorder 567 0 2 0 641 1 0 0

Back pain 566 3 0 0 642 0 0 0

Blood bilirubin increased 567 2 0 0 640 1 1 0

Blood/lymph disorder-Other 568 1 0 0 642 0 0 0

Blurred vision 568 1 0 0 642 0 0 0

Bone pain 568 1 0 0 642 0 0 0

Bronchospasm 569 0 0 0 641 0 1 0

CPK increased 564 3 2 0 640 1 1 0


S1404/III

FDA approved

regimen

(n=569)

Grade


(n=642)

Grade

ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5

Cardiac disorder-Other, spec 568 1 0 0 642 0 0 0

Cardiac troponin T increased 568 1 0 0 642 0 0 0

Colitis 536 31 2 0 629 13 0 0

Colonic perforation 568 0 1 0 642 0 0 0

Confusion 567 2 0 0 641 1 0 0

Cough 568 1 0 0 641 1 0 0

Creatinine increased 567 1 1 0 642 0 0 0

Cystitis noninfective 568 1 0 0 642 0 0 0

Dehydration 566 3 0 0 641 1 0 0

Delirium 568 1 0 0 642 0 0 0

Depression 565 4 0 0 642 0 0 0

Diarrhea 515 53 1 0 624 18 0 0

Dizziness 568 1 0 0 642 0 0 0

Duodenal ulcer 568 1 0 0 642 0 0 0

Dyspepsia 568 1 0 0 642 0 0 0

Dyspnea 557 11 1 0 638 3 1 0

Encephalitis infection 567 1 1 0 642 0 0 0

Encephalopathy 568 1 0 0 642 0 0 0

Endocrine disorders-Other 565 4 0 0 639 2 1 0

Enterocolitis 563 5 0 1 641 1 0 0

Enterocolitis infectious 567 2 0 0 641 1 0 0

Erectile dysfunction 568 1 0 0 642 0 0 0

Esophagitis 568 1 0 0 642 0 0 0

Eye disorders - Other, specify 568 1 0 0 641 0 1 0

Eye pain 569 0 0 0 641 1 0 0

FEV1 decreased 569 0 0 0 641 1 0 0

Facial nerve disorder 569 0 0 0 641 1 0 0

Fall 568 1 0 0 642 0 0 0

Fatigue 541 28 0 0 639 3 0 0

Febrile neutropenia 567 1 1 0 642 0 0 0

Flu like symptoms 568 1 0 0 641 1 0 0

GI disorders-Other, specify 566 3 0 0 642 0 0 0

Gastritis 567 2 0 0 642 0 0 0

Gen disorders/admin site cond 568 1 0 0 641 1 0 0


Headache 556 13 0 0 639 3 0 0

Hepatic pain 569 0 0 0 641 1 0 0

Hepatitis viral 567 2 0 0 642 0 0 0

Hepatobil disorders-Other 568 1 0 0 642 0 0 0

Hiccups 569 0 0 0 641 1 0 0

Hyperglycemia 564 5 0 0 635 3 4 0

Hypersomnia 568 1 0 0 642 0 0 0

Hypertension 562 7 0 0 640 2 0 0

Hyperthyroidism 568 0 1 0 641 1 0 0

Hypertriglyceridemia 561 6 2 0 641 1 0 0


Hypokalemia 567 2 0 0 642 0 0 0

Hyponatremia 554 11 4 0 633 9 0 0

Hypophosphatemia 566 3 0 0 639 3 0 0

Hypotension 566 3 0 0 642 0 0 0


S1404/III

FDA approved

regimen

(n=569)

Grade


(n=642)

Grade

ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5

Hypothyroidism 566 3 0 0 642 0 0 0

Hypoxia 566 3 0 0 640 2 0 0

Immune sys disorders-Other 568 1 0 0 640 2 0 0

Infections/infestations-Other 568 1 0 0 642 0 0 0

Infusion related reaction 568 1 0 0 641 1 0 0

Insomnia 568 1 0 0 642 0 0 0

Joint effusion 569 0 0 0 641 1 0 0

Leukocytosis 568 1 0 0 642 0 0 0

Lipase increased 564 4 1 0 641 1 0 0

Lower GI hemorrhage 568 1 0 0 642 0 0 0

Lung infection 568 1 0 0 638 4 0 0


MS/connective tissue disorder 568 1 0 0 640 2 0 0

Meningitis 566 3 0 0 642 0 0 0

Metab/nutrition disorders-Oth 567 2 0 0 641 0 1 0

Mucositis oral 569 0 0 0 640 2 0 0

Muscle weakness lower limb 568 1 0 0 642 0 0 0

Myalgia 565 4 0 0 641 1 0 0

Myocardial infarction 569 0 0 0 641 1 0 0

Myocarditis 569 0 0 0 641 0 0 1

Myositis 568 1 0 0 641 1 0 0

Nausea 559 10 0 0 641 1 0 0

Neoplasms, all 569 0 0 0 641 0 0 1

Nervous sys disorders-Other 565 3 1 0 640 1 1 0

Neuralgia 567 2 0 0 642 0 0 0

Neutrophil count decreased 519 43 7 0 640 2 0 0

Pain 568 1 0 0 642 0 0 0

Pain in extremity 567 2 0 0 642 0 0 0

Pain of skin 569 0 0 0 641 1 0 0

Pancreatitis 566 2 1 0 637 5 0 0

Papulopustular rash 568 1 0 0 642 0 0 0

Peripheral motor neuropathy 568 1 0 0 642 0 0 0

Peripheral sensory neuropathy 568 0 1 0 642 0 0 0

Pharyngitis 568 1 0 0 642 0 0 0

Pleural effusion 568 1 0 0 642 0 0 0

Pneumonitis 563 6 0 0 637 5 0 0

Proctitis 569 0 0 0 641 1 0 0

Proteinuria 569 0 0 0 641 1 0 0

Pruritus 562 7 0 0 642 0 0 0

Rash acneiform 569 0 0 0 640 2 0 0


Rash pustular 568 1 0 0 642 0 0 0

Resp/thoracic/mediastinal ds 569 0 0 0 641 1 0 0

Respiratory failure 567 0 1 1 642 0 0 0

Restrictive cardiomyopathy 568 1 0 0 642 0 0 0

Secondary Leukemia 569 0 0 0 641 0 0 1

Seizure 569 0 0 0 641 1 0 0

Sepsis 567 0 2 0 641 0 1 0

Serum amylase increased 568 1 0 0 641 1 0 0

Sinus tachycardia 567 2 0 0 642 0 0 0


S1404/III

FDA approved

regimen

(n=569)

Grade


(n=642)

Grade

ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5

Sinusitis 569 0 0 0 641 1 0 0

Skin infection 568 1 0 0 641 1 0 0


Syncope 563 6 0 0 641 1 0 0

Tremor 569 0 0 0 641 1 0 0

Vomiting 561 8 0 0 641 1 0 0

Weight loss 567 2 0 0 642 0 0 0

Wheezing 569 0 0 0 641 0 1 0

White blood cell decreased 550 17 2 0 642 0 0 0



S1512/II

S1512 Phase II


A Phase II and Pilot Trial of PD-1 Blockade with MK-3475 (Pembrolizumab)

in Patients with Resectable or Unresectable Desmoplastic Melanoma (DM)

Participants:


Study Chairs:

K Kendra, S Hu-Lieskovan, A Cochran (ECOG-

ACRIN)

Statisticians:

M Wu, J Moon

Data Coordinator:

V Kim

Date Activated:

10/20/2016

Objectives This study will enroll two separate cohorts to assess

the efficacy of MK-3475 (pembrolizumab) in

desmoplastic melanoma (DM). Cohort A will

evaluate MK-3475 (pembrolizumab) as neoadjuvant

therapy for patients with DM that is deemed

resectable by the treating investigator; including

primary DM, locally advanced DM, and locally

recurrent DM. Cohort B will be a pilot study to

evaluate the use of MK-3475 (pembrolizumab) for

patients with DM that is deemed unresectable by the

treating investigator, including metastatic DM.

Cohort A

To evaluate the pathologic complete response rate in

patients with resectable desmoplastic melanoma

treated with neoadjuvant MK-3475 (pembrolizumab).

To estimate the nine week response rate

(unconfirmed complete and partial responses).

To estimate the median overall survival.

To evaluate safety and tolerability of MK-3475

(pembrolizumab) in the neoadjuvant setting.

Cohort B

To evaluate the complete response rate (confirmed

and unconfirmed) in patients with unresectable

desmoplastic melanoma treated with MK-3475

(pembrolizumab).

To estimate the median progression-free survival.

To estimate the median overall survival.

To evaluate safety and tolerability of MK-3475

(pembrolizumab) in this setting.

Patient Population

Patients must have histologically or cytologically

confirmed primary desmoplastic melanoma. Patients

with disease that, in the judgment of the surgeon is

deemed completely resectable resulting in free

surgical margins, are eligible for Cohort A. Patients


S1512/II

with unresectable disease are eligible for Cohort B.

Patients must not have known brain metastases unless

brain metastases have been treated and patient is

asymptomatic with no residual neurological

dysfunction without receiving enzyme-reducing anti-

epileptic drugs or corticosteroids. Patients enrolled on

Cohort A may have only non-measurable disease

provided it can be confirmed with a fine needle

aspiration. Patients enrolled on Cohort B must have

measurable disease

Patients must not have received prior systemic

therapy for desmoplastic melanoma. Patients must

not have received radiation therapy, non-cytotoxic

agents or investigational agents or systemic

corticosteroids within 14 days prior to registration.

Patients may have received prior surgery.

Patients must have adequate hematologic and hepatic

function with a Zubrod performance status of 0-2.

Patients must not have known, active non-infectious

pneumonitis, an active infection requiring systemic

therapy, or an active autoimmune disease that has

required systemic treatment in the past two years.

Patients must not have received live vaccines within

42 days prior to registration. Patients known to be

HIV positive must have stable and adequate CD4

counts, a serum viral load below 52,000 IU/ml and

must be on stable anti-viral therapy. Women of

childbearing potential must have a negative urine or

serum pregnancy test within 28 days prior to

registration.

Stratification/Descriptive Factors Patients will be stratified by Cohort: A (resectable) vs

B (unresectable).

Accrual Goals Accrual to this study will proceed in two independent

cohorts: A and B.

Cohort A will accrue approximately 51 patients to

achieve 41 eligible patients. Initially, 21 eligible

patients will be enrolled. If two or more pathologic

complete responses are observed, an additional 20

eligible patients will be enrolled.

Cohort B will accrue approximately 26 patients to

achieve 21 eligible patients.

Summary Statement In an effort to improve accrual, this study was

amended to allow patients with only non-measurable

disease to be enrolled on Cohort A (resectable

disease) provided that residual disease can be

confirmed with a fine-needle aspiration. Patients

enrolled on Cohort B (unresectable disease) must still

have measurable disease.

As of December 31, 2018, 18 patients have been

registered, eight to Cohort A and ten to Cohort B.

One patient withdrew consent prior to receiving any

protocol treatment and is not analyzable for any of

the study endpoints.

Sixteen patients have been assessed for adverse

events. No treatment-related adverse events greater

than Grade 3 have been reported.



Institutions Total Reg

H Lee Moffitt CC 6

Ohio State Univ 4

Los Angeles, U of CA 3

So Calif, U of 2

Georgia NCORP 1

Kansas, U of 1

Southeast COR NCORP 1

Total (7 Institutions) 18


S1512/II


Classified by Cohort


TOTAL

Resectable

(Cohort A)

Unresectable

(Cohort B)


ELIGIBLE 18 8 10


Not Analyzable 1 1 0

BASELINE DISEASE STATUS

Measurable 11 6 5

Too Early 6 1 5

RESPONSE ASSESSMENT

Determinable 8 5 3

Too Early 9 2 7


Evaluable 16 7 9

Too Early 1 0 1




Resectable

(Cohort A)

(n=7)

Unresectable

(Cohort B)

(n=10)

AGE

Median 80.8 82.0

Minimum 49.2 70.0

Maximum 85.8 89.6

SEX

Males 6 86% 10 100%

Females 1 14% 0 0%

HISPANIC

No 7 100% 10 100%

RACE

White 7 100% 10 100%

PERFORMANCE STATUS

0 5 71% 6 60%

1 2 29% 4 40%


S1512/II





Resectable

(Cohort A)

(n=7)

Grade

Unresectable

(Cohort B)

(n=9)

Grade

ADVERSE EVENTS <=2 3 4 5 <=2 3 4 5

ALT increased 7 0 0 0 9 0 0 0


Anemia 7 0 0 0 9 0 0 0

Anorexia 7 0 0 0 9 0 0 0

Arthralgia 7 0 0 0 9 0 0 0

Bullous dermatitis 7 0 0 0 9 0 0 0

Constipation 7 0 0 0 9 0 0 0

Diarrhea 7 0 0 0 9 0 0 0

Dyspnea 7 0 0 0 8 1 0 0

Fatigue 7 0 0 0 9 0 0 0

Fever 7 0 0 0 9 0 0 0


Hypercalcemia 7 0 0 0 9 0 0 0

Hyperkalemia 7 0 0 0 9 0 0 0

Hypernatremia 7 0 0 0 9 0 0 0

Hypertension 7 0 0 0 9 0 0 0

Hyperthyroidism 7 0 0 0 9 0 0 0


Hypokalemia 7 0 0 0 9 0 0 0

Hyponatremia 7 0 0 0 9 0 0 0

Hypothyroidism 7 0 0 0 9 0 0 0

Hypoxia 7 0 0 0 8 1 0 0


Nausea 7 0 0 0 9 0 0 0

Platelet count decreased 7 0 0 0 9 0 0 0

Pneumonitis 7 0 0 0 9 0 0 0

Pruritus 7 0 0 0 9 0 0 0



Tremor 7 0 0 0 9 0 0 0



S1607/II

S1607 Phase II


A Phase II Study of Combining Talimogene Laherparepvec (T-VEC) (NSC-

785349) and MK-3475 (Pembrolizumab) (NSC-776864) in Patients with

Advanced Melanoma Who Have Progressed on Anti-PD/L1 Based Therapy

Participants:

SWOG, CTSU

Study Chairs:

S Hu-Lieskovan, A Ribas

Statisticians:

M Wu, J Moon

Data Coordinator:

V Kim

Date Activated:

10/02/2017

Objectives To evaluate the durable response rate of treatment

with talimogene laherparepvec (T-VEC) in

combination with MK-3475 (pembrolizumab)

following progression on prior anti-PD-1 or anti-PD-

L1 therapy alone or in combination with other agents

different from talimogene laherparepvec (T-VEC).

To estimate the response rate (confirmed and

unconfirmed, complete and partial responses) in the

injected lesions.

To estimate the response rate in the non-visceral,

non-injected lesions.

To estimate the response rate in the visceral lesions.

To estimate the overall objective response rate per

RECIST 1.1, progression-free survival, and overall

survival within each cohort.

To evaluate whether adding talimogene

laherparepvec (T-VEC) to PD1 blockade can increase

T-cell infiltration into tumors and whether change in

T-cell infiltration is associated with response.

To evaluate whether adding talimogene

laherparepvec (T-VEC) to PD1 blockade can increase

TCR clonality in tumors and in peripheral blood and

whether increased TCR clonality is associated with

response.

To evaluate whether intra-tumoral injection of

talimogene laherparepvec (T-VEC) is associated with

the tumor immune microenvironment.

To evaluate whether tumor mutational load and

mutations in the IFN pathway is associated with

response to talimogene laherparepvec (T-VEC) plus

MK-3475 (pembrolizumab) therapy in the anti-

PD1/L1 therapy refractory melanoma patients.

Patient Population Patients must have pathologically confirmed Stage

IV or unresectable Stage III melanoma with

cutaneous, mucosal or unknown primary. Patients

with uveal primary are not eligible. Patients will be

enrolled onto one of two independent cohorts: for

Cohort A, patients must have at least one measurable

visceral lesion, defined as any solid organ except for


S1607/II

skin, lymph node, or musculoskeletal tissue; for

Cohort B, patients must have at least one measurable

non-visceral lesion and no evidence of visceral

disease. Patients must not have known active central

nervous system (CNS) metastases. Patients with a

history of CNS metastases must have been

adequately treated with no evidence of progression

for at least 28 days prior to registration and must be

asymptomatic without requiring steroids for at least

14 days prior to registration. Patients must, in the

opinion of the treating investigator, be candidates for

intralesional administration into cutaneous,

subcutaneous, or nodal lesions. Patients must have at

least two injectable lesions.

Patient must have had prior treatment with anti-PD-1

or anti-PD-L1 agents and have documented disease

progression on these agents prior to registration.

Patient must have received anti-PD-1 or PD-L1 based

therapy as the immediate previous line of treatment

and within 56 days prior to registration. Patients must

not have had surgery, chemotherapy, biologic

therapy, hormonal therapy, or radiation therapy

within 14 days prior to registration. Patients must not

have had an investigational agent or monoclonal

antibodies, except anti-PD1/L1 antibodies, within 28

days prior to registration. Patients must not have

received prior treatment with talimogene

laherparepvec (T-VEC) or other oncolytic virus

agents. Patients must not have had any infectious

disease vaccination within seven days prior to

registration.

Patients must have adequate hematologic, hepatic,

and renal function and a Zubrod performance status

of 0-2. Patients must not have severe autoimmune

disease requiring systemic corticosteroids or ongoing

immunosuppression. Patients must not have a known

history of HIV, hepatitis B, or hepatitis C, or

pneumonitis. Patients must not have an active

infection requiring systemic therapy nor a viral-

infection requiring intermittent treatment with an

antiherpatic drug, and must not have active herpatic

skin lesions or prior complications of herpatic

infection which require treatment with an anti-

herpatic drug. Patients must not have organ

allografts, or a history of autoimmune disease, or

clinically significant immunosuppression. Women of

reproductive potential must have a negative serum

pregnancy test within seven days prior to registration.

Patients must have tissue available and must be

willing to submit blood and tissue specimens for the

translational medicine objectives. Patients must be

offered the opportunity to participate in specimen

banking.

Stratification/Descriptive Factors Patients will be stratified based on presence of

visceral lesions: one or more vs none.

Accrual Goals The study will accrue to two independent cohorts.

Cohort A, patients with at least one visceral lesion,

will use a two-stage design. Initially 18 patients will

be enrolled. If at least one response is observed, then

an additional 14 patients will be enrolled for a total of

32 patients.

Cohort B, patients with no visceral lesions, will use a

modified two-stage design. Initially 16 patients will

be enrolled. If two or more durable responses are

observed, then an additional nine patients will be

enrolled for a total of 25 patients.

Summary Statement As of December 31, 2018, eight patients have been

registered, two to the cohort with at least one visceral

lesion and six to the cohort with non-visceral disease

only.

Seven patients have been evaluated for adverse

events. So far, no Grade 4-5 adverse events have

been reported.


S1607/II



Institutions Total Reg

Los Angeles, U of CA 5

Ohio State Univ 1

So Calif, U of 1

ECOG-ACRIN 1

Total (4 Institutions) 8




TOTAL

Visceral

(Cohort A)

Non-Visceral

(Cohort B)


ELIGIBLE 8 2 6


RESPONSE ASSESSMENT

Determinable 3 1 2

Too Early 5 1 4


Evaluable 7 2 5

Too Early 1 0 1


S1607/II




Visceral

(Cohort A)

(n=2)

Non-Visceral

(Cohort B)

(n=6)

AGE

Median 47.7 73.8

Minimum 35.4 37.8

Maximum 60.0 93.7

SEX

Males 1 50% 1 17%

Females 1 50% 5 83%

HISPANIC

Yes 1 50% 0 0%

No 1 50% 6 100%

RACE

White 1 50% 6 100%

Unknown 1 50% 0 0%

PERFORMANCE STATUS

0 1 50% 4 67%

1 1 50% 1 17%

2 0 0% 1 17%


S1607/II





Visceral

(Cohort A)

(n=2)

Grade

Non-Visceral

(Cohort B)

(n=5)

Grade

ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5

Chills 2 0 0 0 0 0 4 0 1 0 0 0

Dyspnea 2 0 0 0 0 0 4 0 0 1 0 0

Fever 2 0 0 0 0 0 4 0 1 0 0 0

Flu like symptoms 1 0 0 1 0 0 4 0 1 0 0 0

Hot flashes 1 1 0 0 0 0 5 0 0 0 0 0

Hyponatremia 2 0 0 0 0 0 4 0 0 1 0 0

Hypoxia 2 0 0 0 0 0 4 0 0 1 0 0

Injection site reaction 1 0 1 0 0 0 5 0 0 0 0 0

Pruritus 2 0 0 0 0 0 4 0 1 0 0 0

Rash maculo-papular 2 0 0 0 0 0 4 1 0 0 0 0

Sinus tachycardia 2 0 0 0 0 0 4 0 1 0 0 0

Skin infection 2 0 0 0 0 0 4 0 1 0 0 0

Tumor pain 2 0 0 0 0 0 4 0 0 1 0 0

MAX. GRADE ANY ADVERSE EVENT 1 0 0 1 0 0 2 0 2 1 0 0


S1609/II

S1609 Phase II


DART: Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors

Participants:

SWOG, CTSU

Study Chairs:

S Patel, Y Chae

Statisticians:

M Othus, M Plets, E Mayerson

Data Coordinators:

C McLeod, J Hayward

Date Activated:

01/13/2017

Objectives To evaluate the RECIST 1.1 overall response rate

(ORR) in subsets of patients with advanced rare

cancers treated with ipilimumab plus nivolumab

combination immunotherapy.

To evaluate toxicities in each cohort.

To estimate overall survival (OS), progression-free

survival (PFS), clinical benefit rate; and to estimate

immune-related ORR (irORR), and immune-related

PFS (irPFS) by unidimensional immune-related

response criteria.

To collect specimens for banking for use in future

correlative biomarker research studies.

Patient Population Patients must have histologically confirmed rare

cancer and/or cancer of unknown primary specified

on the list of eligible rare cancer histologic cohorts in

the S1609 protocol. Patients who do not qualify for

one of the histologic cohorts may be considered for

registration in the "Not Otherwise Categorized"

(NOC) cohort with confirmation by one of the study

chairs. As of September 11, 2017, patients are no

longer required to have been enrolled in EAY131

(NCI-MATCH) to be eligible for this study.

Patients must have measurable disease and have

progressed following at least one line of standard

systemic therapy and there must not be other

approved/standard therapy available that has been

shown to prolong overall survival. Patients are also

eligible if no standard treatment exists that has been

shown to prolong overall survival. Patients must not

have received either prior anti-CTLA4, anti-PD-1, or

anti-PD-L1 therapy. Other immunotherapy is

permitted, provided that it is completed at least seven

days prior to registration. Patients who had a prior

immune-related adverse event with prior

immunotherapy are not eligible. Patients with brain

metastases or primary brain tumors must have

completed treatment, surgery or radiation therapy ≥

28 days prior to registration and have stable disease

at time of registration. Patients with metastatic brain

parenchymal disease must have been treated and off

steroids for seven days prior to registration. Patients

must have been off all other systemic anti-cancer

therapy at least seven days prior to registration and

any therapy-induced toxicity must have recovered to

≤ Grade 1.


S1609/II


2 and have adequate hematologic, hepatic, renal,

thyroid, and adrenal axis function. Patients must not

have active autoimmune disease that has required

systemic treatment in the past two years or any

uncontrolled intercurrent illness. Patients must not

have known active Hepatitis B Virus (HBV) or

Hepatitis C Virus (HCV) infection at time of

registration. Patients with HBV or HCV that have an

undetectable viral load, or in the opinion of the

treating investigator is well controlled, are eligible.

Patients who are known to be HIV-positive at

registration are eligible if they meet the conditions

outlined in the protocol.

Stratification/Descriptive Factors Patients will be described by histologic cohorts.

Accrual Goals The accrual goal for this study is 707 patients to

achieve 636 eligible patients. A two-stage design will

be used for all cohorts, with the exception of the

NOC and "Cancer of Unknown Primary" (CuP)

cohorts. Initially, six eligible patients will be

registered to each histologic cohort. If at least one

response is observed within a cohort, an additional 10

eligible patients will be registered to that cohort. Up

to 16 eligible patients will be registered to the CuP

cohort with no formal first stage response

assessment. Up to 60 eligible patients will be enrolled

to the NOC cohort, and data may be used to open

additional cohorts.


Early Therapeutics and Rare Cancers chapter.


S1614/III

S1614 Phase III


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:


Study Chairs:

J Hwang, A Lok, E Mitchell (ECOG-ACRIN)

Statisticians:

J Unger, E Mayerson

Data Coordinator:

K Carvalho

Date Activated:

02/21/2019

SCHEMA

Cohort 1:

Chronic HBV

Prophylactic

Antiviral Therapy

Upon Indication

Antiviral Therapy

Usual Care

Antiviral Therapy

Upon Indication

Antiviral Therapy

Cohort 2:

Past HBV

R

A

N

D

O

M

I

Z

A

T

I

O

N

R

A

N

D

O

M

I

Z

A

T

I

O

N


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.


2, and have adequate liver, renal, and coagulation

function. Patients must not have known cirrhosis,

known hepatitis-C infection, or history of human

immunodeficiency infection proven by an HIV test

within the past 365 days. Patients must have

complete results for HBsAg, anti-HBc, anti-HBs, and

HBV DNA lab tests as specified in the protocol.

Patients must be able to take oral medications.

Patients must be willing to submit specimens for

ongoing testing of HBV reactivation. Patients must

be offered the opportunity to participate in the

translational medicine studies.

Stratification/Descriptive Factors Patients with chronic HBV infection will be

randomized within Cohort 1, with randomization

stratified by planned cancer therapy type: any

cytotoxic therapy vs immunotherapy alone vs

targeted therapy alone vs immunotherapy and

targeted therapy.

Patients with past HBV infection will be randomized

within Cohort 2 with randomization stratified by the

following factors: (1) planned cancer therapy type:

any cytotoxic therapy vs immunotherapy alone vs

targeted therapy alone vs immunotherapy and

targeted therapy; and (2) anti-HBs status: positive vs

negative.

Accrual Goals The accrual goal for this study is 444 patients, 222

patients per cohort to achieve 200 eligible patients

per cohort. A single formal interim analysis for

efficacy for each cohort will be conducted when one

half of patients have reached one year of follow-up.


Symptom Control and QOL chapter.


S1616/II

S1616 Phase II


A Phase II Randomized Study of Nivolumab (NSC-732442) with Ipilimumab

(NSC-748726) or Ipilimumab Alone in Advanced Melanoma Patients

Refractory to an Anti-PD-1 or Anti-PD-L1 Agent

Participants:

SWOG, CTSU

Study Chairs:

A VanderWalde, A Ribas

Statisticians:

M Wu, J Moon

Data Coordinator:

J Sanchez

Date Activated:

07/17/2017

SCHEMA

R

A

N

D

O

M

I

Z

A

T

I

O

N

Ipilimumab + Nivolumab

Note: For every one patient randomized to receive single agent ipilimumab,

three will be randomized to receive the combination of ipilimumab and

nivolumab

Ipilimumab

Nivolumab


S1616/II

Objectives To compare progression free survival (PFS) of

patients with advanced melanoma refractory to an

anti-PD-1 or anti-PD-L1 agent, treated with

combination therapy ipilimumab plus nivolumab

versus ipilimumab alone.

To estimate difference in T-cell infiltrate between on-

study biopsy samples of patients who respond to

combination therapy (including confirmed and

unconfirmed, complete and partial response per

RECIST 1.1) as compared to those who do not

respond.

To evaluate the objective response rate (ORR)

(confirmed and unconfirmed complete or partial

responses) in each treatment arm.

To evaluate overall survival in each treatment arm.

To evaluate the toxicity profile of patients in each

treatment arm.

Patient Population

Patients must have pathologically confirmed

melanoma that is either Stage IV or unresectable

Stage III. Patients may have primaries of cutaneous,

mucosal, or unknown origin. Patients with uveal

(ocular) primary are not eligible. Patients must have

measurable disease. If the only measurable disease is

cutaneous or subcutaneous, lesions must be at least

10 mm in greatest dimension and able to be serially

recorded using calipers and photographs. Patients

must not have central nervous system metastases

unless adequately treated and patient is asymptomatic

without requiring steroids for at least 14 days prior to

registration.

Patients must have had prior treatment with anti-PD-

1 or anti-PD-L1 agents and had documented disease

progression either while on these agents or after

stopping therapy with these agents without

intervening therapy. Patients must not have achieved

a confirmed partial or complete response to the anti-

PD-1 or anti-PD-L1 agents prior to progression.

Patients must not have had any systemic therapy

within 21 days prior to registration. Patients must not

have had prior radiation therapy within 14 days prior

to registration. Patients must not have had prior

treatment with ipilimumab or other CTLA-4

antagonists.

Patients must be at least 18 years of age and have a

Zubrod performance status of 0-2 with adequate

hepatic, renal, and hematologic function. Patients

with a known history of HIV must have an adequate

CD4 count. Patients must not have a known active

Hepatitis B, or Hepatitis C infection. Patients must

not have received systemic treatment with

corticosteroids or other immunosuppressive

medications within 14 days prior to registration.

Patients must not have organ allografts or a history of

immune-mediated pneumonitis or colitis that required

steroid treatment. Women of reproductive potential

must have a negative serum pregnancy test within

two days prior to registration.

Patients must be willing to undergo biopsies and

submit tissue and blood for the translational medicine

objectives.

Accrual Goals Patients will be randomized using a 3:1 ratio to

receive combination therapy ipilimumab and

nivolumab versus single therapy ipilimumab. In other

words, 63 patients will be randomized to receive the

combination regimen and 21 will be randomized to

receive the single agent regimen. Assuming an

ineligibility rate of 10% the total accrual goal is 94

patients to achieve 84 eligible patients.

Summary Statement As of December 31, 2018, 28 patients have been

registered. One patient is currently ineligible due to

not having received prior anti-PD1 or anti-PD-L1

therapy.

On the combination arm, 17 patients have been

assessed for adverse events. One patient has

experienced a treatment-related Grade 4 adverse

event, lymphopenia. On the single agent ipilimumab

arm, seven patients have been assessed for adverse

events. No treatment-related Grade 4 adverse events

have been reported on this arm.


S1616/II



Institutions

Total

Reg Institutions

Total

Reg

Los Angeles, U of CA 3 Kansas, U of 1

Ohio State Univ 3 Rochester, Univ of 1

Tennessee, U of 3 NRG 7

CRC West MI NCORP 2 ALLIANCE 4

New Mexico MU-NCORP 2 Total (10 Institutions) 28

Northwestern Univ 2



TOTAL Ipilimumab

Nivolumab +

Ipilimumab


INELIGIBLE 1 1 0

ELIGIBLE 27 7 20


RESPONSE ASSESSMENT

Determinable 19 6 13

Too Early 8 1 7


Evaluable 24 7 17

Too Early 3 0 3


S1616/II



Ipilimumab

(n=7)

Nivolumab +

Ipilimumab

(n=20)

AGE

Median 60.7 63.6

Minimum 50.7 46.0

Maximum 70.2 86.9

SEX

Males 3 43% 11 55%

Females 4 57% 9 45%

HISPANIC

Yes 1 14% 0 0%

No 6 86% 18 90%

Unknown 0 0% 2 10%

RACE

White 7 100% 16 80%

Asian 0 0% 2 10%

Unknown 0 0% 2 10%

PERFORMANCE STATUS

0 7 100% 11 55%

1 0 0% 7 35%

2 0 0% 1 5%

Data pending 0 0% 1 5%

Treatment Summary Registrations ending December 31, 2018; Data as of January 16, 2019

TOTAL




16






LOST TO FOLLOW-UP 0

CONSENT WITHDRAWAL AFTER

TREATMENT INITIATION

0


S1616/II



Adverse Events with No Entries for Grades 2 to 5 Have Been Suppressed


Ipilimumab

(n=7)

Grade

Nivolumab + Ipilimumab

(n=17)

Grade

ADVERSE EVENTS 0 1 2 3 4 5 0 1 2 3 4 5

ALT increased 6 1 0 0 0 0 12 2 2 1 0 0

AST increased 6 1 0 0 0 0 14 2 0 1 0 0

Abdominal pain 6 0 1 0 0 0 15 2 0 0 0 0

Acute kidney injury 7 0 0 0 0 0 16 0 0 1 0 0

Adrenal insufficiency 6 0 1 0 0 0 16 0 0 1 0 0

Alkaline phosphatase increased 6 1 0 0 0 0 14 2 0 1 0 0

Anemia 7 0 0 0 0 0 16 0 0 1 0 0

Anorexia 6 0 1 0 0 0 13 1 2 1 0 0

Arthralgia 5 2 0 0 0 0 15 1 0 1 0 0

Autoimmune disorder 5 0 2 0 0 0 17 0 0 0 0 0

Dehydration 7 0 0 0 0 0 16 0 0 1 0 0

Diarrhea 6 1 0 0 0 0 12 2 1 2 0 0

Dyspnea 7 0 0 0 0 0 16 0 1 0 0 0

Endocrine disorders-Other 7 0 0 0 0 0 16 0 0 1 0 0

Fatigue 2 4 1 0 0 0 12 1 3 1 0 0

Fever 7 0 0 0 0 0 15 1 0 1 0 0

GERD 6 0 1 0 0 0 17 0 0 0 0 0

GI disorders-Other, specify 7 0 0 0 0 0 16 0 1 0 0 0

Headache 6 0 1 0 0 0 16 1 0 0 0 0

Hyperglycemia 6 1 0 0 0 0 14 2 1 0 0 0

Hypertension 7 0 0 0 0 0 15 0 2 0 0 0

Hypocalcemia 7 0 0 0 0 0 16 0 0 1 0 0

Hypokalemia 7 0 0 0 0 0 15 0 0 1 1 0

Hyponatremia 7 0 0 0 0 0 15 1 0 1 0 0

Hypotension 7 0 0 0 0 0 16 0 0 1 0 0

Hypothyroidism 6 0 1 0 0 0 16 1 0 0 0 0

Lung infection 7 0 0 0 0 0 16 0 0 1 0 0

Lymphocyte count decreased 7 0 0 0 0 0 15 0 1 0 1 0

Metab/nutrition disorders-Other 7 0 0 0 0 0 16 0 1 0 0 0

Nausea 5 2 0 0 0 0 16 0 0 1 0 0

Pruritus 6 1 0 0 0 0 9 5 2 1 0 0

Rash acneiform 7 0 0 0 0 0 15 1 1 0 0 0

Rash maculo-papular 5 1 0 1 0 0 11 3 2 1 0 0

Urinary incontinence 7 0 0 0 0 0 16 0 1 0 0 0

Weight loss 6 1 0 0 0 0 16 0 1 0 0 0

MAX. GRADE ANY ADVERSE EVENT 1 2 3 1 0 0 1 2 5 8 1 0


S1801/II

S1801 Phase II


A Phase II Randomized Study of Adjuvant versus Neoadjuvant MK-3475

(Pembrolizumab) for Clinically Detectable Stage III-IV High Risk Melanoma

Participants:


Study Chairs:

S Patel, K Grossmann, E Buchbinder

Statisticians:

M Othus, J Moon

Data Coordinator:

V Kim

Date Activated:

12/06/2018

SCHEMA

Objectives To compare event-free survival (EFS) in patients

with high-risk resectable melanoma randomized to

neoadjuvant MK-3475 (pembrolizumab) with

patients randomized to adjuvant MK-3475

(pembrolizumab).

To assess the frequency and severity of toxicities on

each of the arms.

To compare between arms overall survival (OS),

disease control at 24 weeks, locoregional control in

the surgical site(s), and total number of MK-3475

(pembrolizumab) doses received.

On the neoadjuvant arm, to estimate the pathologic

response rate, the RECIST 1.1 response rate

(confirmed CR and PR), and the iRECIST response

rate (confirmed CR and PR), before surgical

resection.

To describe the proportion of patients on each arm

who received the surgery planned at randomization.

Patient Population Patients must have clinically detectable Stage III or

Stage IV resectable melanoma. Patients with

melanoma of mucosal or acral origin are eligible.

Patients with melanoma of uveal origin or with a

history of brain metastases documented by CT or

MRI within 42 days are not eligible. Patients are

eligible at initial presentation or at the time of the

Neoadjuvant

MK-3475

(Pembrolizumab)

R

A

N

D

O

M

I

Z

A

T

I

O

N

Adjuvant Arm

Neoadjuvant

Arm

Surgical

Resection

Adjuvant

MK-3475

(Pembrolizumab)

Adjuvant

MK-3475

(Pembrolizumab)

Surgical

Resection

R

E

G

I

S

T

R

A

T

I

O

N

R

E

G

I

S

T

R

A

T

I

O

N


S1801/II

first detected nodal, satellite/in-transit, distant

metastases, or recurrent disease in prior

lymphadenectomy basin or distant site. Patients with

multiple regional nodal basin involvement are

eligible. Gross or microscopic extracapsular nodal

extension is permitted.

Patients must not have received previous neoadjuvant

treatment for their melanoma. Patients may have

received prior non-immunotherapy adjuvant therapy.

Patients must not have had prior immunotherapy or

vaccine therapies. Patients must not be planning to

receive concomitant other biologic therapy, hormonal

therapy, other chemotherapy, or surgery. Patients

may have received prior radiation therapy, including

after prior surgical resection.

Patients must be at least 18 years of age and have a

Zubrod performance status of 0-2 and have adequate

bone marrow, hepatic, renal, and cardiac function.

Patients must not have a history of non-infectious

pneumonitis that required steroids or current

pneumonitis. Patients must not have an active

infection requiring systemic therapy. Patients must

not have active autoimmune disease that has required

systemic treatment in the past two years, and must

not have received live vaccines within 42 days prior

to randomization. Patients known to be HIV positive

are eligible if they have stable and adequate CD4

counts. Patients must not have known active

Hepatitis B Virus or Hepatitis C Virus infection.

Prior malignancy is allowed providing it does not

require concurrent therapy. Women of childbearing

potential must have a negative pregnancy test within

28 days prior to randomization.

Patients must be offered the opportunity to participate

in specimen banking. Patients randomized to

Neoadjuvant arm must be willing to submit tissue to

determine pathologic response.

Stratification/Descriptive Factors Randomization will be stratified by the following

factors: (1) LDH ≤ institutional upper limit of normal

vs > institutional upper limit of normal; (2) Nodal

involvement: 1 node vs 2-3 nodes vs other (including

4+ nodes, matted nodal mass, or metastatic disease)

at randomization.

Accrual Goals The accrual goal of this study is to randomize 556

patients with a goal of 500 eligible patients. A futility

analysis will be performed at 50% of expected

events.

Summary Statement This study was activated on December 6, 2018. As of

December 31, 2018, no patients have been registered.

ECOG-ACRIN Cancer Research Group EA6134 Study Progress and Safety Report Fall 2018

Page 1

EA6134 A RANDOMIZED PHASE III TRIAL OF DABRAFENIB + TRAMETINIB FOLLOWED BY IPILIMUMAB + NIVOLUMAB AT PROGRESSION VS. IPILIMUMAB + NIVOLUMAB FOLLOWED BY DABRAFENIB + TRAMETINIB AT PROGRESSION IN PATIENTS WITH ADVANCED BRAFV600 MUTANT MELANOMA

Sponsor(s)

Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Michael Atkins Statistician Dr. Sandra Lee Data Specialist Kerry Higgins Phase of Study III Type of Study Therapeutic Committee Melanoma Accrual Objective 300 Patients Participating Groups ECOG-ACRIN, CTSU NSC# 732442, 748726, 763093, 763760 Clinicaltrials.gov Study ID NCT02224781 Study Status Open to Accrual Date Proposed January 29, 2014 Date Activated July 13, 2015 Date Suspended February 2, 2016 Date Reactivated April 11, 2016 Schema


Page 2

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.


Page 3

For the patient reported outcomes (PROs), the primary objective is to evaluate the overall clinical benefit between initial treatments (i.e., arm A: ipilimumab + nivolumab (with subsequent dabrafenib + trametinib). vs. arm B: dabrafenib + trametinib (with subsequent ipilimumab + nivolumab)), accounting for toxicities and overall survival. The quality-adjusted time without symptoms of disease progression or toxicity of treatment (Q-TWiST) analysis will be used to provide an integrated measure of quality and quantity of survival time. The Q-TWiST score based on overall survival at 2 years will be computed and compared. In addition, the differences in overall function over 2 years between initial treatment with dabrafenib + trametinib vs. ipilimumab + nivolumab will be assessed. Lastly, the effects of treatment crossover and treatment administration sequence on symptom burden and overall function will be evaluated. Progress to Date This study was activated on July 13, 2015 (Step 1 and Step 2). The study was suspended due to acute shortage in the supply of Dabrafenib and Trametinib capsules between February 2, 2016, and April 11, 2016. As of July 17, 2018, 150 patients enrolled to step 1, and 26 to step 2. Table 1a summarizes accrual by institution. Table 1b has accrual by group, and Table 1c shows projected accrual status as of July 17, 2018. Expected cumulative accrual and actual cumulative accrual are shown in Figure 1. This report is based on the data as of July 17, 2018. Patient status is displayed in Table 2 with patients accrued at that time. Demographics of patients by treatment arm are summarized in Table 3 for Steps 1 and 2. Record status on clinical report form is summarized in Table 4. The distribution of the reasons for treatment continuation of protocol treatment is summarized in Table 5. As of July 17, 2018 there were 110 cases (70 in arm A, 69in arm B in step 1) and 22 cases (9 in arm C and 13 in arm D in step 2) who reported treatment-related toxicities. Toxicity data is summarized in Table 6. Table 7 displays one case with treatment-related adverse events reported on ECOG-ACRIN CRFs. Based on CTEP-AERS reporting system, there were 11 cases with lethal adverse events: 46007 (arm A) respiratory failure, 46021 (arm A) neoplasms, 46028 (arm A) general disorder, 46052 (arm A) thromboembolic event, 46070 (arm A) nervous system disorder, 46102 (arm A) neoplasms, 46125 (arm A) neoplasms, 46003 (arm B) stroke, 46013 (arm B) neoplasms, 46018 (arm B) death NOS and 46012 (arm C) neoplasms. Cases 46003, 46007, 46012, 46018, 46021, 46052, 46102, 46125 have been reviewed using the data collected on ECOG-ACRIN CRFs and only the respiratory failure from case 46007 was considered treatment-related. Table 8 summarizes QOL data received.


Page 4

Table 1a. Accrual by ECOG-ACRIN Institution

Institution Name Step 1 Step 2 Cancer Research Consortium of West Michigan NCORP 1 0 Cancer Research for the Ozarks NCORP 3 0 Case Western Reserve University 3 0 Catholic Health Initiatives NCORP 1 0 Colorado Cancer Research Program NCORP 1 0 Dayton NCORP 4 2 Froedtert and the Medical College of Wisconsin 1 0 Georgia Cares Minority Underserved NCORP 1 0 Georgia NCORP 3 0 Hackensack University Medical Center 1 1 Heartland Cancer Research NCORP 4 0 Indiana Univ/Melvin and Bren Simon Cancer Center 3 1 Johns Hopkins Univ/Sidney Kimmel Cancer Center 3 1 Medical University of South Carolina MU NCORP 1 0 Metro Minnesota Community Oncology Res Consortium 5 2 Michigan Ca Res Consortium NCORP 3 1 Montana Cancer Consortium NCORP 1 0 Nevada Cancer Research Foundation NCORP 3 0 New Mexico MU NCORP 1 0 New York Oncology Hematology PC -Albany Med Center 1 0 NorthShore Univ HealthSystem-Evanston Hospital 1 0 Northwest NCI Community Oncology Research Program 1 0 Northwestern University 5 2 Ohio State University Comprehensive Cancer Center 3 0 Pacific Cancer Research Consortium NCORP 8 1 Saint Luke's University Hospital-Bethlehem Campus 1 0 Sanford NCORP of the North Central Plains 1 0 Stanford Cancer Institute Palo Alto 1 0 University of Alabama at Birmingham Cancer Center 4 1 University of Miami Miller Schl Med-SylvesterCaCtr 3 0 University of Michigan Comprehensive Cancer Center 2 0 University of Pittsburgh Cancer Institute (UPCI) 9 0 University of Wisconsin Hospital and Clinics 1 0 Vanderbilt University/Ingram Cancer Center 4 1 Wichita NCORP 1 0 Wisconsin NCORP 5 1 Total 94 14

Table 1b. Accrual by Group

Step 1 Step 2 ECOG-ACRIN 94 14 SWOG 27 7 ALLIANCE 9 2 NRG 20 3 Total 150 26


Page 5

Table 1c. Projected Accrual

Step 1 Step 2

Accrual goal 300 Planned accrual rate 192/yr Accrual to date 150 26 Annual accrual rate

Overall 53/yr 9/yr Last 6 months 56/yr 12/yr

Projected date of closure March 2021


Page 6

Table 2. Patient Status as of July 17, 2018

Step 1 Step 2 Cases Entered 150 26 Ineligible 1 0 Never Started Assigned Therapy 0 0

Reason for ineligibility (n=1): Surgery < 4 weeks from registration (46143).

Table 3. Demographics Step 1

Variable Level Arm A (n=75)

Arm B (n=75)

Total (n=150)

Sex Male 41 (54.7) 47 (62.7) 88 (58.7) Female 34 (45.3) 28 (37.3) 62 (41.3)

Race White 73 (98.6) 72 (98.6) 145 (98.6) Asian 1 (1.4) 1 (1.4) 2 (1.4) Unknown/Unreported 1 2 3

Ethnicity Hispanic 1 (1.4) 4 (5.6) 5 (3.4) Non-Hispanic 73 (98.6) 68 (94.4) 141 (96.6) Unknown/Missing 1 3 4

Age Median 59 56 59 Minimum 30 26 26 Maximum 81 83 83

Step 2

Variable Level Arm C (n=13)

Arm D (n=13)

Total (n=26)

Sex Male 7 (53.8) 8 (61.5) 15 (57.7) Female 6 (46.2) 5 (38.5) 11 (42.3)

Race White 12 (100.0) 13 (100.0) 25 (100.0) Unknown/Unreported 1 0 1

Ethnicity Non-Hispanic 12 (100.0) 12 (100.0) 24 (100.0) Unknown/Missing 1 1 2



Page 7

Table 4. Record Status

Form Name Forms

Due Forms

Received % Demography 146 146 100 Patient Characteristics 169 169 100 Treatment Agent: Dabrafenib 451 449 99.56 Treatment Agent: Ipilimumab - Induction 141 141 100 Treatment Agent: Nivolumab - Induction 141 141 100 Treatment Agent: Nivolumab - Maintenance 178 177 99.44 Treatment Agent: Trametinib 450 448 99.56 Adverse Event Form 774 752 97.16 Hematology/Chemistry 169 169 100 Late Adverse Event Form 2 2 100 Other Adverse Event Form 600 599 99.83 Disease Follow-Up Status Form (RECIST 1.1) 889 879 98.88 Off Treatment 14 14 100 Off-Treatment with Intent to Reg Next Step 90 90 100

Table 5. Reasons Off Treatment Step 1

For Patients Not Registered To Subsequent Steps (Includes all patients who started treatment and

for whom off-treatment data have been received)

Reasons N % Adverse event/side effects/complications 28 41.8 Death on study 6 9.0 Disease progression- relapse during active treatment 23 34.3 Other 3 4.5 Patient withdrawal/refusal after beginning protocol therapy 4 6.0 Treatment completed per protocol criteria 3 4.5 Total off treatment 67 100.0

Step 2 (Includes all patients who started treatment and

for whom off-treatment data have been received)

Reasons N % Adverse event/side effects/complications 1 6.7 Disease progression- relapse during active treatment 12 80.0 Treatment completed per protocol criteria 2 13.3 Total off treatment 15 100.0


Page 8

Table 6. Toxicity Incidence Step 1

Toxicity Type

Treatment Arm A (n=70) B (n=69)

Grade Grade 3 4 5 3 4 5

(%) (%) (%) (%) (%) (%) Anemia 1 - - 3 - - Disseminated intravascular coagulation - 1 - - - - Febrile neutropenia - - - 3 - - Leukocytosis 3 - - - - - Cardiac disorders - Other, specify - 1 - - - - Myocarditis 1 - - - - - Fatigue 7 - - 9 - - Fever - - - 9 - - Pain - - - 1 - - Edema limbs 1 - - - - - Infusion related reaction 1 - - - - - Rash acneiform - - - 1 - - Rash maculo-papular 9 - - 4 - - Endocrine disorders - Other, specify - 1 - - - - Abdominal pain 1 - - - - - Colitis 4 - - - - - Diarrhea 23 1 - - - - Enterocolitis 1 - - - - - Gastrointestinal disorders - Other, specify 1 - - - - - Ileus 1 - - - - - Nausea 10 - - - - - Vomiting 4 - - 1 - - Hepatic failure 1 - - - - - Autoimmune disorder 3 - - - - - Infections and infestations - Other, specify - - - 1 - - Sepsis - 1 - - 1 - Urinary tract infection 1 - - - - - Enterocolitis infectious 3 - - - - - Gallbladder infection - - - 1 - - Alanine aminotransferase increased 6 1 - - - - Aspartate aminotransferase increased 6 1 - - - - Blood bilirubin increased 1 3 - - - - Creatinine increased 4 - - 1 - - Lipase increased 4 9 - 4 - - Lymphocyte count decreased - - - 1 - - Neutrophil count decreased - - - 3 - - Serum amylase increased 3 1 - - 1 - Ejection fraction decreased - - - 3 - - Anorexia 3 - - - - - Dehydration 4 - - 1 - - Hypercalcemia 1 - - - - - Hyperglycemia 4 1 - - - - Hypoalbuminemia 6 - - - - - Hypokalemia 3 - - 1 - -


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Toxicity Type



(%) (%) (%) (%) (%) (%) Hyponatremia 3 - - 6 1 - Hypophosphatemia 1 - - - - - Arthralgia 7 - - 1 - - Back pain 1 - - - - - Musculoskeletal and connective tissue disorder - Other, specify 1 - - - - - Myalgia 1 - - - - - Myositis 1 - - - - - Pain in extremity - - - 1 - - Generalized muscle weakness 3 - - - - - Headache 1 - - - - - Hypersomnia 1 - - - - - Peripheral sensory neuropathy 1 - - - - - Syncope - - - 4 - - Tremor 1 - - - - - Retinal detachment - - - 1 - - Adult respiratory distress syndrome - 1 - - - - Hypoxia 1 - - - - - Pneumonitis 1 - - - - - Respiratory failure - - 1 - - - Acute kidney injury 3 - - - - - Hypertension 3 - - - - - Hypotension 1 - - 1 - - Thromboembolic event - - - 1 - - WORST DEGREE 49 16 1 43 4 -

Step 2

Toxicity Type

Treatment Arm C (n=9) D (n=13) Grade Grade

3 4 5 3 4 5 (%) (%) (%) (%) (%) (%)

Anemia - - - 8 - - Fatigue - - - 15 - - Fever 11 - - 8 - - Rash maculo-papular 22 - - - - - Lipase increased - - - 8 - - Lymphocyte count decreased - - - 8 - - Dehydration - - - 8 - - Hypernatremia 11 - - - - - Hyponatremia 11 - - 8 - - Nervous system disorders - Other, specify - - - 8 - - Syncope 11 - - - - - Pneumonitis - - - 8 - - WORST DEGREE 44 - - 46 - -


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Table 7. Lethal Adverse Events that are Possibly Related to Treatment

Case Arm Description of Event 46007 A Respiratory failure

Table 8. QOL

QOL Timepoint

Patients Reaching

Timepoint % Forms

Completed Baseline Step 1 145 86.2 End of Cycle 1 in Step 1 - Arm A 70 51.4 End of Cycle 1 in Step 1 - Arm B 69 88.4 End of Cycle 2 in Step 1 - Arm A 65 38.5 End of Cycle 2 in Step 1 - Arm B 65 67.7 Disease stability or 6 Mos. Step 1-Arm A 53 20.8 Disease stability or 6 Mos. Step 1-Arm B 55 30.9 End of Step 1 Treatment 47 100.0 Baseline Step 2 25 72.0 End of Cycle 1 in Step 2 - Arm C 11 54.5 End of Cycle 1 in Step 2 - Arm D 13 53.8 End of Cycle 2 in Step 2 - Arm C 10 70.0 End of Cycle 2 in Step 2 - Arm D 12 41.7 Disease stability or 6 Mos. Step 2-Arm C 8 50.0 Disease stability or 6 Mos. Step 2-Arm D 11 36.4 End of Step 2 Treatment 9 100.0 12 Mos. from study entry - Arm A 36 22.2 12 Mos. from study entry - Arm B 36 0.0 18 Mos. from study entry - Arm A 22 13.6 18 Mos. from study entry - Arm B 23 4.3


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EA6141 RANDOMIZED PHASE II/III STUDY OF NIVOLUMAB PLUS IPILIMUMAB PLUS SARGRAMOSTIM VERSUS NIVOLUMAB PLUS IPILIMUMAB IN PATIENTS WITH UNRESECTABLE STAGE III OR STAGE IV MELANOMA

Sponsor(s) Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Frank Hodi Statistician Dr. Sandra Lee Data Specialist Matthew Shimizu Phase of Study II/III Type of Study Therapeutic Committee Melanoma Accrual Objective 240 Patients Participating Groups ECOG-ACRIN, CTSU NSC# 732442, 748726 Clinicaltrials.gov Study ID NCT02339571 Study Status Open to Accrual Date Proposed July 9, 2014 Date Activated September 10, 2015 Date Suspended June 23, 2017 Schema


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Purpose of Study Primary Endpoint: To compare the overall survival (OS) of nivolumab/ipilimumab/sargramostin versus nivolumab/ipilumumab. Secondary Endpoints: (1) To compare Progression Free Survival (PFS) between nivolumab/ipilimumab/ sargramostim versus nivolumab/ipilimumab. (2) To assess for differences in tolerability, specifically rate of high grade events, between nivolumab/ipilimumab/ sargramostim versus nivolumab/ipilimumab. (3) To explore comparisons of immune-related response criteria to standard criteria as endpoint evaluations. (4) To explore PD-L1 and PD-L2 status by IHC of patient tumors and clinical activity and side effect profile. (5) To explore QOL of patients treated with nivolumab/ipilimumab/sargramostin versus nivolumab/ipilumumab. Study Population Patients with previously untreated unresectable stage III or IV melanoma. Summary of Study Design In this randomized phase II/III study, patients with advanced melanoma will be equally randomized to of Ipi-Nivo vs. Ipi-Nivo-GM using the stratification factors (BRAF mutation status, melanoma m stage). The stratified randomization will be based on the permuted block method. The primary objective is to compare overall survival between Nivo vs. Nivo-GM and Ipi-Nivo vs. Ipi-Nivo-GM. The secondary objectives are to evaluate the progression-free survival, response rate, safety and utility of immune related response criteria (irRC). The primary comparison will be overall survival (OS). It will be an ITT analysis in all patients. The median OS for Ipi+Nivo is assumed to be 2 years. By adding GM, there will be 50% improvement in the median OS. Accrual is anticipated to be 20 patients per month in general. After 40 patients have been randomized/treated and followed for at least 12 weeks, CTEP-AERS data will be reviewed carefully to ensure Ipi/Niovo containing regimen is safe to administer in the cooperative group setting. Although expected accrual rate is 40 patients/month, it will be slower at the beginning and this toxicity analysis is planned to be conducted while patients are accruing. If at least 20 patients have experienced grade 3 or higher treatment-related AEs (via CTEP-AERS reporting), accrual will be suspended and the AE data will be reviewed by ECOG-ACRIN DSMC. Otherwise accrual will continue. This study is mainly designed as a phase III study with an overall two-sided type I error rate of 0.05 and 83.5% power (after adjusting for the phase II comparison). For a phase III study with 5 interim analyses, it requires about 400 patients (with 265 deaths as a total number of deaths). To adjust for the phase II portion of the study, this design is slightly modified as shown below. Accrual will be suspended after 240 patients are randomized. The first interim analysis will be conducted when 113 deaths are observed. Accrual for 240 patients will take about one year, but it will take at least another 1.6 years to observe 113 deaths. This comparison will be considered as a phase II portion of the study. As a phase II study, OS will be compared using a one-sided type I error rate of 0.2. There will be approximately 90% power for the phase II part. Only if it is significant, we will proceed to the phase III part. In that case, the study will reopen for accrual and continue with accrual for another 160 patients. Since the phase II comparison will cost about 5.54% power, the power for phase III part is increased to 89%, to compensate for the loss of power for phase II comparison.


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For the logistical issues of reopening a phase III part, it is assumed it will begin 3 months after the phase II analysis is completed. For the phase III part, interim analyses of OS will be performed for all semi-annual DSMC meetings beginning when approximately 50% of the planned full information (133 deaths among all patients) has occurred, continuing until either criteria for early stopping are met or full information is reached. To preserve the overall type I error rate, critical values at the interim analyses will be determined using the Lan-DeMets spending function corresponding to the O'Brien-Fleming boundary. Under the accrual rate, follow up time, and failure rate assumptions above, interim analyses would be expected to occur at 0.25, 0.75, 1.3, 1.8, 2.3, 2.8 years after phase III accrual begins, at information times of 50%, 63%, 75%, 86%, 95%, and 100%. It will take approximately 2 years of additional follow up time after the last patient is randomized in phase III part. This study will also be monitored for early stopping for inefficacy. The approach of this monitoring will be based on the method proposed by Freidlin et al. (2010). Inefficacy monitoring will start around 50% information time. The study will be stopped if there is not at least a small trend in favor of the alternative hypothesis starting at this time. Specifically, an inefficacy monitoring boundary will begin at this time at a hazard ratio greater than 1 and will gradually increase to 20% of the targeted benefit at full information, subject to the requirement that two-sided 95% confidence interval for the log hazard ratio does not contain the design-alternative log hazard ratio of 0.67. The immune response will be assessed using the utility of Immune related response criteria (irRC). Standard response criteria (based on the RECIST) will be applied to assess clinical response. Immune response rate and clinical response rate will be compared between the two treatment arms. Progress to Date This study was activated on September 10, 2015 and suspended on June 23, 2017 as it reached the first stage accrual goal. As of June 23, 2017, 250 patients have enrolled. Table 1a summarizes accrual by institution. Table 1b has accrual by group and Table 1c shows projected accrual status as of July 17, 2018. Patient status as of July 17, 2018 is displayed in Table 2. Demographics of patients by treatment arm are summarized in Table 3. Record status as on clinical report form is summarized in Table 4. The distribution of the reasons for treatment discontinuation is summarized in Table 5. Toxicity data were reported for 123 cases in arm A and 120 cases in arm B as of July 17, 2018. Treatment-related toxicities are summarized in Table 6. The worst-degree grade 3 or higher toxicity rate was 53% in arm A and 69% in arm B. There were 3 grade 5 AEs in arm A and 1 in arm B. These cases with at least possibly treatment related grade 5 AEs are listed in Table 7. There are additional grade 5 AEs reported via CTEP-AERS system. They are: case 16010 (arm A) Dyspnea, 16011 (arm A) neoplasms progression, 16058 (arm A) GI disorder, 16064 (arm A) respiratory failure, 16078 (arm A) deaths NOS, 16121 (arm A) aspiration, 16196 (arm A) cardiac disorder, 16232 (arm B) multiorgan failure, 16233 (arm A) Deaths NOS and 16126 (arm B) neoplasms progression, 16242 (arm A), 16245 (arm A) deaths NOS. Of these, cases 16010, 16011, 16064, 16121, 16196, 16126, 16233 were reviewed at ECOG-ACRIN and considered as not treatment-related. Secondary primary tumor is listed in Table 8.


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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


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


Cases Entered 250 Ineligible 3 Never Started Assigned Therapy 2

Reason for ineligibility (n=3): No measurable disease (16242); Bilirubin > 1.5 X ULN (16226); No baseline PET-CT (16062). Reason for not starting therapy (n=2): Withdrawal/refusal before beginning protocol therapy (16014); Death before therapy (16143).

Table 3. Demographics

Variable Level Arm A

(n=126) Arm B

(n=124) Total

(n=250) Sex Male 85 (67.5) 66 (53.2) 151 (60.4)

Female 41 (32.5) 58 (46.8) 99 (39.6) Race White 119 (99.2) 113 (95.8) 232 (97.5)

African-American 0 (0.0) 2 (1.7) 2 (0.8) Asian 0 (0.0) 2 (1.7) 2 (0.8) Native American 1 (0.8) 1 (0.8) 2 (0.8) Unknown/Unreported 6 6 12




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Form Name Forms

Due Forms

Received % Demography 250 250 100 Patient Characteristics 250 249 99.6 Treatment Agent: Ipilimumab 808 808 100 Treatment Agent: Nivolumab 2419 2417 99.92 Treatment Agent: Sargramostim 1463 1461 99.86 Adverse Events 2575 2575 100 Hematology/Chemistry 250 248 99.2 Late Adverse Events 14 14 100 Disease Follow-Up Status Form (RECIST 1.1) 2809 2805 99.86 Off Treatment 193 193 100

Table 5. Reasons Off Treatment

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

Reasons N %

Adverse event/side effects/complications 97 50.0 Alternative therapy 5 2.6 Death on study 7 3.6 Disease progression- relapse during active treatment 51 26.3 Other 16 8.2 Patient off-treatment for other complicating disease 3 1.5 Patient withdrawal/refusal after beginning protocol therapy 10 5.2 Treatment completed per protocol criteria 5 2.6 Total off treatment 194 100.0


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Table 6. Toxicity Incidence

Toxicity Type



(%) (%) (%) (%) (%) (%) Hearing impaired 1 - - - 1 - Anemia 1 - - 2 - - Blood and lymphatic system disorders - Other, specify 1 - - 1 - - Leukocytosis 1 - - - - - Atrioventricular block complete 1 - - - - - Myocarditis 1 - - - - - Death NOS - - 1 - - - Fatigue 5 - - 4 - - Fever - - - 1 - - Multi-organ failure - - - - - 1 Pain 1 - - - - - Non-cardiac chest pain 1 - - - - - Pruritus 2 - - 1 - - Rash maculo-papular 8 - - 9 - - Adrenal insufficiency 4 - - 3 - - Endocrine disorders - Other, specify 5 - - 3 - - Hyperthyroidism 1 - - - - - Hypothyroidism 1 - - 1 - - Abdominal pain 2 - - 2 - - Colitis 2 - - 10 - - Constipation 1 - - - - - Dental caries 1 - - - - - Diarrhea 7 2 1 15 - - Duodenal ulcer 1 - - - - - Dysphagia - - - 1 - - Enterocolitis 1 - - 1 - - Gastrointestinal disorders - Other, specify 1 - - - - - Mucositis oral - - - 2 - - Nausea 1 - - 3 - - Vomiting 2 - - 2 - - Lower gastrointestinal hemorrhage 1 - - - - - Hepatobiliary disorders - Other, specify - - - 1 1 - Allergic reaction 1 - - - - - Immune system disorders - Other, specify - - - 3 - - Autoimmune disorder 2 - - 1 - - Infections and infestations - Other, specify 1 - - 1 - - Skin infection 1 - - - - - Lung infection 1 - - 1 - - Fall 1 - - - - - Alanine aminotransferase increased 10 - - 11 - - Alkaline phosphatase increased 2 - - 2 - - Aspartate aminotransferase increased 3 1 - 10 - - Blood bilirubin increased 1 - - - - - Cardiac troponin I increased - - - 1 - - CPK increased - - - 1 1 - Creatinine increased - - - 2 - - Investigations - Other, specify - - - 1 - -


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Toxicity Type



(%) (%) (%) (%) (%) (%) Lipase increased 7 4 - 11 6 - Lymphocyte count decreased 1 1 - 1 - - Platelet count decreased 1 1 - - - - Serum amylase increased 5 - - 3 1 - Urine output decreased - 1 - - - - Acidosis - - - 1 1 - Anorexia 4 - - - - - Dehydration 2 - - 4 - - Hypercalcemia - - - - 2 - Hyperglycemia 1 - - 3 3 - Hyperkalemia 1 - - - - - Hyperuricemia - 2 - 1 2 - Hypokalemia - 2 - 2 - - Hyponatremia 2 - - 4 - - Hypophosphatemia - - - 1 - - Metabolism and nutrition disorders - Other, specify - - - 1 - - Back pain - - - 1 - - Bone pain 1 - - - - - Joint effusion - - - 1 - - Pain in extremity - - - 1 - - Generalized muscle weakness 2 - - - - - Muscle weakness lower limb 2 - - - - - Muscle weakness right-sided - - - 1 - - Dizziness 1 - - - - - Dysphasia - - - 1 - - Headache 3 - - 1 - - Nervous system disorders - Other, specify 1 - - - - - Peripheral motor neuropathy - - - 1 - - Peripheral sensory neuropathy - 1 - 1 - - Seizure 1 - - 1 - - Syncope 1 - - 1 - - Uveitis 1 - - - - - Anxiety - - - 1 - - Confusion - - - 1 - - Aspiration - - 1 - - - Dyspnea 1 - - 5 2 - Hypoxia 1 - - 1 - - Pneumonitis 2 - - 3 - - Respiratory, thoracic and mediastinal disorders - Other, specify - - - - 1 - Renal and urinary disorders - Other, specify 1 - - - - - Chronic kidney disease - 1 - - - - Acute kidney injury - - - 2 - - Hypertension - - - 1 - - Hypotension 2 1 - 1 - - Thromboembolic event - - - 1 - - WORST DEGREE 38 13 2 53 15 1


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Case Arm Description of Event 16058 A Diarrhea 16242 A Aspiration 16245 A Death NOS 16232 B Multi-organ failure

Table 8. Second Primary Cancers

Site Arm A Liver, Gall Bladder, Bile Duct 1

ECOG-ACRIN Cancer Research Group E3612 Study Progress and Safety Report Fall 2018

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E3612 A RANDOMIZED PHASE II TRIAL OF IPILIMUMAB WITH OR WITHOUT BEVACIZUMAB IN PATIENTS WITH UNRESECTABLE STAGE III OR STAGE IV MELANOMA

Sponsor(s) Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Frank Hodi Statistician Dr. Sandra Lee Data Specialist Matthew Shimizu Phase of Study II Type of Study Therapeutic Committee Melanoma Accrual Objective 168 Patients Participating Groups ECOG-ACRIN, CTSU DCP Treatment Credit 1.0 NSC# 704865, 732442 Clinicaltrials.gov Study ID NCT01950390 Study Status Closed to Accrual Date Proposed October 4, 2012 Date Activated December 13, 2013 Date Terminated September 25, 2017 Final Accrual 169 Patients Schema


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Purpose of Study Primary Endpoint (1) To compare overall survival for patients receiving ipilimumab plus bevacizumab versus ipilimumab alone. Secondary Endpoints (1) To evaluate the progression free survival, response rate and safety in patients receiving ipilimumab plus bevacizumab versus ipilimumab alone. (2) To evaluate the utility of immune related response criteria (irRC) in patients receiving ipilimumab plus bevacizumab versus ipilimumab alone. Study Population Patients with measurable metastatic melanoma, no more than one prior therapy for metastatic disease, no prior therapy with bevacizumab or ipilimumab. Summary of Study Design In this randomized phase II study, patients with advanced melanoma will be equally randomized to Arm A: Iplimumab (Ipi) or Arm B: Ipi + Bevacizumab using the stratification factors (Prior Therapy and BRAF mutation status). The stratified randomization will be based on the permuted block method. The primary objective is to compare overall survival between Arms A vs. B. The secondary objectives are to evaluate the progression-free survival, response rate, safety and utility of immune related response criteria (irRC) in patients in Arms A vs. B. The primary comparison will be OS in arms A vs. B. It will be an ITT analysis in all eligible patients. It is assumed that the median OS in patients treated in arm A will be around 11 months and the median OS will be improved to 16.5 months (50% improvement) in arm B. If the OS follows an exponential distribution, this difference corresponds to an improvement of one-year OS rate from 47% (in arm A) to 60% (in arm B). A comparison of arms A vs. B will be made using a stratified logrank test with one-sided type I error of 10%. One interim analysis will be performed at 50% information time (57 deaths), with the final analysis at 114 deaths. To preserve the overall type I error rate, critical values at the analyses will be determined using the O'Brien and Fleming boundary. Under the accrual and failure rate assumptions below, one interim and final analyses are expected to occur at 12 and 28 months after activation. The repeated confidence interval (RCI) of Jennison-Turnbull will also be evaluated at the interim analysis. This design will provide power of 80%. Progress to Date This study was open between December 13, 2013 and September 25, 2017. Final accrual was 169 patients. Table 1a summarizes accrual by institution and Table 1b has accrual by group. Patient status as of July17, 2018 is displayed in Table 2. Demographics of patients by treatment arm are summarized in Table 3. Record status on clinical report form is summarized in Table 4. The distribution of the reasons for treatment discontinuation of protocol treatment is summarized in Table 5. One hundred and sixty-four patients have reported toxicity (82 in each arm) as of July 17, 2018. Treatment-related grade 3 or higher toxicities are summarized in Table 6. Table 7 summarizes 2 cases with (treatment-related) lethal toxicities reported via ECOG-ACRIN CRFs. Based on CTEP AERS reporting, there were 13 additional cases with lethal adverse events: 36005 (arm A) cardiac arrest, 36122 (arm A) death NOS, 36131 (arm A) neoplasms, 36143 (arm A) cardiac arrest, 36148 (arm A) heart failure, 36160 (arm A) neoplasms, 36169 (arm A) death NOS, 36017 (arm B) aspiration, 36113 (arm B) death, 36142 (arm B) neoplasms, 36155 (arm B) neoplasms, 36158 (arm B) cardiac arrest and 36163 (arm B) sepsis. All these cases have been reviewed using the data collected on ECOG-ACRIN CRFs. All of them were considered having lethal adverse events unrelated to the treatment. Table 8 summaries second primary cancers.


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Institution Name Step 1

Baystate Medical Center 2 Beth Israel Deaconess Medical Center 4 Cancer Alliance of Nebraska 2 Cancer Research Consortium of West Michigan NCORP 2 Cancer Research for the Ozarks NCORP 3 Case Western Reserve University 10 Columbus NCORP 6 Dana-Farber/Harvard Cancer Center 8 Dayton NCORP 1 Delaware/Christiana Care NCORP 1 Eastern Connecticut Hematology and Oncology Assoc 3 Emory University/Winship Cancer Institute 3 Fox Chase Cancer Center 2 Froedtert and the Medical College of Wisconsin 3 Geisinger Cancer Institute NCORP 2 Georgia NCORP 2 Hackensack University Medical Center 4 Heartland Cancer Research NCORP 9 Indiana Univ/Melvin and Bren Simon Cancer Center 7 Iowa-Wide Oncology Research Coalition NCORP 1 Mayo Clinic 1 MedStar Georgetown University Hospital 2 Michigan Ca Res Consortium NCORP 4 Montefiore MU NCORP 5 Nevada Cancer Research Foundation NCORP 9 NorthShore Univ HealthSystem-Evanston Hospital 1 Northwestern University 6 Ohio State University Comprehensive Cancer Center 2 Thomas Jefferson University Hospital 3 University of Alabama at Birmingham Cancer Center 6 University of Michigan Comprehensive Cancer Center 3 University of Pittsburgh Cancer Institute (UPCI) 13 University of Wisconsin Hospital and Clinics 7 Wichita NCORP 3 Wisconsin NCORP 2 Total 142


ECOG-ACRIN 142 SWOG 6 ALLIANCE 12 NRG 9 Total 169


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Cases Entered 169 Ineligible 7 Never Started Assigned Therapy 4

Reason for ineligibility (n=7): Brain mets (36021); Baseline AE (36096); Issues with baseline imaging (35057, 36119, 36156, 36163); High AST level (36145). Reason for not starting therapy (n=4): Ineligibility (36021, 36145); Withdrawal (36053); Adverse events (36123). Duplicate registration: 36038

Table 3. Demographics

Variable Level Arm A (n=85)

Arm B (n=84)

Total (n=169)

Sex Male 57 (67.1) 41 (48.8) 98 (58.0) Female 28 (32.9) 43 (51.2) 71 (42.0)

Race White 81 (97.6) 80 (100.0) 161 (98.8) African-American 1 (1.2) 0 (0.0) 1 (0.6) Asian 1 (1.2) 0 (0.0) 1 (0.6) Unknown/Unreported 2 4 6




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Form Name Forms

Due Forms

Received % Demography 169 169 100 Patient Characteristics 169 169 100 Treatment Agent: Bevacizumab 823 821 99.76 Treatment Agent: Ipilimumab 741 739 99.73 Adverse Event Form 1567 1543 98.47 Hematology/Chemistry 1425 1422 99.79 Late Adverse Event Form 2 1 50 Other Adverse Event Form 1159 1158 99.91 Disease Follow-Up Status Form (RECIST 1.1) 1578 1574 99.75 Off Treatment 158 158 100

Table 5. Reasons Off Treatment

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

Reasons N %

Adverse event/side effects/complications 38 24.1 Alternative therapy 1 0.6 Death on study 8 5.1 Disease progression- relapse during active treatment 95 60.1 Other 9 5.7 Patient withdrawal/refusal after beginning protocol therapy 6 3.8 Treatment completed per protocol criteria 1 0.6 Total off treatment 158 100.0


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Table 6. Toxicity

Step 1

Toxicity Type



(%) (%) (%) (%) (%) (%) Anemia 1 - - 4 - - Atrial fibrillation - - - 1 - - Fatigue 5 - - 10 - - Fever 1 - - - - - Gait disturbance - - - 1 - - Sudden death NOS - - - - - 1 Erythema multiforme - - - 1 - - Pruritus - - - 2 - - Rash maculo-papular 9 - - 6 - - Skin ulceration - - - - 1 - Adrenal insufficiency 2 1 - 2 - - Endocrine disorders - Other, specify 1 - - 1 - - Hypothyroidism - - - 1 - - Abdominal pain 4 - - - - - Colitis 6 - - 6 - - Colonic perforation 1 - - 1 - - Diarrhea 17 - - 7 - - Gastrointestinal disorders - Other, specify - - - 1 - - Mucositis oral - - - 1 - - Nausea - - - 2 - - Pancreatitis - - - 1 - - Proctitis - - - 1 - - Rectal fistula - - - 1 - - Vomiting - - - 1 - - Cholecystitis - - - 1 - - Autoimmune disorder 4 - - - - - Infections and infestations - Other, specify - - - 1 - - Sepsis - 1 - - - - Sinusitis - - - 1 - - Wound infection - - - 1 - - Alanine aminotransferase increased 5 1 - 2 - - Aspartate aminotransferase increased 4 - - 2 - - Blood bilirubin increased 1 - - - - - Investigations - Other, specify - - - 1 - - Lipase increased 4 1 - 2 1 - Lymphocyte count decreased - 1 - - - - Platelet count decreased - 1 - - - - Serum amylase increased 1 - - - 1 - Anorexia - - - 2 - - Dehydration 1 - - 9 - - Hyperuricemia - - - - 1 -


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Toxicity Type



(%) (%) (%) (%) (%) (%) Hypoglycemia - 1 - - - - Hypokalemia 2 - - 1 - - Hyponatremia 5 - - 1 2 - Hypophosphatemia - - - 1 - - Metabolism and nutrition disorders - Other, specify - - - 1 - - Arthralgia - - - 1 - - Myalgia - - - 1 - - Generalized muscle weakness 1 - - 4 - - Headache 1 - - 2 - - Peripheral motor neuropathy 1 - - - - - Reversible posterior leukoencephalopathy syndrome - - - 1 - - Confusion - - - 1 - - Cough - - - 1 - - Dyspnea 2 - - - - - Proteinuria - - - 1 - - Acute kidney injury - - 1 - - - Hypertension 1 - - 35 - - Thromboembolic event - - - 1 - - WORST DEGREE 32 7 1 50 7 1


Case Arm Description of Event 36064 36086

A B

Acute kidney injury Sudden death NOS

Table 8. Second Primary Cancers

Site Arm A Arm B Head And Neck - 1 Renal Cell 1 - Skin Cancer Not Melanoma 1 -

MELANOMA COMMITTEE - SWOG 2019... · metastatic BRAFV600E/K mutant melanoma. To compare the...

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