MELANOMA COMMITTEE - SWOG 2019/Melanoma.pdfT-VEC + MK-3475 (Pembrolizumab) 11 7 1 19 S1616 MELAN, Adv, Ipilimumab ± Nivolumab Randomization Ipilimumab 4 3 4 12 Nivolumab + Ipilimumab

OCTOBER 2 - 5, 2019 SWOG MELANOMA 1

MELANOMA COMMITTEE

PRIVILEGED COMMUNICATION NOT FOR PUBLICATION OR REFERENCE


CONTENTS

S1320 Phase II ............................................................................................................................................................... 6

S1404 Phase III ............................................................................................................................................................ 16

S1512 Phase II ............................................................................................................................................................. 27

S1607 Phase II ............................................................................................................................................................. 32

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

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

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

S1801 Phase II ............................................................................................................................................................. 48


Patient Registrations to Studies

by 12 Month Intervals

MELANOMA COMMITTEE

Screening registrations and registrations to Biologic only studies are excluded.

SWOG LAPS MEMBER NCORP NON-SWOG

193

89

277

1040

308

136

0

100

200

300

400

500

600

700

800

900

1000

1100

Time of Registration

Jul 2013Jun 2014

Jul 2014Jun 2015

Jul 2015Jun 2016

Jul 2016Jun 2017

Jul 2017Jun 2018

Jul 2018Jun 2019

56

96

67

107

161

178

224

477

63

150


Patient Registrations by Study and Arm MELANOMA COMMITTEE

Jan 2019

Jun 2019

Jul 2018

Dec 2018

Jan 2018

Jun 2018

All

Patients

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

Lead In Registration

Lead-in Continuous Dosing 12 18 28 249

Randomization

Continuous Dosing 11 6 15 108

Intermittent Dosing 10 6 13 103

21 12 28 211

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

Registration

MK-3475 (Pembrolizumab) 8 7 6 26

S1607 MELAN, Adv, T-VEC, MK-3475

Registration

T-VEC + MK-3475 (Pembrolizumab) 11 7 1 19

S1616 MELAN, Adv, Ipilimumab ± Nivolumab

Randomization

Ipilimumab 4 3 4 12

Nivolumab + Ipilimumab 13 10 7 33

17 13 11 45

S1801 Melan, Adv, Adjuvant vs Neoadjuvant MK-3475 (Pembrolizumab)

Randomization

Adjuvant Arm (Pre-surgery) 15 0 0 15

Neoadjuvant MK-3475 (Pembrolizumab) 14 0 0 14

29 0 0 29

Surgery

Surgery 14 0 0 14

Adjuvant Therapy

Post-Surgery MK-3475 (Pembrolizumab) 3 0 0 3


Non-SWOG Studies with SWOG-Credited Registrations MELANOMA COMMITTEE

Studies with Accrual from January 2018 - June 2019

SWOG Accrual

SWOG

Champion

Jan 2019

Jun 2019

Jul 2018

Dec 2018

Jan 2018

Jun 2018

SWOG

Total

Total

Accrued

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

Nivolumab vs Ipilimumab + Nivolumab/Dabrafenib + Trametinib

B Chmielowski 9 4 2 39 198

Date Activated: 12/15/15

Most Recent Progress Report

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

Date Activated: 03/01/16 Date Temporarily Closed: 06/23/17


EA6174 Merkel, Adjuvant Pembrolizumab vs Standard of Care

Observation

C Hsu 1 0 0 1 11

Date Activated: 07/23/18



S1320/II

S1320 Phase II

Coordinating Group: SWOG

A Randomized Phase II Trial of Intermittent versus Continuous Dosing of

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

Mutant Melanoma

Participants:

SWOG, CTSU (Supported by ECOG-ACRIN)

Study Chairs:

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

Statisticians:

M Othus, J Moon, L Qian

Data Coordinator:

J Sanchez

Date Activated:

07/22/2014

Date Closed:

04/19/2019

SCHEMA

Objectives To compare progression-free survival with

intermittent dosing versus continuous dosing of

dabrafenib and trametinib among patients with

metastatic BRAFV600E/K mutant melanoma.

To compare the response rate (complete and partial

response, confirmed and unconfirmed), overall

survival, and survival after progression between the

two dosing schedules.

R

A

N

D

O

M

I

Z

A

T

I

O

N

Continuous Treatment

Intermittent Treatment

R

E

G

I

S

T

R

A

T

I

O

N

Continuous Treatment Lead-in


S1320/II

To compare the frequency and severity of fever

greater than Grade 1 per CTCAE 4.0 of the two

dosing schedules.

To estimate the frequency and severity of toxicities

of the two dosing schedules.

To bank tissue and whole blood in anticipation of

future studies to evaluate molecular events associated

with clinical benefit and disease progression in

patients treated with continuous versus intermittent

dabrafenib and trametinib.

Patient Population Patients must have histologically or cytologically

confirmed Stage IV or unresectable Stage III

melanoma. Patients must have BRAF mutation-

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

BRAFV600 mutant status must be documented by a

CLIA-certified laboratory. Patients must have

measurable disease as defined by RECIST 1.1.

Contrast-enhanced CT scans of the neck, chest,

abdomen and pelvis are required. A whole body

PET/CT scan with diagnostic quality images and

intravenous iodinated contrast may be used in lieu of

a contrast enhanced CT of the neck, chest, abdomen

and pelvis. Contrast may be omitted if the treating

investigator believes that exposure to contrast poses

an excessive risk to the patient. Patients with a

history of brain metastases are eligible if the patient

is asymptomatic with no residual neurological

dysfunction and has not received enzyme-reducing

anti-epileptic drugs or corticosteroids for at least

seven days prior to registration. Patients must have

serum LDH obtained prior to registration for

treatment randomization stratification and accurate

staging.

Patients must not have received a prior BRAF or

MEK inhibitor. Prior surgery, radiotherapy,

immunotherapy, or chemotherapy are allowed.

Patients must have adequate hematologic, hepatic,

cardiac, and renal function and a Zubrod performance

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

or current evidence of retinal vein occlusion (RVO)

or central serous retinopathy (CSR). Patients must

not have any predisposing factors for RVO or CSR

such as uncontrolled glaucoma, ocular hypertension,

uncontrolled systemic hypertension, diabetes

mellitus, or a history of hyperviscosity or

hypercoagulability syndromes. An ophthalmic exam

is required for all patients. Patients must not have

evidence of optic disc cupping, visual field defects,

or an intraocular pressure greater than 21 mmHg.

Patients must be able to take oral medications and

must not have any impairment of gastrointestinal

disease that may significantly alter the absorption of

protocol treatment. Patients must discontinue

treatment with therapeutic warfarin prior to

registration. Patients must not have a history of

pneumonitis or interstitial lung disease. Patients with

known hepatitis B, or hepatitis C are not eligible.

Patients known to be HIV positive must have CD4

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

IU/ml, and must be able to discontinue antiretroviral

therapy. Patients must have a dermatology exam

within 28 days prior to registration.

Patients must be offered the opportunity to participate

in specimen banking.

Stratification/Descriptive Factors Treatment randomization will be stratified by the

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

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

immune checkpoint inhibitors targeting CTLA-4,

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

Accrual Goals The accrual goal is 206 eligible randomized patients.

An interim analysis testing for harm will be

performed when 78 progression events have

occurred.

Summary Statement Having met its accrual goal, this study was

permanently closed on April 19, 2019. The final

accrual was 249 patients participating in lead-in

continuous treatment. Four patients were ineligible

for the following reasons: inadequate baseline disease

assessment (1), inadequate cardiac function (1), not

having a V600E or V600K BRAF mutation (1), and

inadequate hematologic function (1). In addition,

three eligible patients who never received protocol

treatment were never randomized and are not

evaluable for any of the study endpoints. Most

patients who were unable to complete the one cycle

of lead-in continuous dosing came off protocol

treatment either due to adverse events or disease

progression. One patient was never randomized and

remained on continuous dosing off protocol (coded as

Reason Off Treatment = "Other – not protocol

specified").

A total of 242 patients have been assessed for adverse

events related to lead-in continuous dosing. There has

been one treatment-related death due to sepsis. This

patient also experienced Grade 4 acute kidney injury

and Grade 4 ejection fraction decrease. An additional


S1320/II

six patients experienced treatment-related Grade 4

adverse events due to the following: CPK increased

and MS/connective tissue disorder, sepsis,

hypocalcemia, neutrophil count decreased,

hyponatremia, and the other due to hypocalcemia and

pneumonitis (1 patient each).

Two hundred and eleven patients were randomized

between intermittent and continuous dosing. Five

patients were ineligible for the following reasons:

ineligible for the trial at the initial registration (3),

disease progression during the lead-in continuous

dosing phase (2). Seven patients have discontinued

protocol treatment for reasons coded as "other – not

protocol specified": treatment delay longer than 14

days, not due to toxicity (2), other primary cancer (1),

and a change in treatment plan by the medical team

(4).

On the continuous dosing arm, 103 patients have

been assessed for adverse events. Six patients have

experienced Grade 4 treatment-related adverse events

due to the following reasons: sepsis (2), anemia and

increases in ALT and AST, dyspnea, lipase increase

and creatinine increase (1 patient each). On the

intermittent dosing arm, 100 patients have been

assessed for adverse events. Three patients have

experienced Grade 4 treatment-related adverse events

due to the following reasons: fever, lipase increase,

and acute kidney injury (1 patient each).

Registration by Institution

Lead-In Continuous Dosing

Institutions

Total

Reg Institutions

Total

Reg

Kaiser Perm NCORP 30 Colorado, U of 2

Kansas, U of 17 CRC West MI NCORP 2

Ohio State Univ 17 Ozarks NCORP 2

Utah, U of 12 PCRC NCORP 2

Loyola University 8 Bay Area NCORP 1

San Francisco, U-CA 8 Boston Medical Ctr 1

Southeast COR NCORP 8 CORA NCORP 1

Wichita NCORP 8 Dayton NCORP 1

Michigan, U of 7 Hawaii MU-NCORP 1

Arkansas, U of 6 Lahey Hosp & Med Ctr 1

Heartland NCORP 6 UF Cancer Center/Arkansas, U of 1

Los Angeles, U of CA 4 Wisconsin NCORP 1

Nevada CRF NCORP 4 ECOG-ACRIN 49

Rochester, Univ of 4 NRG 22

Columbus NCORP 3 ALLIANCE 15

KaiserPermanenteSCAL/Kaiser Perm NCORP 3 Total (32 Institutions) 249

Arizona CC, Univ of 2


S1320/II

Registration, Eligibility, and Evaluability


Data as of August 9, 2019

Lead-in

Continuous

Dosing

NUMBER REGISTERED 249

INELIGIBLE 4

ELIGIBLE 245

Not Analyzable 3

ADVERSE EVENT ASSESSMENT

Evaluable 242

Treatment Summary



Lead-in

Continuous

Dosing

NUMBER ON PROTOCOL TREATMENT 0

NUMBER OFF PROTOCOL TREATMENT

REASON OFF TREATMENT

242

Treatment completed as planned 207

Adverse Event or side effects 18

Refusal unrelated to adverse event 1

Progression/relapse 13

Death 2

Other - not protocol specified 1

Reason under review 0

MAJOR PROTOCOL DEVIATIONS 0

LOST TO FOLLOW-UP 0

CONSENT WITHDRAWAL AFTER

TREATMENT INITIATION

16


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=242)

Grade

ADVERSE EVENTS <=2 3 4 5

AST increased 236 6 0 0

Abdominal pain 241 1 0 0

Acute kidney injury 241 0 1 0

Anemia 238 4 0 0

Anorexia 240 2 0 0

Arthralgia 241 1 0 0

Blood bilirubin increased 241 1 0 0

Blood/lymph disorder-Other 241 1 0 0

CPK increased 241 0 1 0

Cardiac troponin T increased 241 1 0 0

Chills 239 3 0 0

Constipation 241 1 0 0

Dehydration 235 7 0 0

Diarrhea 239 3 0 0

Dyspnea 241 1 0 0

ECG QT corrected int prolong 241 1 0 0

Ejection fraction decreased 241 0 1 0

Epistaxis 241 1 0 0

Erythema multiforme 241 1 0 0

Fatigue 237 5 0 0

Febrile neutropenia 239 3 0 0

Fever 237 5 0 0

Fracture 241 1 0 0

Gastric hemorrhage 241 1 0 0

Generalized muscle weakness 240 2 0 0

Headache 240 2 0 0

Hyperglycemia 240 2 0 0

Hypertension 238 4 0 0

Hypoalbuminemia 241 1 0 0

Hypocalcemia 240 0 2 0

Hypokalemia 241 1 0 0

Hyponatremia 231 10 1 0

Hypophosphatemia 241 1 0 0

Hypotension 238 4 0 0

Hypoxia 241 1 0 0

Leukocytosis 241 1 0 0

Lipase increased 240 2 0 0

Lung infection 241 1 0 0

Lymphocyte count decreased 236 6 0 0

MS/connective tissue disorder 240 1 1 0

Metab/nutrition disorders-Other 241 1 0 0

Mucositis oral 241 1 0 0

Nausea 240 2 0 0


S1320/II

Lead-in Continuous Dosing

(n=242)

Grade

ADVERSE EVENTS <=2 3 4 5

Neutrophil count decreased 233 8 1 0

Platelet count decreased 241 1 0 0

Pneumonitis 241 0 1 0

Proteinuria 241 1 0 0

Rash acneiform 239 3 0 0

Rash maculo-papular 238 4 0 0

Retinopathy 241 1 0 0

Sepsis 239 0 2 1

Skin infection 240 2 0 0

Skin/subq tissue ds-Other 241 1 0 0

Thromboembolic event 239 3 0 0

Tx related secondary malig 240 2 0 0

Upper GI hemorrhage 241 1 0 0

Urinary tract infection 240 2 0 0

Vasc disorders-Other, spec 241 1 0 0

Vomiting 240 2 0 0

White blood cell decreased 238 4 0 0

MAX. GRADE ANY ADVERSE EVENT 172 62 7 1


S1320/II

Randomization by 6 Month IntervalsDivisions by ARM

Randomization

Continuous Dosing Intermittent Dosing

0

10

20

30

40

50


JulDec2014

JanJun

2015

JulDec2015

JanJun

2016

JulDec2016

JanJun

2017

JulDec2017

JanJun

2018

JulDec2018

JanJun

2019

13

5

12

15

11

23

10

13

6

13

7

12

13

10

1

20

1110

6


Randomization


TOTAL

Continuous

Dosing

Intermittent

Dosing

NUMBER REGISTERED 211 108 103

INELIGIBLE 5 3 2

ELIGIBLE 206 105 101

Analyzable, Pend. Elig. 2 2 0

RESPONSE ASSESSMENT

Determinable 186 96 90

Not Determinable 4 3 1

Too Early 16 6 10


Evaluable 203 103 100

Too Early 3 2 1


S1320/II

Patient Characteristics

Randomization


Continuous

Dosing

(n=105)

Intermittent

Dosing

(n=101)

AGE

Median 58.7 62.5

Minimum 22.7 20.9

Maximum 88.6 88.8

SEX

Males 62 59% 70 69%

Females 43 41% 31 31%

HISPANIC

Yes 2 2% 4 4%

No 100 95% 97 96%

Unknown 3 3% 0 0%

RACE

White 103 98% 98 97%

Native American 1 1% 0 0%

Multi-Racial 0 0% 1 1%

Unknown 1 1% 2 2%

LDH

Elevated (>IULN) 39 37% 38 38%

Normal 66 63% 63 62%

PRIOR IMMUNE CHECKPOINT INHIBITOR

Yes 31 30% 30 30%

No 74 70% 71 70%

PRIOR IMMUNOTHERAPY

Yes 36 34% 40 40%

No 67 64% 61 60%

Data pending 2 2% 0 0%

PERFORMANCE STATUS

0 59 56% 58 57%

1 43 41% 41 41%

2 1 1% 2 2%


STAGE

III 13 12% 12 12%

IV 92 88% 89 88%


S1320/II

Treatment Summary

Randomization


Total




165




Progression/relapse 113

Death 4




LOST TO FOLLOW-UP 0



10


Randomization




Continuous Dosing

(n=103)

Grade

Intermittent Dosing

(n=100)

Grade

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

ALT increased 101 1 1 0 99 1 0 0

AST increased 98 4 1 0 98 2 0 0

Acute kidney injury 103 0 0 0 99 0 1 0

Alkaline phosphatase increased 102 1 0 0 97 3 0 0

Anemia 100 2 1 0 98 2 0 0

Anorexia 103 0 0 0 99 1 0 0

Arthralgia 101 2 0 0 99 1 0 0

Back pain 102 1 0 0 100 0 0 0

Blood bilirubin increased 102 1 0 0 100 0 0 0

Chills 102 1 0 0 99 1 0 0

Confusion 103 0 0 0 99 1 0 0

Creatinine increased 102 0 1 0 100 0 0 0

Dehydration 102 1 0 0 100 0 0 0

Diarrhea 101 2 0 0 99 1 0 0

Dry skin 102 1 0 0 100 0 0 0

Dyspnea 102 0 1 0 100 0 0 0

ECG QT corrected int prolong 102 1 0 0 99 1 0 0

Ejection fraction decreased 99 4 0 0 96 4 0 0


S1320/II

Continuous Dosing

(n=103)

Grade

Intermittent Dosing

(n=100)

Grade

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

Eye disorders - Other, specify 103 0 0 0 99 1 0 0

Fatigue 95 8 0 0 97 3 0 0

Fever 97 6 0 0 99 0 1 0

Flu like symptoms 101 2 0 0 100 0 0 0

Gastric hemorrhage 102 1 0 0 100 0 0 0

Generalized muscle weakness 101 2 0 0 98 2 0 0

Glucose intolerance 102 1 0 0 100 0 0 0

Hand-Foot syndrome 102 1 0 0 100 0 0 0

Hypercalcemia 103 0 0 0 99 1 0 0

Hyperglycemia 100 3 0 0 98 2 0 0

Hypertension 96 7 0 0 97 3 0 0

Hypoalbuminemia 102 1 0 0 100 0 0 0

Hyponatremia 99 4 0 0 98 2 0 0

Hypophosphatemia 103 0 0 0 99 1 0 0

Hypotension 101 2 0 0 99 1 0 0

Hypothyroidism 102 1 0 0 100 0 0 0

Infections/infestations-Other 103 0 0 0 99 1 0 0

Investigations-Other, specify 103 0 0 0 99 1 0 0

LV systolic dysfunction 102 1 0 0 99 1 0 0

Lipase increased 100 2 1 0 97 2 1 0

Localized edema 102 1 0 0 100 0 0 0

Lung infection 102 1 0 0 100 0 0 0

Lymphocyte count decreased 99 4 0 0 99 1 0 0

Mucositis oral 102 1 0 0 100 0 0 0

Myalgia 103 0 0 0 99 1 0 0

Nausea 103 0 0 0 99 1 0 0

Neutrophil count decreased 100 3 0 0 100 0 0 0

Pain in extremity 102 1 0 0 100 0 0 0

Platelet count decreased 102 1 0 0 100 0 0 0

Rash acneiform 101 2 0 0 100 0 0 0

Rash maculo-papular 101 2 0 0 99 1 0 0

Resp/thoracic/mediastinal ds 102 1 0 0 100 0 0 0

Retinal detachment 103 0 0 0 98 2 0 0

Sepsis 101 0 2 0 100 0 0 0

Serum amylase increased 103 0 0 0 98 2 0 0

Skin/subq tissue ds-Other 102 1 0 0 100 0 0 0

Syncope 102 1 0 0 100 0 0 0

Thromboembolic event 100 2 1 0 100 0 0 0

Tx related secondary malig 103 0 0 0 98 2 0 0

Urinary tract infection 103 0 0 0 99 1 0 0

Urinary tract obstruction 102 1 0 0 100 0 0 0

White blood cell decreased 100 3 0 0 99 1 0 0

MAX. GRADE ANY ADVERSE

EVENT

59 38 6 0 66 31 3 0


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, ECOG-ACRIN)

Study Chairs:

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

T Petrella (CCTG)

Statisticians:

M Othus, J Moon, H Li, L Qian

Data Coordinators:

L Kingsbury, J Sanchez

Date Activated:

10/15/2015

Date Closed:

08/15/2017

SCHEMA

R

A

N

D

O

M

I

Z

A

T

I

O

N

FDA approved regimen:

Physician/Patient choice of

Interferon alfa-2b/Ipilimumab

MK-3475 (Pembrolizumab)

R

E

G

I

S

T

R

A

T

I

O

N

Tissue Submission*

*PD-L1 status determined by central laboratory

and blinded to the investigator and patient


S1404/III

Objectives

Co-Primary Objectives:

To compare overall survival (OS) of patients with

resected Stage III and IV melanoma treated with

physician/patient choice of either high dose

interferon alfa-2b or ipilimumab versus MK-3475

(pembrolizumab).

To compare OS of patients with resected Stage III

and IV melanoma treated with physician/patient

choice of either high dose interferon alfa-2b or

ipilimumab versus MK-3475 (pembrolizumab)

among patients who are PD-L1 positive.

To compare relapse-free survival (RFS) of patients

with resected Stage III and IV melanoma treated with

physician/patient choice of either high dose

interferon alfa-2b or ipilimumab versus MK-3475

(pembrolizumab).

Secondary Objectives:

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

negative or PD-L1 indeterminate in this population.

To compare OS and RFS between the two arms

within the PD-L1 positive and PD-L1 negative

subgroups and to investigate the interaction between

PD-L1 status (positive versus negative) and treatment

arm.

To assess the safety and tolerability of the regimens.

Patient Population

Patients must have histologically confirmed selected

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

melanoma of cutaneous or mucosal origin or

unknown primary. Patients must not have melanoma

of ocular origin. Patients are eligible for this trial

either at initial presentation of their melanoma, at

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

metastases, or recurrent disease in prior

lymphadenectomy basin or distant site. Patients must

not have a history of brain metastases. Patients who

have multiple regional nodal basin involvement are

eligible. Gross or microscopic extracapsular nodal

extension is permitted. All disease must have been

completely resected with negative pathologic margins

and no clinical, radiologic, or pathologic evidence of

any incompletely resected melanoma. Patients must

have available and be willing to submit adequate

tissue for PD-L1 testing.

Patients may have received prior radiotherapy,

including after the surgical resection that rendered the

patient disease-free. Patients must not have received

neoadjuvant treatment for their melanoma. Patients

must not have received prior immunotherapy,

including but not limited to ipilimumab, interferon

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

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

therapies. Patients must be registered within 98 days

of the last surgery performed to render the patient

free of disease.

Patients must have a Zubrod performance status of 0-

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

cardiac function. Patients must not have active

autoimmune disease that has required systemic

treatment in the past two years. Patients must not

have an active infection requiring systemic

therapy. Patients must not have pneumonitis or a

history of non-infectious pneumonitis that

required steroids. Patients known to be HIV

positive must have adequate CD4 counts and

low viral load. Patients must not have known

active hepatitis B or C infections. Patients

must not have received live vaccines within 42

days prior to enrollment. Women of childbearing

potential must have a negative pregnancy test

within 28 days prior to randomization.

Stratification/Descriptive Factors

Treatment randomization will be stratified by the

following: (1) surgically resected AJCC stage:

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

positive vs negative vs indeterminate; (3) planned

control arm regimen: high dose interferon vs

ipilimumab.

Accrual Goals

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

eligible patients. Up to two interim analyses of

overall survival will be performed when 55% and

80% of the expected deaths across both arms

combined have been observed. An interim analysis of

relapse-free survival (RFS) will be performed when

75% of the expected RFS events have been observed.

Summary Statement

This study was permanently closed after reaching its

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

to the PD-L1 status screening step. Sixty-six patients

are currently ineligible for the following reasons:

incorrect stage of disease (20), inadequate/incomplete


S1404/III

resection of disease (22), radiologic or clinical

evidence that patient was not disease free (10) , lack

of adequate tissue for PD-L1 testing (10) , inadequate

renal function , concurrent radiation therapy ,

recurrent satellite metastases , recurrent distant

metastases (1 patient each) .

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

eight are currently ineligible, 37 who were ineligible

at the screening step and one patient due to a positive

pregnancy test. Ninety-seven patients, 89 of them

randomized to the control arm, did not receive any

protocol treatment, coded as a major protocol

deviation, and are not evaluable for adverse events.

On the control arm, 569 patients have been assessed

for adverse events. There have been two treatment

related deaths, one due to enterocolitis, the other due

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

both patients were receiving ipilimumab. An

additional 37 patients have experienced treatment-

related Grade 4 adverse events. These have been

primarily hematologic among patients who received

high-dose interferon and immune-related among

patients who received ipilimumab. One patient

experienced Grade 4 acute inflammatory

demyelinating polyneuropathy (coded as "Nervous

system disorders - Other).

On the pembrolizumab arm, 641 patients have been

assessed for adverse events. There have been two

treatment-related deaths, one due to myocarditis , the

other due to a secondary leukemia (AML, also coded

as "Neoplasms, all"). An additional 13 patients have

experienced treatment-related Grade 4 adverse

events. Notable Grade 4 adverse events include four

cases of hyperglycemia, one case of acidosis, one

case of diabetic ketoacidosis (coded as

Metabolic/nutrition disorders - Other), one case of

Type 1 diabetes (coded as "Endocrine disorders-

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

myasthenia gravis (coded as "Nervous system

disorders, Other") and another experienced Grade 4

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

Initial Registrations by 3 Month IntervalsInitial Registration

Total

0

50

100

150

200

250

300


OctDec2015

JanMar

2016

AprJun

2016

JulSep2016

OctDec2016

JanMar

2017

AprJun

2017

JulSep2017

164

259

73

268

207

185

8

262


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 CC, Univ of 11 All Other SWOG Institutions 22

Mt Sinai Med Ctr 11 ECOG-ACRIN 323

Northwest NCORP 11 ALLIANCE 150

CORA NCORP 10 CCTG 130

New Mexico MU-NCORP 10 NRG 113

Southeast COR NCORP 10 Total (61 Institutions) 1426

Wayne State Univ 10


Initial Registration


Tissue for PD

-L1 testing

NUMBER REGISTERED 1426

INELIGIBLE 66

ELIGIBLE 1360

Analyzable, Pend. Elig. 15


S1404/III


Randomization

FDA approved regimen MK-3475 (Pembrolizumab)

0

50

100

150

200

250

300


OctDec2015

JanMar

2016

AprJun

2016

JulSep2016

OctDec2016

JanMar

2017

AprJun

2017

JulSep2017

68

118

29

147

99110

2

105

65

127

30

133

96

102

2

112


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 CC, Univ of 11 All Other SWOG Institutions 24

Northwest NCORP 11 ECOG-ACRIN 302

Mt Sinai Med Ctr 10 ALLIANCE 144

Southeast COR NCORP 10 CCTG 122

CORA NCORP 9 NRG 106

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


Randomization


TOTAL

FDA approved

regimen

MK-3475

(Pembrolizumab)


INELIGIBLE 38 20 18

ELIGIBLE 1307 658 649


Evaluable 1210 569 641

Not Evaluable 97 89 8


S1404/III


Randomization


FDA approved

regimen

(n=658)

MK-3475

(Pembrolizumab)

(n=649)

AGE

Median 57.0 56.3

Minimum 18.3 20.0

Maximum 86.0 82.6

SEX

Males 398 60% 382 59%

Females 260 40% 267 41%

HISPANIC

Yes 18 3% 26 4%

No 621 94% 606 93%

Unknown 19 3% 17 3%

RACE

White 625 95% 622 96%

Black 5 1% 2 0%

Asian 6 1% 4 1%

Pacific Islander 1 0% 0 0%

Native American 0 0% 2 0%

Multi-Racial 3 0% 0 0%

Unknown 18 3% 19 3%

STAGE

IIIA 68 10% 76 12%

IIIB 327 50% 312 48%

IIIC 223 34% 220 34%

IV 40 6% 41 6%

PLANNED CONTROL-ARM REGIMEN

High Dose Interferon 157 25% 153 25%

Ipilimumab 466 75% 457 75%

PERFORMANCE STATUS

0 550 84% 543 84%

1 108 16% 106 16%


S1404/III

Treatment Summary

Randomization


Total




1283







LOST TO FOLLOW-UP 4



136


Randomization




FDA approved regimen

(n=569)

Grade


(n=641)

Grade

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

ALT increased 523 39 7 0 622 19 0 0

AST increased 535 30 4 0 628 13 0 0

Abdominal pain 563 6 0 0 639 2 0 0

Acidosis 568 1 0 0 639 1 1 0

Acute kidney injury 567 2 0 0 639 2 0 0

Adrenal insufficiency 560 8 1 0 637 4 0 0


Anemia 569 0 0 0 640 1 0 0

Anorexia 565 4 0 0 640 1 0 0

Anxiety 567 2 0 0 641 0 0 0

Arthralgia 566 3 0 0 638 3 0 0

Arthritis 568 1 0 0 641 0 0 0

Atelectasis 568 1 0 0 641 0 0 0

Atrial fibrillation 568 1 0 0 641 0 0 0

Atrial flutter 569 0 0 0 640 1 0 0

Autoimmune disorder 567 0 2 0 640 1 0 0

Back pain 566 3 0 0 641 0 0 0


Blood/lymph disorder-Other 568 1 0 0 641 0 0 0

Blurred vision 568 1 0 0 641 0 0 0


S1404/III


(n=569)

Grade


(n=641)

Grade

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

Bone pain 568 1 0 0 641 0 0 0

Bronchospasm 569 0 0 0 640 0 1 0

CPK increased 564 3 2 0 639 1 1 0

Cardiac disorder-Other, spec 568 1 0 0 641 0 0 0

Cardiac troponin T increased 568 1 0 0 641 0 0 0

Colitis 535 32 2 0 628 13 0 0

Colonic perforation 568 0 1 0 641 0 0 0

Confusion 567 2 0 0 640 1 0 0

Cough 568 1 0 0 640 1 0 0

Creatinine increased 567 1 1 0 641 0 0 0

Cystitis noninfective 568 1 0 0 641 0 0 0

Dehydration 566 3 0 0 640 1 0 0

Delirium 568 1 0 0 641 0 0 0

Depression 565 4 0 0 641 0 0 0

Diarrhea 515 53 1 0 623 18 0 0

Dizziness 568 1 0 0 641 0 0 0

Duodenal ulcer 568 1 0 0 641 0 0 0

Dyspepsia 568 1 0 0 641 0 0 0

Dyspnea 557 11 1 0 637 3 1 0

Encephalitis infection 567 1 1 0 641 0 0 0

Encephalopathy 568 1 0 0 641 0 0 0

Endocrine disorders-Other 565 4 0 0 638 2 1 0

Enterocolitis 563 5 0 1 640 1 0 0

Enterocolitis infectious 567 2 0 0 640 1 0 0

Erectile dysfunction 568 1 0 0 641 0 0 0

Esophagitis 568 1 0 0 641 0 0 0


Eye pain 569 0 0 0 640 1 0 0

FEV1 decreased 569 0 0 0 640 1 0 0

Facial nerve disorder 569 0 0 0 640 1 0 0

Fall 568 1 0 0 641 0 0 0

Fatigue 540 29 0 0 638 3 0 0

Febrile neutropenia 567 1 1 0 641 0 0 0


GI disorders-Other, specify 566 3 0 0 641 0 0 0

Gastritis 567 2 0 0 641 0 0 0

Gen disorders/admin site cond 567 2 0 0 640 1 0 0


Headache 556 13 0 0 638 3 0 0

Hepatic pain 569 0 0 0 640 1 0 0

Hepatitis viral 567 2 0 0 641 0 0 0

Hepatobil disorders-Other 568 1 0 0 641 0 0 0

Hiccups 569 0 0 0 640 1 0 0

Hyperglycemia 565 4 0 0 634 3 4 0

Hypersomnia 568 1 0 0 641 0 0 0

Hypertension 562 7 0 0 639 2 0 0

Hyperthyroidism 568 0 1 0 640 1 0 0

Hypertriglyceridemia 561 6 2 0 640 1 0 0


Hypokalemia 566 3 0 0 641 0 0 0

Hyponatremia 554 11 4 0 632 9 0 0


S1404/III


(n=569)

Grade


(n=641)

Grade

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

Hypophosphatemia 566 3 0 0 638 3 0 0

Hypotension 566 3 0 0 641 0 0 0


Hypoxia 566 3 0 0 639 2 0 0

Immune sys disorders-Other 568 1 0 0 639 2 0 0

Infections/infestations-Other 568 1 0 0 641 0 0 0

Infusion related reaction 568 1 0 0 640 1 0 0

Insomnia 568 1 0 0 641 0 0 0

Joint effusion 569 0 0 0 640 1 0 0

Leukocytosis 567 2 0 0 641 0 0 0

Lipase increased 564 4 1 0 640 1 0 0

Lower GI hemorrhage 568 1 0 0 641 0 0 0

Lung infection 568 1 0 0 637 4 0 0


MS/connective tissue disorder 568 1 0 0 639 2 0 0

Meningitis 566 3 0 0 641 0 0 0

Metab/nutrition disorders-Other 567 2 0 0 640 0 1 0

Mucositis oral 569 0 0 0 639 2 0 0

Muscle weakness lower limb 568 1 0 0 641 0 0 0

Myalgia 565 4 0 0 640 1 0 0

Myocardial infarction 569 0 0 0 640 1 0 0

Myocarditis 569 0 0 0 640 0 0 1

Myositis 568 1 0 0 640 1 0 0

Nausea 559 10 0 0 640 1 0 0

Neoplasms, all 569 0 0 0 640 0 0 1

Nervous sys disorders-Other 565 3 1 0 639 1 1 0

Neuralgia 567 2 0 0 641 0 0 0

Neutrophil count decreased 519 43 7 0 639 2 0 0

Pain 568 1 0 0 641 0 0 0


Pain of skin 569 0 0 0 640 1 0 0

Pancreatitis 566 2 1 0 636 5 0 0

Papulopustular rash 568 1 0 0 641 0 0 0

Peripheral motor neuropathy 568 1 0 0 641 0 0 0

Peripheral sensory neuropathy 568 0 1 0 641 0 0 0

Pharyngitis 568 1 0 0 641 0 0 0

Pleural effusion 568 1 0 0 641 0 0 0

Pneumonitis 563 6 0 0 636 5 0 0

Proctitis 569 0 0 0 640 1 0 0

Pruritus 562 7 0 0 641 0 0 0

Rash acneiform 569 0 0 0 639 2 0 0


Rash pustular 568 1 0 0 641 0 0 0

Resp/thoracic/mediastinal ds 569 0 0 0 640 1 0 0

Respiratory failure 567 0 1 1 641 0 0 0

Restrictive cardiomyopathy 568 1 0 0 641 0 0 0

Retinal detachment 569 0 0 0 640 0 1 0

Retinal tear 569 0 0 0 640 1 0 0

Secondary Leukemia 569 0 0 0 640 0 0 1

Seizure 569 0 0 0 640 1 0 0

Sepsis 567 0 2 0 640 0 1 0


S1404/III


(n=569)

Grade


(n=641)

Grade

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

Serum amylase increased 568 1 0 0 640 1 0 0

Sinus tachycardia 567 2 0 0 641 0 0 0

Sinusitis 569 0 0 0 640 1 0 0

Skin infection 568 1 0 0 640 1 0 0


Syncope 563 6 0 0 640 1 0 0

Tremor 569 0 0 0 640 1 0 0

Vitreous hemorrhage 569 0 0 0 640 1 0 0

Vomiting 561 8 0 0 640 1 0 0

Weight loss 567 2 0 0 641 0 0 0

Wheezing 569 0 0 0 640 0 1 0

White blood cell decreased 550 17 2 0 641 0 0 0


EVENT

255 275 37 2 517 109 13 2


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, L Qian

Data Coordinator:

M Shi

Date Activated:

10/20/2016

Objectives This study will enroll two separate cohorts to assess

the efficacy of MK-3475 (pembrolizumab) in

desmoplastic melanoma (DM). Cohort A will

evaluate MK-3475 (pembrolizumab) as neoadjuvant

therapy for patients with DM that is deemed

resectable by the treating investigator; including

primary DM, locally advanced DM, and locally

recurrent DM. Cohort B will be a pilot study to

evaluate the use of MK-3475 (pembrolizumab) for

patients with DM that is deemed unresectable by the

treating investigator, including metastatic DM.

Cohort A

To evaluate the pathologic complete response rate in

patients with resectable desmoplastic melanoma

treated with neoadjuvant MK-3475 (pembrolizumab).

To estimate the nine week response rate

(unconfirmed complete and partial responses).

To estimate the median overall survival.

To evaluate safety and tolerability of MK-3475

(pembrolizumab) in the neoadjuvant setting.

Cohort B

To evaluate the complete response rate (confirmed

and unconfirmed) in patients with unresectable

desmoplastic melanoma treated with MK-3475

(pembrolizumab).

To estimate the median progression-free survival.

To estimate the median overall survival.

To evaluate safety and tolerability of MK-3475

(pembrolizumab) in this setting.

Patient Population Patients must have histologically or cytologically

confirmed primary desmoplastic melanoma. Patients

with disease that, in the judgment of the surgeon is

deemed completely resectable resulting in free

surgical margins, are eligible for Cohort A. Patients

with unresectable disease are eligible for Cohort B.


S1512/II

Patients must not have known brain metastases unless

brain metastases have been treated and patient is

asymptomatic with no residual neurological

dysfunction without receiving enzyme-reducing anti-

epileptic drugs or corticosteroids. Patients enrolled on

Cohort A may have only non-measurable disease

provided it can be confirmed with a fine needle

aspiration. Patients enrolled on Cohort B must have

measurable disease

Patients must not have received prior systemic

therapy for desmoplastic melanoma. Patients must

not have received radiation therapy, non-cytotoxic

agents or investigational agents or systemic

corticosteroids within 14 days prior to registration.

Patients may have received prior surgery.

Patients must have adequate hematologic and hepatic

function with a Zubrod performance status of 0-2.

Patients must not have known, active non-infectious

pneumonitis, an active infection requiring systemic

therapy, or an active autoimmune disease that has

required systemic treatment in the past two years.

Patients must not have received live vaccines within

42 days prior to registration. Patients known to be

HIV positive must have stable and adequate CD4

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

must be on stable anti-viral therapy. Women of

childbearing potential must have a negative urine or

serum pregnancy test within 28 days prior to

registration.

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

B (unresectable).

Accrual Goals

Accrual to this study will proceed in two independent

cohorts: A and B.

Cohort A will accrue approximately 30 patients to

achieve 25 eligible patients.

Cohort B will accrue approximately 26 patients to

achieve 21 eligible patients.

Summary Statement On July 2, 2019, the trial design for Cohort A was

modified, reducing the accrual goal to 25 eligible

patients.

As of June 30, 2019, 26 patients have been

registered, 12 to Cohort A and 14 to Cohort B. One

patient withdrew consent prior to receiving any

protocol treatment and is not analyzable for any of

the study endpoints.

Twenty-three patients have been assessed for adverse

events. One patient in Cohort B has experienced

treatment-related Grade 4 lung infection and sepsis.


Registrations ending June 30, 2019

Institutions

Total

Reg Institutions

Total

Reg

H Lee Moffitt CC 10 Utah, U of 2

Ohio State Univ 4 Georgia NCORP 1

Los Angeles, U of CA 3 Northwestern Univ 1

Kansas, U of 2 Southeast COR NCORP 1

So Calif, U of 2 Total (9 Institutions) 26


S1512/II


Classified by Cohort

Registrations ending June 30, 2019; Data as of August 8, 2019

TOTAL

Resectable

(Cohort A)

Unresectable

(Cohort B)


ELIGIBLE 26 12 14


Not Analyzable 1 1 0

BASELINE DISEASE STATUS

Measurable 15 7 8

Non Measurable 1 1 0

Too Early 9 3 6

RESPONSE ASSESSMENT

Determinable 11 5 6

Not Determinable 1 0 1

Too Early 12 5 7

Not Applicable 1 1 0


Evaluable 23 10 13

Too Early 2 1 1




Resectable

(Cohort A)

(n=11)

Unresectable

(Cohort B)

(n=14)

AGE

Median 80.8 80.4

Minimum 49.2 58.7

Maximum 91.1 89.6

SEX

Males 8 73% 13 93%

Females 3 27% 1 7%

HISPANIC

No 11 100% 14 100%

RACE

White 11 100% 14 100%

PERFORMANCE STATUS

0 8 73% 9 64%

1 3 27% 5 36%


S1512/II

Treatment Summary



TOTAL

Resectable

(Cohort A)

Unresectable

(Cohort B)

NUMBER ON PROTOCOL TREATMENT 10 2 8



15 9 6

Treatment completed as planned 7 7 0

Adverse Event or side effects 0 0 0

Refusal unrelated to adverse event 1 0 1

Progression/relapse 1 0 1

Death 0 0 0

Other - not protocol specified 0 0 0

Reason under review 6 2 4

MAJOR PROTOCOL DEVIATIONS 0 0 0

LOST TO FOLLOW-UP 0 0 0



1 1 0





Resectable (Cohort A)

(n=10)

Grade

Unresectable (Cohort B)

(n=13)

Grade

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

ALT increased 10 0 0 0 13 0 0 0

Abdominal distension 10 0 0 0 13 0 0 0


Anemia 10 0 0 0 13 0 0 0

Anorexia 10 0 0 0 13 0 0 0

Arthralgia 10 0 0 0 13 0 0 0


Bullous dermatitis 10 0 0 0 13 0 0 0

CPK increased 10 0 0 0 12 1 0 0

Cardiac troponin I increased 10 0 0 0 13 0 0 0

Confusion 10 0 0 0 13 0 0 0

Constipation 10 0 0 0 13 0 0 0

Diarrhea 10 0 0 0 13 0 0 0

Dizziness 10 0 0 0 13 0 0 0

Dysphagia 10 0 0 0 13 0 0 0

Dyspnea 10 0 0 0 12 1 0 0

Edema limbs 10 0 0 0 13 0 0 0

Endocrine disorders-Other 10 0 0 0 13 0 0 0


S1512/II

Resectable (Cohort A)

(n=10)

Grade

Unresectable (Cohort B)

(n=13)

Grade

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


Fall 10 0 0 0 13 0 0 0

Fatigue 10 0 0 0 13 0 0 0

Fever 10 0 0 0 13 0 0 0



Headache 10 0 0 0 13 0 0 0

Hypercalcemia 10 0 0 0 13 0 0 0

Hyperkalemia 10 0 0 0 13 0 0 0

Hypernatremia 10 0 0 0 13 0 0 0

Hypertension 10 0 0 0 13 0 0 0

Hyperthyroidism 10 0 0 0 13 0 0 0


Hypokalemia 10 0 0 0 13 0 0 0

Hyponatremia 10 0 0 0 13 0 0 0


Hypoxia 10 0 0 0 12 1 0 0

Insomnia 10 0 0 0 13 0 0 0

Lung infection 10 0 0 0 12 0 1 0


MS/connective tissue disorder 10 0 0 0 12 1 0 0

Myalgia 10 0 0 0 13 0 0 0

Myositis 10 0 0 0 12 1 0 0

Nausea 10 0 0 0 13 0 0 0

Neoplasms, all 10 0 0 0 13 0 0 0

Pain 10 0 0 0 13 0 0 0


Paresthesia 10 0 0 0 13 0 0 0

Platelet count decreased 10 0 0 0 13 0 0 0

Pneumonitis 10 0 0 0 13 0 0 0

Pruritus 10 0 0 0 13 0 0 0


Sepsis 10 0 0 0 12 0 1 0


Tremor 10 0 0 0 13 0 0 0

Urinary incontinence 10 0 0 0 13 0 0 0

Vomiting 10 0 0 0 13 0 0 0


EVENT

10 0 0 0 9 3 1 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

Study Chairs:

S Hu-Lieskovan, A Ribas

Statisticians:

M Wu, J Moon, L Qian

Data Coordinator:

M Shi

Date Activated:

10/02/2017

Objectives To evaluate the durable response rate of treatment

with talimogene laherparepvec (T-VEC) in

combination with MK-3475 (pembrolizumab)

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

L1 therapy alone or in combination with other agents

different from talimogene laherparepvec (T-VEC).

To estimate the response rate (confirmed and

unconfirmed, complete and partial responses) in the

injected lesions.

To estimate the response rate in the non-visceral,

non-injected lesions.

To estimate the response rate in the visceral lesions.

To estimate the overall objective response rate per

RECIST 1.1, progression-free survival, and overall

survival within each cohort.

To evaluate whether adding talimogene

laherparepvec (T-VEC) to PD1 blockade can increase

T-cell infiltration into tumors and whether change in

T-cell infiltration is associated with response.

To evaluate whether adding talimogene

laherparepvec (T-VEC) to PD1 blockade can increase

TCR clonality in tumors and in peripheral blood and

whether increased TCR clonality is associated with

response.

To evaluate whether intra-tumoral injection of

talimogene laherparepvec (T-VEC) is associated with

the tumor immune microenvironment.

To evaluate whether tumor mutational load and

mutations in the IFN pathway is associated with

response to talimogene laherparepvec (T-VEC) plus

MK-3475 (pembrolizumab) therapy in the anti-

PD1/L1 therapy refractory melanoma patients.

Patient Population Patients must have pathologically confirmed Stage

IV or unresectable Stage III melanoma with

cutaneous, mucosal or unknown primary. Patients

with uveal primary are not eligible. Patients will be

enrolled onto one of two independent cohorts: for

Cohort A, patients must have at least one measurable

visceral lesion, defined as any solid organ except for

skin, lymph node, or musculoskeletal tissue; for

Cohort B, patients must have at least one measurable

non-visceral lesion and no evidence of visceral

disease. Patients must not have known active central


S1607/II

nervous system (CNS) metastases. Patients with a

history of CNS metastases must have been

adequately treated with no evidence of progression

for at least 28 days prior to registration and must be

asymptomatic without requiring steroids for at least

14 days prior to registration. Patients must, in the

opinion of the treating investigator, be candidates for

intralesional administration into cutaneous,

subcutaneous, or nodal lesions. Patients must have at

least two injectable lesions.

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

or anti-PD-L1 agents and have documented disease

progression on these agents prior to registration.

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

therapy as the immediate previous line of treatment

and within 56 days prior to registration. Patients must

not have had surgery, chemotherapy, biologic

therapy, hormonal therapy, or radiation therapy

within 14 days prior to registration. Patients must not

have had an investigational agent or monoclonal

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

days prior to registration. Patients must not have

received prior treatment with talimogene

laherparepvec (T-VEC) or other oncolytic virus

agents. Patients must not have had any infectious

disease vaccination within seven days prior to

registration.

Patients must have adequate hematologic, hepatic,

and renal function and a Zubrod performance status

of 0-2. Patients must not have severe autoimmune

disease requiring systemic corticosteroids or ongoing

immunosuppression. Patients must not have a known

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

pneumonitis. Patients must not have an active

infection requiring systemic therapy nor a viral-

infection requiring intermittent treatment with an

anti-hepatic drug, and must not have active hepatic

skin lesions or prior complications of hepatic

infection which require treatment with an anti-hepatic

drug. Patients must not have organ allografts, or a

history of autoimmune disease, or clinically

significant immunosuppression. Women of

reproductive potential must have a negative serum

pregnancy test within seven days prior to registration.

Patients must have tissue available and must be

willing to submit blood and tissue specimens for the

translational medicine objectives. Patients must be

offered the opportunity to participate in specimen

banking.

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

visceral lesions: one or more vs none.

Accrual Goals The study will accrue to two independent cohorts.

Cohort A, patients with at least one visceral lesion,

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

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

an additional 14 patients will be enrolled for a total of

32 patients.

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

modified two-stage design. Initially 16 patients will

be enrolled. If two or more durable responses are

observed, then an additional nine patients will be

enrolled for a total of 25 patients.

Summary Statement As of June 30, 2019, 19 patients have been

registered, 5 to the cohort with at least one visceral

lesion and 14 to the cohort with non-visceral disease

only.

Eighteen patients have been assessed for adverse

events. No treatment-related adverse events greater

than Grade 3 have been reported.


S1607/II



Institutions Total Reg

Los Angeles, U of CA 8

So Calif, U of 3

Ohio State Univ 2

Utah, U of 2

ECOG-ACRIN 3

NRG 1

Total (6 Institutions) 19




TOTAL

Visceral

(Cohort A)

Non-Visceral

(Cohort B)


ELIGIBLE 19 5 14


RESPONSE ASSESSMENT

Determinable 9 3 6

Too Early 10 2 8


Evaluable 18 5 13

Too Early 1 0 1


S1607/II




Visceral

(Cohort A)

(n=5)

Non-Visceral

(Cohort B)

(n=14)

AGE

Median 51.5 60.9

Minimum 35.4 37.8

Maximum 76.0 93.7

SEX

Males 3 60% 6 43%

Females 2 40% 8 57%

HISPANIC

Yes 2 40% 1 7%

No 3 60% 13 93%

RACE

White 3 60% 13 93%

Pacific Islander 0 0% 1 7%

Unknown 2 40% 0 0%

PERFORMANCE STATUS

0 1 20% 11 79%

1 4 80% 2 14%

2 0 0% 1 7%


S1607/II

Treatment Summary



TOTAL

Visceral

(Cohort A)

Non-Visceral

(Cohort B)

NUMBER ON PROTOCOL TREATMENT 13 2 11



6 3 3

Treatment completed as planned 0 0 0

Adverse Event or side effects 0 0 0

Refusal unrelated to adverse event 0 0 0

Progression/relapse 6 3 3

Death 0 0 0

Other - not protocol specified 0 0 0

Reason under review 0 0 0

MAJOR PROTOCOL DEVIATIONS 0 0 0

LOST TO FOLLOW-UP 0 0 0



0 0 0


S1607/II





Visceral (Cohort A)

(n=5)

Grade

Non-Visceral (Cohort B)

(n=13)

Grade

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

Abdominal pain 5 0 0 0 0 0 12 1 0 0 0 0

Anemia 5 0 0 0 0 0 12 0 1 0 0 0

Anorexia 5 0 0 0 0 0 12 0 1 0 0 0

Blood bilirubin increased 5 0 0 0 0 0 12 1 0 0 0 0

Chills 5 0 0 0 0 0 10 2 1 0 0 0

Dyspnea 5 0 0 0 0 0 12 0 0 1 0 0

Fatigue 5 0 0 0 0 0 9 2 0 2 0 0

Fever 4 1 0 0 0 0 12 0 1 0 0 0

Flu like symptoms 4 0 0 1 0 0 9 1 3 0 0 0

Headache 5 0 0 0 0 0 12 0 1 0 0 0

Hot flashes 4 1 0 0 0 0 13 0 0 0 0 0

Hyponatremia 5 0 0 0 0 0 12 0 0 1 0 0

Hypothyroidism 5 0 0 0 0 0 12 0 1 0 0 0

Hypoxia 5 0 0 0 0 0 12 0 0 1 0 0

Injection site reaction 4 0 1 0 0 0 11 1 1 0 0 0

Lymphocyte count decreased 5 0 0 0 0 0 12 1 0 0 0 0

MS/connective tissue disorder 5 0 0 0 0 0 12 1 0 0 0 0

Malaise 5 0 0 0 0 0 12 1 0 0 0 0

Nausea 5 0 0 0 0 0 10 1 2 0 0 0

Neutrophil count decreased 5 0 0 0 0 0 12 1 0 0 0 0

Non-cardiac chest pain 5 0 0 0 0 0 12 1 0 0 0 0

Platelet count decreased 5 0 0 0 0 0 12 1 0 0 0 0

Pruritus 5 0 0 0 0 0 12 0 1 0 0 0

Rash maculo-papular 5 0 0 0 0 0 12 1 0 0 0 0

Sinus tachycardia 5 0 0 0 0 0 12 0 1 0 0 0

Skin infection 5 0 0 0 0 0 12 0 1 0 0 0

Tumor pain 5 0 0 0 0 0 12 0 0 1 0 0

Vomiting 5 0 0 0 0 0 12 1 0 0 0 0

White blood cell decreased 5 0 0 0 0 0 12 1 0 0 0 0


EVENT

3 1 0 1 0 0 3 3 5 2 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 Magner, S Gurung

Date Activated:

01/13/2017

Objectives To evaluate the RECIST 1.1 overall response rate

(ORR) in subsets of patients with advanced rare

cancers treated with ipilimumab plus nivolumab

combination immunotherapy.

To evaluate the overall response rate (ORR) in

patients with gestational trophoblastic tumors treated

with ipilimumab plus nivolumab combination

immunotherapy.

To evaluate the RECIST 1.1 overall response rate

(ORR) in patients PD-L1 amplified cancers treated

with nivolumab immunotherapy.

To evaluate toxicities in each cohort.

To estimate overall survival (OS), progression-free

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

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

PFS (irPFS) by unidimensional immune-related

response criteria.

To collect specimens for banking for use in future

correlative biomarker research studies.

Patient Population Patients must have histologically confirmed rare

cancer and/or cancer of unknown primary specified

on the list of eligible rare cancer histologic cohorts in

the S1609 protocol or with PD-L1 amplification only.

As of September 11, 2017, patients are no longer

required to have been enrolled in EAY131 (NCI-

MATCH) to be eligible for this study.

Patients must have measurable disease and have

progressed following at least one line of standard

systemic therapy and there must not be other

approved/standard therapy available that has been

shown to prolong overall survival. Patients are also

eligible if no standard treatment exists that has been

shown to prolong overall survival. Patients in one of

the histologically defined rare cancer cohorts maybe

have received either prior anti-CTLA-4 or other prior

anti-PD-1/anti-PD-L1 therapy, but not both, provided

that it is completed at least 4 weeks prior to

registration. Patients in the PD-L1 amplification

cohort must not have received anti-PD-1/anti-PD-L1

therapy; prior anti-CTLA-4 is allowed provided that

it is completed at least 4 weeks prior to registration.

Patients who had a prior immune-related adverse

event with prior immunotherapy are not eligible.


S1609/II

Patients with brain metastases or primary brain

tumors must have completed treatment, surgery or

radiation therapy at least 28 days prior to registration

and have stable disease at time of registration.

Patients with metastatic brain parenchymal disease

must have been treated and off steroids for seven

days prior to registration. Patients must have been off

all other systemic anti-cancer therapy at least seven

days prior to registration and any therapy-induced

toxicity must have recovered to Grade 1 or less.


2 and have adequate hematologic, hepatic, renal,

thyroid, and adrenal axis function. Patients must not

have active autoimmune disease that has required

systemic treatment in the past two years or any

uncontrolled intercurrent illness. Patients must not

have known active Hepatitis B Virus (HBV) or

Hepatitis C Virus (HCV) infection at time of

registration. Patients with HBV or HCV that have an

undetectable viral load, or in the opinion of the

treating investigator is well controlled, are eligible.

Patients who are known to be HIV-positive at

registration are eligible if they meet the conditions

outlined in the protocol.

Stratification/Descriptive Factors Patients will be described by histologic cohorts, with

the exception of PD-L1 amplification patients.

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

achieve 636 eligible patients. A two-stage design will

be used for all cohorts, with the exception of the

NOC and "Cancer of Unknown Primary" (CuP)

cohorts. Initially, six eligible patients will be

registered to each histologic cohort. If at least one

response is observed within a cohort, an additional 10

eligible patients will be registered to that cohort. Up

to 16 eligible patients will be registered to the CuP

cohort with no formal first stage response

assessment. Up to 60 eligible patients will be enrolled

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

additional cohorts.

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

Early Therapeutics and Rare Cancers chapter.


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 Coordinators:

S Dzingle, R Topacio

Date Activated:

02/21/2019

SCHEMA

Cohort 1:

Chronic HBV

Prophylactic

Antiviral Therapy

Upon Indication

Antiviral Therapy

Usual Care

Antiviral Therapy

Upon Indication

Antiviral Therapy

Cohort 2:

Past HBV

R

A

N

D

O

M

I

Z

A

T

I

O

N

R

A

N

D

O

M

I

Z

A

T

I

O

N


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

balanced by planned cancer therapy type: any

cytotoxic therapy vs immunotherapy alone vs

targeted therapy alone vs immunotherapy and

targeted therapy.

Patients with past HBV infection will be randomized

within Cohort 2 with randomization balanced by the

following factors: (1) planned cancer therapy type:

any cytotoxic therapy vs immunotherapy alone vs

targeted therapy alone vs immunotherapy and

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

negative.

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

patients per cohort to achieve 200 eligible patients

per cohort. A single formal interim analysis for

efficacy for each cohort will be conducted when one

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

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

Symptom Control and QOL chapter.


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

Study Chairs:

A VanderWalde, A Ribas

Statisticians:

M Wu, L Qian, J Moon

Data Coordinator:

J Sanchez

Date Activated:

07/17/2017

SCHEMA

R

A

N

D

O

M

I

Z

A

T

I

O

N

Ipilimumab + Nivolumab

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

three will be randomized to receive the combination of ipilimumab and

nivolumab

Ipilimumab

Nivolumab


S1616/II

Objectives To compare progression free survival (PFS) of

patients with advanced melanoma refractory to an

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

combination therapy ipilimumab plus nivolumab

versus ipilimumab alone.

To estimate difference in T-cell infiltrate between on-

study biopsy samples of patients who respond to

combination therapy (including confirmed and

unconfirmed, complete and partial response per

RECIST 1.1) as compared to those who do not

respond.

To evaluate the objective response rate (ORR)

(confirmed and unconfirmed complete or partial

responses) in each treatment arm.

To evaluate overall survival in each treatment arm.

To evaluate the toxicity profile of patients in each

treatment arm.

Patient Population Patients must have pathologically confirmed

melanoma that is either Stage IV or unresectable

Stage III. Patients may have primaries of cutaneous,

mucosal, or unknown origin. Patients with uveal

(ocular) primary are not eligible. Patients must have

measurable disease. If the only measurable disease is

cutaneous or subcutaneous, lesions must be at least

10 mm in greatest dimension and able to be serially

recorded using calipers and photographs. Patients

must not have central nervous system metastases

unless adequately treated and patient is asymptomatic

without requiring steroids for at least 14 days prior to

registration.

Patients must have had prior treatment with anti-PD-

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

progression either while on these agents or after

stopping therapy. Patients must not have achieved a

confirmed partial or complete response to the anti-

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

Patients must not have had any systemic therapy

within 21 days prior to registration. Patients must not

have had prior radiation therapy within 14 days prior

to registration. Patients must not have had prior

treatment with ipilimumab or other CTLA-4

antagonists.

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

Zubrod performance status of 0-2 with adequate

hepatic, renal, and hematologic function. Patients

with a known history of HIV must have an adequate

CD4 count. Patients must not have a known active

Hepatitis B, or Hepatitis C infection. Patients must

not have received systemic treatment with

corticosteroids or other immunosuppressive

medications within 14 days prior to registration.

Patient must not have organ allografts or a history of

immune-mediated pneumonitis or colitis that required

steroid treatment. Women of reproductive potential

must have a negative serum pregnancy test within

two days prior to registration.

Patients must be willing to undergo biopsies and

submit tissue and blood for the translational medicine

objectives.

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

receive combination therapy ipilimumab and

nivolumab versus single therapy ipilimumab. In other

words, 63 patients will be randomized to receive the

combination regimen and 21 will be randomized to

receive the single agent regimen. Assuming an

ineligibility rate of 10% the total accrual goal is 94

patients to achieve 84 eligible patients.


registered. Two patients are currently ineligible: one

due to not having received prior anti-PD-1 or anti-

PD-L1 therapy, the other due to not having

documented progression while on anti-PD-1 or anti-

PD-LI therapy.

On the combination arm, 31 patients have been

assessed for adverse events. One patient has

experienced treatment-related Grade 4 adverse

events, lymphopenia and hypokalemia. On the single

agent arm, 11 patients have been assessed for adverse

events. No treatment-related adverse events greater

than Grade 3 have been reported on this arm.


S1616/II



Institutions

Total

Reg Institutions

Total

Reg

Los Angeles, U of CA 5 Eisenhower Med Ctr/San Diego, U of CA 1

Northwestern Univ 5 Kaiser Perm NCORP 1

Tennessee, U of 5 Kansas, U of 1

CRC West MI NCORP 3 Rochester, Univ of 1

Ohio State Univ 3 NRG 8

H Lee Moffitt CC 2 ALLIANCE 4

New Mexico MU-NCORP 2 ECOG-ACRIN 3

Dayton NCORP 1 Total (15 Institutions) 45



TOTAL Ipilimumab

Nivolumab +

Ipilimumab


INELIGIBLE 2 1 1

ELIGIBLE 43 11 32


RESPONSE ASSESSMENT

Determinable 34 9 25

Too Early 9 2 7


Evaluable 42 11 31

Too Early 1 0 1


S1616/II



Ipilimumab

(n=11)

Nivolumab +

Ipilimumab

(n=32)

AGE

Median 61.7 63.0

Minimum 50.7 34.4

Maximum 75.2 86.9

SEX

Males 7 64% 20 63%

Females 4 36% 12 38%

HISPANIC

Yes 2 18% 0 0%

No 8 73% 30 94%

Unknown 1 9% 2 6%

RACE

White 11 100% 27 84%

Asian 0 0% 3 9%

Unknown 0 0% 2 6%

PERFORMANCE STATUS

0 8 73% 18 56%

1 2 18% 9 28%

2 0 0% 3 9%


Treatment Summary


TOTAL




31






LOST TO FOLLOW-UP 0



0


S1616/II



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


Ipilimumab

(n=11)

Grade

Nivolumab + Ipilimumab

(n=31)

Grade

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

ALT increased 10 1 0 0 0 0 21 5 3 2 0 0

AST increased 10 1 0 0 0 0 20 8 1 2 0 0

Abdominal pain 10 0 1 0 0 0 28 2 1 0 0 0

Adrenal insufficiency 10 0 1 0 0 0 30 0 0 1 0 0

Alkaline phosphatase increased 10 1 0 0 0 0 27 3 0 1 0 0

Anemia 11 0 0 0 0 0 27 2 0 2 0 0

Anorexia 10 1 0 0 0 0 25 1 4 1 0 0

Arthralgia 8 3 0 0 0 0 27 3 0 1 0 0

Autoimmune disorder 9 0 2 0 0 0 31 0 0 0 0 0

Back pain 11 0 0 0 0 0 30 0 1 0 0 0

Bloating 11 0 0 0 0 0 30 0 1 0 0 0

Blurred vision 10 1 0 0 0 0 30 0 1 0 0 0

Colitis 11 0 0 0 0 0 29 1 0 1 0 0

Creatinine increased 11 0 0 0 0 0 30 0 1 0 0 0

Dehydration 11 0 0 0 0 0 29 0 1 1 0 0

Diarrhea 9 2 0 0 0 0 20 4 3 4 0 0

Dyspnea 11 0 0 0 0 0 29 1 1 0 0 0

Endocrine disorders-Other 11 0 0 0 0 0 30 0 0 1 0 0

Enterocolitis 11 0 0 0 0 0 30 0 0 1 0 0

Fatigue 4 4 3 0 0 0 20 4 6 1 0 0

Fever 10 1 0 0 0 0 27 3 0 1 0 0

GERD 10 0 1 0 0 0 31 0 0 0 0 0

GI disorders-Other, specify 11 0 0 0 0 0 29 1 1 0 0 0

Generalized muscle weakness 10 0 1 0 0 0 30 0 1 0 0 0

Genital edema 11 0 0 0 0 0 30 0 1 0 0 0

Headache 10 0 1 0 0 0 27 3 1 0 0 0

Hyperglycemia 10 1 0 0 0 0 27 3 1 0 0 0

Hypertension 11 0 0 0 0 0 30 0 1 0 0 0

Hyperthyroidism 11 0 0 0 0 0 29 1 1 0 0 0

Hypocalcemia 11 0 0 0 0 0 30 0 0 1 0 0

Hypokalemia 11 0 0 0 0 0 28 1 0 1 1 0

Hyponatremia 11 0 0 0 0 0 26 3 0 2 0 0

Hypotension 11 0 0 0 0 0 29 0 1 1 0 0

Hypothyroidism 10 0 1 0 0 0 30 1 0 0 0 0

Laryngeal edema 11 0 0 0 0 0 30 0 1 0 0 0

Lung infection 11 0 0 0 0 0 30 0 0 1 0 0

Lymphocyte count decreased 10 1 0 0 0 0 27 1 2 0 1 0

MS/connective tissue disorder 11 0 0 0 0 0 30 0 1 0 0 0

Metab/nutrition disorders-Oth 11 0 0 0 0 0 30 0 1 0 0 0

Mucositis oral 11 0 0 0 0 0 27 2 2 0 0 0

Myalgia 11 0 0 0 0 0 29 1 1 0 0 0

Nausea 7 4 0 0 0 0 28 1 1 1 0 0

Neck pain 11 0 0 0 0 0 30 0 1 0 0 0

Neuralgia 11 0 0 0 0 0 30 0 1 0 0 0


S1616/II

Ipilimumab

(n=11)

Grade

Nivolumab + Ipilimumab

(n=31)

Grade

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

Pain in extremity 11 0 0 0 0 0 27 3 1 0 0 0

Pruritus 9 2 0 0 0 0 19 7 4 1 0 0

Rash acneiform 10 1 0 0 0 0 29 1 1 0 0 0

Rash maculo-papular 8 2 0 1 0 0 18 8 4 1 0 0

Skin ulceration 11 0 0 0 0 0 30 0 1 0 0 0

Skin/subq tissue ds-Other 11 0 0 0 0 0 29 1 1 0 0 0

Syncope 11 0 0 0 0 0 30 0 0 1 0 0

Urinary incontinence 11 0 0 0 0 0 30 0 1 0 0 0

Uveitis 11 0 0 0 0 0 30 0 0 1 0 0

Vomiting 10 1 0 0 0 0 29 1 0 1 0 0

Weight loss 10 1 0 0 0 0 28 2 1 0 0 0


EVENT

1 6 3 1 0 0 4 3 9 14 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 (ECOG-ACRIN)

Statisticians:

M Othus, J Moon, L Qian

Data Coordinator:

M Shi

Date Activated:

12/06/2018

SCHEMA

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

with high-risk resectable melanoma randomized to

neoadjuvant MK-3475 (pembrolizumab) with

patients randomized to adjuvant MK-3475

(pembrolizumab).

To assess the frequency and severity of toxicities on

each of the arms.

To compare between arms overall survival (OS),

disease control at 24 weeks, locoregional control in

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

(pembrolizumab) doses received.

On the neoadjuvant arm, to estimate the pathologic

response rate, the RECIST 1.1 response rate

(confirmed CR and PR), and the iRECIST response

rate (confirmed CR and PR), before surgical

resection.

To describe the proportion of patients on each arm

who received the surgery planned at randomization.

Neoadjuvant

MK-3475

(Pembrolizumab)

R

A

N

D

O

M

I

Z

A

T

I

O

N

Adjuvant Arm

Neoadjuvant

Arm

Surgical

Resection

Adjuvant

MK-3475

(Pembrolizumab)

Adjuvant

MK-3475

(Pembrolizumab)

Surgical

Resection

R

E

G

I

S

T

R

A

T

I

O

N

R

E

G

I

S

T

R

A

T

I

O

N


S1801/II

Patient Population Patients must have clinically detectable Stage III or

Stage IV resectable melanoma. Patients with

melanoma of mucosal or acral origin are eligible.

Patients with melanoma of uveal origin or with a

history of brain metastases documented by CT or

MRI within 42 days are not eligible. Patients are

eligible at initial presentation or at the time of the

first detected nodal, satellite/in-transit, distant

metastases, or recurrent disease in prior

lymphadenectomy basin or distant site. Patients with

multiple regional nodal basin involvement are

eligible. Gross or microscopic extracapsular nodal

extension is permitted.

Patients must not have received previous neoadjuvant

treatment for their melanoma. Patients may have

received prior non-immunotherapy adjuvant therapy.

Patients must not have had prior immunotherapy or

vaccine therapies. Patients must not be planning to

receive concomitant other biologic therapy, hormonal

therapy, other chemotherapy, or surgery. Patients

may have received prior radiation therapy, including

after prior surgical resection.

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

Zubrod performance status of 0-2 and have adequate

bone marrow, hepatic, renal, and cardiac function.

Patients must not have a history of non-infectious

pneumonitis that required steroids or current

pneumonitis. Patients must not have an active

infection requiring systemic therapy. Patients must

not have active autoimmune disease that has required

systemic treatment in the past two years, and must

not have received live vaccines within 42 days prior

to randomization. Patients known to be HIV positive

are eligible if they have stable and adequate CD4

counts. Patients must not have known active

Hepatitis B Virus or Hepatitis C Virus infection.

Prior malignancy is allowed providing it does not

require concurrent therapy. Women of childbearing

potential must have a negative pregnancy test within

28 days prior to randomization.

Patients must be offered the opportunity to participate

in specimen banking. Patients randomized to

Neoadjuvant arm must be willing to submit tissue to

determine pathologic response.

Stratification/Descriptive Factors Randomization will be stratified by the following

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

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

disease at randomization: IIIB vs IIIC vs IIID/IV.

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

patients with a goal of 500 eligible patients. A futility

analysis will be performed at 50% of expected

events.


registered, 15 on the adjuvant arm, 14 on the

neoadjuvant arm.

Ten patients have been assessed for adverse events

related to neoadjuvant pembrolizumab. No treatment-

related adverse events greater than Grade 3 have been

reported on this arm.

As of June 30, 2019, 14 patients have been registered

to the surgery step. One patient is currently ineligible

due to having disease progression which rendered the

patient unable to receive the planned surgery. There

are no adverse event data to report at this time. Sites

are reminded to submit data on the post-surgical

adverse event assessment in a timely manner. One

patient on the adjuvant arm refused to continue on the

clinical trial after receiving surgery. Another patient

was removed from protocol therapy after a post-

surgical disease assessment revealed evidence of

distant metastases.

As of June 30, 2019, three patients have enrolled for

adjuvant therapy following surgery, including one

patient on the neoadjuvant arm. One patient is

currently ineligible due to disease progression

following surgery. No adverse events have been

reported.


S1801/II


Adjuvant Arm Neoadjuvant Pembrolizumab

0

10

20


Feb2019

Mar2019

Apr2019

May2019

Jun2019

22

6

1

42

6

6


Randomization


Institutions

Total

Reg Institutions

Total

Reg

CRC West MI NCORP 4 Montana NCORP 1

Kaiser Perm NCORP 3 So Calif, U of 1

Northwestern Univ 3 Utah, U of 1

Wisconsin NCORP 3 ALLIANCE 3

Arizona CC, Univ of 2 ECOG-ACRIN 3

Heartland NCORP 2 NRG 1

Harrington CC 1 Total (14 Institutions) 29

Michigan CRC NCORP 1


S1801/II


Randomization


TOTAL Adjuvant Arm

Neoadjuvant

Pembrolizumab


ELIGIBLE 29 15 14


RESPONSE ASSESSMENT

Determinable 1 0 1

Too Early 13 0 13



Evaluable 10 0 10

Too Early 4 0 4



S1801/II



Adjuvant Arm

(n=15)

Neoadjuvant

Pembrolizumab

(n=14)

AGE

Median 61.9 60.6

Minimum 30.5 25.6

Maximum 88.6 84.5

SEX

Males 11 73% 7 50%

Females 4 27% 7 50%

HISPANIC

Yes 1 7% 1 7%

No 14 93% 10 71%

Unknown 0 0% 3 21%

RACE

White 14 93% 13 93%

Asian 1 7% 0 0%

Unknown 0 0% 1 7%

LDH

Low/Normal 12 80% 12 86%

High 3 20% 2 14%

STAGE

IIIB 5 33% 6 43%

IIIC 7 47% 6 43%

IIID/IV 3 20% 2 14%


S1801/II


Randomization



Neoadjuvant Pembrolizumab

(n=10)

Grade

ADVERSE EVENTS 0 1 2 3 4 5

ALT increased 7 1 2 0 0 0

AST increased 8 1 1 0 0 0

Abdominal pain 9 1 0 0 0 0

Arthralgia 8 1 1 0 0 0

CPK increased 9 0 1 0 0 0

Colitis 9 0 1 0 0 0

Creatinine increased 9 1 0 0 0 0

Diarrhea 9 0 0 1 0 0

Fatigue 5 3 2 0 0 0

Generalized muscle weakness 9 0 1 0 0 0

Hyperglycemia 9 0 0 1 0 0

Mucositis oral 9 1 0 0 0 0

Myalgia 9 0 1 0 0 0

Myositis 9 0 1 0 0 0

Nausea 8 2 0 0 0 0

Pruritus 9 1 0 0 0 0

Rash maculo-papular 9 1 0 0 0 0

Vomiting 9 1 0 0 0 0


EVENT

3 4 2 1 0 0


S1801/II


Classified by Randomization Arm

Surgery


TOTAL Adjuvant Arm

Neoadjuvant

Pembrolizumab


INELIGIBLE 1 0 1

ELIGIBLE 13 12 1


RESPONSE ASSESSMENT



Too Early 13 12 1

ECOG-ACRIN Cancer Research Group EA6174 Study Progress and Safety Report Spring 2019

Page 1

EA6174 A PHASE III RANDOMIZED TRIAL COMPARING ADJUVANT PEMBROLIZUMAB TO STANDARD OF CARE OBSERVATION IN COMPLETELY RESECTED MERKEL CELL CARCINOMA

Sponsor(s) Coordinating Group ECOG-ACRIN Chairperson(s) Dr. Brian Gastman Statistician Dr. Sandra Lee Data Specialist Matthew Talbot Phase of Study III Type of Study Therapeutic Committee Accrual Objective

Melanoma 500 Patients

Participating Groups ECOG-ACRIN, ECOG-ACRIN, SWOG, ALLIANCE, NRG

NSC# 776864 Clinicaltrials.gov Study ID NCT03712605 Study Status Open to Accrual Date Activated October 1, 2018 Schema


Page 2

Purpose of Study Primary Objective: To compare OS and RFS as co-primary endpoints within the two arms Secondary Objectives: To evaluate adverse events, evaluate distant metastasis free survival (DMFS), evaluate the impact of radiation on clinical outcomes (OS, RFS, DMFS). Study Population Patients with Merkel cell carcinoma with pathologic stages (AJCC version 8) I-IIIb. Interim analysis for OS will begin when OS endpoint reaches approximately 50% information time. For the OS endpoint, it is expected to have 4 interim analyses (at information times of .50, .65, .78, and .88) and a final analysis. Full information for OS corresponds to 112 deaths. For the efficacy analysis, critical values for interim analyses will be determined using the O’Brien-Fleming boundary to preserve the overall one-sided type I error rate of 0.020. For the futility analysis, conditional power and hazard ratio for OS will be computed at each interim analysis. If the conditional power is less than 10% and estimated hazard ratio is greater than 0.89, the OS analysis will be considered in favor of the null hypothesis. The hazard ratio of 0.89 is based on 20% of the alternative effect size, i.e. exp(log(0.56)X.2)).

Summary of Study Design The co-primary endpoint will be RFS and OS. RFS is defined as the time from randomization until disease recurrence of death from any cause. OS is defined as the time from randomization until death. Since moderate percentage of ling-term cures have been observed in this patient population, we used a model proposed by Berkson and Gage (1952) and Goldman (1984). This model specifies that the target population is a mixture, with proportion p who will be cured, and (1 – p) who will fail according to an exponential distribution with rate β. The OS or RFS function D(t) for the arm with pembrolizumab (A) and without pembrolizumab (B) is expressed as:

DB(t) = p + (1 - p) exp(- β t) DA(t) = {p + (1 - p) exp(- β t)}ө

where ө represents a hazard ratio under the proportional hazards alternative.

Based on the Merkelcell.org OS data for Merkel cell patients stage I- IIIB, the estimated cure rate is 62% and median OS for those not cured is 1.8 years. This corresponds to 1-yr, 2-yr, 3-yr, 4-yr, 5-yr, 6-yr, 7-yr, and 8-yr OS rates of .88, .80, .74, .70, .68, .66, .65 and .64, respectively in the control arm. For RFS, the estimated cure rate is 56% and median RFS for those not cured is 1 year. This corresponds to 1-yr, 2-yr, 3-yr, 4-yr, 5-yr, 6-yr, 7-yr, and 8-yr RFS rates of .78, .67, .62, .59, .57, .57, .56 and .56, respectively in the control arm. An ITT analysis using the stratified log-rank test will be performed to compare OS and RFS between the two arms.

Accrual of 500 patients will take approximately 2 years and additional follow up time will be 2.5 years. Thus, total study duration will be in the range of 4.5 years. Accrual rate of 250 patients/year is based on a survey conducted at ECOG-ACRIN and SWOG institutes.

Under the proportional hazards alternative, we hypothesize that pembrolizumab will reduce the hazard for death by 44% (hazard ratio ө =0.56). The full information is 112 deaths for the OS endpoint. This design provides approximately 80% power with one-sided type I error rate of 0.020 for the OS endpoint. Under the proportional hazards alternative, we hypothesize that pembrolizumab will reduce the hazard for relapse by 44% (hazard ratio ө =0.56). The full information is 154 events for RFS endpoint. This design provides approximately 80% power with one-sided type I error rate of 0.005 for the RFS endpoint. An


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ITT analysis using the stratified log-rank test will be performed. For the co-primary endpoint of OS and RFS, overall one-sided type I error rate of 0.025 was divided such that the full information for OS is reached at 4.5 years and for RFS is reached at year 4.3. The study will be considered positive if the either endpoint demonstrates significant effects of pembrolizumab.

Interim analysis for OS will begin when the OS endpoint reaches approximately 50% information time. For the OS endpoint, it is expected to have 4 interim analyses (at information times of .50, .65, .78, and .88) and a final analysis. Full information for OS corresponds to 112 deaths. For the efficacy analysis, critical values for interim analyses will be determined using the O’Brien-Fleming boundary to preserve the overall one-sided type I error rate of 0.020. For the futility analysis, conditional power and hazard ratio for OS will be computed at each interim analysis. If the conditional power is less than 10% and estimated hazard ratio is greater than 0.89, the OS analysis will be considered in favor of the null hypothesis. The hazard ratio of 0.89 is based on 20% of the alternative effect size, i.e. exp(log(0.56)X.2)).

For the RFS endpoint, the first interim analysis will begin when accrual is closed and all patients are off randomized treatment. It is expected to occur at year 3.3. Subsequently interim analyses will be repeated every 6 months. It is expected to have 2 interim analyses (at information time of .87 and .95) and a final analysis. Full information for RFS corresponds to 154 RFS events. For the efficacy analysis, O’Brien and Fleming boundary will be used with an overall one-sided type I error rate of 0.005. For the futility analysis, conditional power and hazard ratio for RFS will be computed at each interim analysis. If the conditional power is less than 10% and estimated hazard ratio is greater than .89, then, the RFS analysis will be considered in favor of the null hypothesis. Progress to Date This study was activated on October 1, 2018. As of February 7, 2019, three patients have enrolled. Table 1a summarizes accrual by institution and Table 1b has accrual by group. Patient status as of February 7, 2019 is displayed in Table 2. Demographics of patients by treatment arm are summarized in Table 3.

Table 1a. Accrual by ECOG-ACRIN Institution

Institution Name Step 1 Georgia NCORP 1 Heartland Cancer Research NCORP 1 Total 2

Table 1b. Accrual by Group

ECOG-ACRIN 2 ALLIANCE 1 Total 3

Table 2. Patient Status as of February 7, 2019

Cases Entered 3 Ineligible 0 Never Started Assigned Therapy 0


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Table 3. Demographics

Variable Level Arm A

(n=1) Arm B

(n=2) Total (n=3)

Sex Male 1 (100.0) 1 (50.0) 2 (66.7) Female 0 (0.0) 1 (50.0) 1 (33.3)

Race White 1 (100.0) 2 (100.0) 3 (100.0) Ethnicity Non-Hispanic 1 (100.0) 2 (100.0) 3 (100.0) Age Median 55 65 57

Minimum 55 57 55 Maximum 55 73 73


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EA6134 DREAMSEQ (DOUBLET, RANDOMIZED EVALUATION IN ADVANCED MELANOMA SEQUENCING) A PHASE III TRIAL

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


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Purpose of Study The primary objective is to evaluate whether initial treatment with either combination ipilimumab-nivolumab (with subsequent dabrafenib in combination with trametinib) or dabrafenib in combination with trametinib (with subsequent ipilimumab-nivolumab) significantly improves 2 year overall survival (OS). Progression-free survival (PFS), response and adverse events (AE) data will also be evaluated. Study Population Patients with metastatic or progressive unresectable melanoma and BRAF mutation, less than 2 prior treatments for advanced disease and no prior treatment with a BRAF or MEK inhibitor or a CTLA4 or PD1 pathway blocker. Summary of Study Design In this randomized phase III study, patients with unresectable stage III or stage IV BRAFV600 mutant melanoma will be equally randomized to A: ipilimumab-nivolumab (with subsequent dabrafenib in combination with trametinib) or B: dabrafenib in combination with trametinib (with subsequent ipilimumab-nivolumab) using the stratification factors (ECOG PS, Serum LDH). The primary objective is to evaluate whether initial treatment with either combination ipilimumab-nivolumab (with subsequent dabrafenib in combination with trametinib) or dabrafenib in combination with trametinib (with subsequent ipilimumab-nivolumab) significantly improves 2 year overall survival. The primary endpoint for this study is the 2-year overall survival (OS) rate. Since the proportional hazard assumption is not appropriate for the proposed treatment arms, the most meaningful endpoint is the 2-year OS rate. The sample size calculation was conducted using the 2-year OS as a binary data. The primary analysis will be an ITT analysis based on the 2-year OS rate, using the Mantel-Haenszel test. The number of cases censored before two years is expected to be minimal in this study. The sample size for 2-year OS rate of 70% in arm A vs. 50% in arm will be 270 for 90% power. This is based on the two-sided type I error rate of 0.05 and allows for three interim analyses. An additional 10% (30 patients) have been added to cover for potential ineligibility or patient loss at the crossover time point. Assuming accrual rate of 16/month, accrual is estimated to take a maximum of 19 months. In addition, the follow-up time will be 2 years to assess the 2-year OS rate endpoint. Note that a clinically meaningful difference in 2-year OS rate is 70% vs. 50%. This assumption was used for the above power calculation of 90%. Formal interim analysis based on the difference of 2-year OS rate between the two arms will be conducted, starting at 33% information time (that is when first 100 patients enrolled are followed for 2 years). We expect this will be around 30 months after the study activates. After that, interim analysis will be repeated every 6 months. It is expected to at 64% and 100% information time. To preserve the overall type I error rate, critical values at the interim analyses will be determined using a truncated version of the Lan-DeMets spending function corresponding to the O'Brien-Fleming boundary. At each interim analysis, the difference in 2-year OS rates in arms A and B will be estimated. The repeated confidence interval (RCI) of Jennison-Turnbull will be provided. Strata will be taken into account for the RCI monitoring. As secondary clinical objectives, PFS, clinical response, toxicity profiles will be evaluated. This study also has extensive laboratory objectives and patient reported outcome objectives as outlined under the purpose of this study. For the laboratory correlatives, (i) the association of inherited variation with immune mediated adverse events (irAE) and response to ipilimumab + nivolumab will be evaluated and (ii) the utility of circulating BRAF levels in determining the response and resistance to either BRAF/MEK directed and/or combination immunotherapy will be evaluated.


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For the patient reported outcomes (PROs), the primary objective is to evaluate the overall clinical benefit between initial treatments (i.e., arm A: ipilimumab + nivolumab (with subsequent dabrafenib + trametinib). vs. arm B: dabrafenib + trametinib (with subsequent ipilimumab + nivolumab)), accounting for toxicities and overall survival. The quality-adjusted time without symptoms of disease progression or toxicity of treatment (Q-TWiST) analysis will be used to provide an integrated measure of quality and quantity of survival time. The Q-TWiST score based on overall survival at 2 years will be computed and compared. In addition, the differences in overall function over 2 years between initial treatment with dabrafenib + trametinib vs. ipilimumab + nivolumab will be assessed. Lastly, the effects of treatment crossover and treatment administration sequence on symptom burden and overall function will be evaluated. Progress to Date This study was activated on July 13, 2015 (Step 1 and Step 2). The study was suspended due to acute shortage in the supply of Dabrafenib and Trametinib capsules between February 2, 2016, and April 11, 2016. As of February 7, 2019, 170 patients enrolled to step 1, and 38 to step 2. Table 1a summarizes accrual by institution. Table 1b has accrual by group, and Table 1c shows projected accrual status as of February 7, 2019. Expected cumulative accrual and actual cumulative accrual are shown in Figure 1. This report is based on the data as of February 7, 2019. Patient status is displayed in Table 2 with patients accrued at that time. Demographics of patients by treatment arm are summarized in Table 3 for Steps 1 and 2. Record status on clinical report form is summarized in Table 4. The distribution of the reasons for treatment continuation of protocol treatment is summarized in Table 5. As of February 7, 2019 there were 159 cases (81 in arm A, 78 in arm B in step 1) and 33 cases (14 in arm C and 19 in arm D in step 2) who reported treatment-related toxicities. Toxicity data is summarized in Table 6. Table 7 displays one case with treatment-related adverse events reported on ECOG-ACRIN CRFs. Based on CTEP-AERS reporting system, there were 11 cases with lethal adverse events: 46007 (arm A) respiratory failure, 46021 (arm A) neoplasms, 46028 (arm A) general disorder, 46052 (arm A) thromboembolic event, 46070 (arm A) nervous system disorder, 46102 (arm A) neoplasms, 46125 (arm A) neoplasms, 46003 (arm B) stroke, 46013 (arm B) neoplasms, 46018 (arm B) death NOS and 46012 (arm C) neoplasms. Cases 46003, 46007, 46012, 46018, 46021, 46052, 46102, 46125 have been reviewed using the data collected on ECOG-ACRIN CRFs and only the respiratory failure from case 46007 was considered treatment-related. Table 8 summarizes QOL data received.


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Institution Name Step 1 Step 2 Cancer Research Consortium of West Michigan NCORP 1 0 Cancer Research for the Ozarks NCORP 4 1 Case Western Reserve University 4 0 Catholic Health Initiatives NCORP 2 0 Colorado Cancer Research Program NCORP 1 0 Dayton NCORP 4 2 Emory University/Winship Cancer Institute 1 0 Froedtert and the Medical College of Wisconsin 1 0 Georgia Cares Minority Underserved NCORP 1 0 Georgia NCORP 3 0 Hackensack University Medical Center 2 1 Heartland Cancer Research NCORP 4 0 Indiana Univ/Melvin and Bren Simon Cancer Center 4 1 Johns Hopkins Univ/Sidney Kimmel Cancer Center 3 1 Medical University of South Carolina MU NCORP 1 0 Metro Minnesota Community Oncology Res Consortium 6 2 Michigan Ca Res Consortium NCORP 3 1 Montana Cancer Consortium NCORP 1 0 Nevada Cancer Research Foundation NCORP 3 1 New Mexico MU NCORP 1 0 New York Oncology Hematology PC -Albany Med Center 1 0 NorthShore Univ HealthSystem-Evanston Hospital 1 0 Northwest NCI Community Oncology Research Program 1 1 Northwestern University 5 2 Ohio State University Comprehensive Cancer Center 3 0 Pacific Cancer Research Consortium NCORP 9 1 Saint Luke's University Hospital-Bethlehem Campus 1 0 Sanford NCORP of the North Central Plains 1 0 Stanford Cancer Institute Palo Alto 1 0 University of Alabama at Birmingham Cancer Center 4 1 University of Miami Miller Schl Med-SylvesterCaCtr 3 1 University of Michigan Comprehensive Cancer Center 2 0 University of Pittsburgh Cancer Institute (UPCI) 9 0 University of Wisconsin Hospital and Clinics 2 1 Vanderbilt University/Ingram Cancer Center 4 1 Wichita NCORP 2 0 Wisconsin NCORP 7 1 Total 106 19


Step 1 Step 2 ECOG-ACRIN 106 19 SWOG 32 12 ALLIANCE 9 2 NRG 23 5 Total 170 38


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Table 1c. Projected Accrual

Step 1 Step 2 Accrual goal 300 Planned accrual rate 192/yr Accrual to date 170 38 Annual accrual rate Overall 50/yr 11/yr Last 6 months 40/yr 20/yr

Projected date of closure May 2022


Step 1 Step 2 Cases Entered 170 38 Ineligible 1 0 Never Started Assigned Therapy 0 0

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


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Table 3. Demographics Step 1

Variable Level Arm A (n=88)

Arm B (n=82)

Total (n=170)

Sex Male 49 (55.7) 53 (64.6) 102 (60.0) Female 39 (44.3) 29 (35.4) 68 (40.0)

Race White 85 (98.8) 79 (98.8) 164 (98.8) Asian 1 (1.2) 1 (1.3) 2 (1.2) Unknown/Unreported 2 2 4

Ethnicity Hispanic 1 (1.2) 5 (6.3) 6 (3.6) Non-Hispanic 85 (98.8) 74 (93.7) 159 (96.4) Unknown/Missing 2 3 5

Age Median 59 57 59 Minimum 30 26 26 Maximum 81 84 84

Step 2

Variable Level Arm C (n=17)

Arm D (n=21)

Total (n=38)

Sex Male 10 (58.8) 12 (57.1) 22 (57.9) Female 7 (41.2) 9 (42.9) 16 (42.1)

Race White 16 (100.0) 21 (100.0) 37 (100.0) Unknown/Unreported 1 0 1

Ethnicity Non-Hispanic 16 (100.0) 19 (100.0) 35 (100.0) Unknown/Missing 1 2 3


Table 4. Record Status

Form Name Forms

Due Forms

Received % Demography 167 167 100.0 Patient Characteristics 202 202 100.0 Treatment Agent: Dabrafenib 618 610 98.7 Treatment Agent: Ipilimumab - Induction 171 171 100.0 Treatment Agent: Nivolumab - Induction 172 172 100.0 Treatment Agent: Nivolumab - Maintenance 253 253 100.0 Treatment Agent: Trametinib 618 610 98.7 Adverse Event Form 1043 1024 98.2 Hematology/Chemistry 202 202 100.0 Late Adverse Event Form 6 6 100.0 Other Adverse Event Form 820 820 100.0 Disease Follow-Up Status Form (RECIST 1.1) 1219 1208 99.1 Off Treatment 20 20 100.0 Off-Treatment with Intent to Reg Next Step 114 114 100.0


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Table 5. Reasons Off Treatment

Step 1

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

for whom off-treatment data have been received)

Reasons N % Adverse event/side effects/complications 30 38.5 Death on study 6 7.7 Disease progression- relapse during active treatment 24 30.8 Other 5 6.4 Patient off-treatment for other complicating disease 1 1.3 Patient withdrawal/refusal after beginning protocol therapy 4 5.1 Treatment completed per protocol criteria 8 10.3 Total off treatment 78 100.0

Step 2 (Includes all patients who started treatment and

for whom off-treatment data have been received)

Reasons N % Adverse event/side effects/complications 2 10.0 Death on study 1 5.0 Disease progression- relapse during active treatment 14 70.0 Other 1 5.0 Treatment completed per protocol criteria 2 10.0 Total off treatment 20 100.0


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Table 6. Toxicity Incidence

Step 1

Toxicity Type

Treatment Arm A (n=81) B (n=78)

Grade Grade 3 4 5 3 4 5

(%) (%) (%) (%) (%) (%) Anemia 1 - - 3 - - Disseminated intravascular coagulation - 1 - - - - Febrile neutropenia - - - 3 - - Leukocytosis 2 - - - - - Cardiac disorders - Other, specify - 1 - - - - Myocarditis 1 - - - - - Adrenal insufficiency 1 - - - - - Endocrine disorders - Other, specify 2 1 - - - - Retinal detachment - - - 1 - - Abdominal pain 2 - - - - - Colitis 5 - - - - - Diarrhea 22 1 - 1 - - Enterocolitis 1 - - - - - Gastrointestinal disorders - Other, specify 1 - - - - - Ileus 1 - - - - - Nausea 10 - - - - - Pancreatitis 1 - - - - - Vomiting 6 - - 1 - - Fatigue 7 - - 8 - - Fever - - - 8 - - Flu like symptoms 1 - - - - - Pain - - - 1 - - Edema limbs 1 - - - - - Infusion related reaction 1 - - - - - Hepatic failure 1 - - - - - Cytokine release syndrome 1 - - - - - Autoimmune disorder 2 - - - - - Infections and infestations - Other, specify - - - 1 - - Meningitis 1 - - - - - Sepsis - 1 - - 1 - Urinary tract infection 2 - - - - - Enterocolitis infectious 2 - - - - - Lung infection 1 - - - - - Gallbladder infection - - - 1 - - Fall 1 - - - - - Alanine aminotransferase increased 5 2 - - - - Aspartate aminotransferase increased 6 1 - - - - Blood bilirubin increased 1 2 - - - - Creatinine increased 4 - - 1 - - Lipase increased 6 9 - 5 3 - Lymphocyte count decreased - - - 3 - - Neutrophil count decreased - - - 3 - - Serum amylase increased 5 1 - - 1 -


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Toxicity Type



(%) (%) (%) (%) (%) (%) Ejection fraction decreased - - - 5 - - Anorexia 4 - - - - - Dehydration 6 - - 1 - - Hypercalcemia 1 - - - - - Hyperglycemia 4 1 - - - - Hypoalbuminemia 5 - - - - - Hypokalemia 2 - - 1 - - Hyponatremia 5 - - 5 1 - Hypophosphatemia 1 - - - - - Arthralgia 6 - - 1 - - Back pain 1 - - - - - Musculoskeletal and connective tissue disorder - Other, specify 1 - - - - - Myalgia 1 - - - - - Myositis 2 - - - - - Pain in extremity - - - 1 - - Generalized muscle weakness 2 - - - - - Treatment related secondary malignancy - - - 1 - - Headache 4 - - - - - Hypersomnia 1 - - - - - Peripheral sensory neuropathy 1 - - - - - Syncope - - - 4 - - Tremor 1 - - - - - Proteinuria 1 - - - - - Acute kidney injury 2 - - - - - Adult respiratory distress syndrome - 1 - - - - Hypoxia 1 - - - - - Pneumonitis 1 - - - - - Respiratory failure - - 1 - - - Rash acneiform - - - 1 - - Rash maculo-papular 9 - - 5 - - Hypertension 2 - - 1 - - Hypotension 2 - - 1 - - Thromboembolic event - - - 1 - - WORST DEGREE 51 16 1 46 6 -


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Step 2

Toxicity Type Treatment Arm

C (n=14) D (n=19)


(%) (%) (%) (%) (%) (%) Anemia - - - 5 - - Adrenal insufficiency - - - 5 - - Endocrine disorders - Other, specify - - - 5 - - Diarrhea 7 - - - - - Nausea 7 - - - - - Pancreatitis - - - 5 - - Fatigue 7 - - 11 - - Fever 7 - - 5 - - Infections and infestations - Other, specify - - - 5 - - Alanine aminotransferase increased - - - 5 - - Aspartate aminotransferase increased - - - 5 - - Lipase increased - - - 5 5 - Lymphocyte count decreased - - - 5 - - Serum amylase increased - - - 5 - - Dehydration - - - 5 - - Hypernatremia 7 - - - - - Hyponatremia 7 - - 5 - - Nervous system disorders - Other, specify - - - 5 - - Syncope 7 - - - - - Pneumonitis - - - 5 - - Pruritus - - - 5 - - Rash maculo-papular 14 - - - - - Hypotension - - - 5 - - WORST DEGREE 29 - - 47 5 -

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

Case Arm Description of Event 46007 A Respiratory failure


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

Site Arm A

Thyroid 1

Table 9. QOL Table

QOL Timepoint

Patients Reaching

Timepoint % Forms

Completed Baseline Step 1 166 84.3 End of Cycle 1 in Step 1 - Arm A 80 52.5 End of Cycle 1 in Step 1 - Arm B 78 89.7 End of Cycle 2 in Step 1 - Arm A 77 36.4 End of Cycle 2 in Step 1 - Arm B 76 68.4 Disease stability or 6 Mos. Step 1-Arm A 71 21.1 Disease stability or 6 Mos. Step 1-Arm B 71 36.6 End of Step 1 Treatment 57 100.0 Baseline Step 2 36 72.2 End of Cycle 1 in Step 2 - Arm C 15 66.7 End of Cycle 1 in Step 2 - Arm D 17 64.7 End of Cycle 2 in Step 2 - Arm C 15 73.3 End of Cycle 2 in Step 2 - Arm D 15 40.0 Disease stability or 6 Mos. Step 2-Arm C 13 53.8 Disease stability or 6 Mos. Step 2-Arm D 14 35.7 End of Step 2 Treatment 11 100.0 12 Mos. from study entry - Arm A 56 23.2 12 Mos. from study entry - Arm B 55 0.0 18 Mos. from study entry - Arm A 40 20.0 18 Mos. from study entry - Arm B 38 5.3


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

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


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


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semi-annual DSMC meetings beginning when approximately 50% of the planned full information (133 deaths among all patients) has occurred, continuing until either criteria for early stopping are met or full information is reached. To preserve the overall type I error rate, critical values at the interim analyses will be determined using the Lan-DeMets spending function corresponding to the O'Brien-Fleming boundary. Under the accrual rate, follow up time, and failure rate assumptions above, interim analyses would be expected to occur at 0.25, 0.75, 1.3, 1.8, 2.3, 2.8 years after phase III accrual begins, at information times of 50%, 63%, 75%, 86%, 95%, and 100%. It will take approximately 2 years of additional follow up time after the last patient is randomized in phase III part. This study will also be monitored for early stopping for inefficacy. The approach of this monitoring will be based on the method proposed by Freidlin et al. (2010). Inefficacy monitoring will start around 50% information time. The study will be stopped if there is not at least a small trend in favor of the alternative hypothesis starting at this time. Specifically, an inefficacy monitoring boundary will begin at this time at a hazard ratio greater than 1 and will gradually increase to 20% of the targeted benefit at full information, subject to the requirement that two-sided 95% confidence interval for the log hazard ratio does not contain the design-alternative log hazard ratio of 0.67. The immune response will be assessed using the utility of Immune related response criteria (irRC). Standard response criteria (based on the RECIST) will be applied to assess clinical response. Immune response rate and clinical response rate will be compared between the two treatment arms. Progress to Date This study was activated on September 10, 2015 and suspended on June 23, 2017 as it reached the first stage accrual goal. As of June 23, 2017, 250 patients have enrolled. Table 1a summarizes accrual by institution. Table 1b has accrual by group and Table 1c shows projected accrual status as of June 23, 2017. Patient status as of February 7, 2019 is displayed in Table 2. Demographics of patients by treatment arm are summarized in Table 3. Record status as on clinical report form is summarized in Table 4. The distribution of the reasons for treatment discontinuation is summarized in Table 5. Toxicity data were reported for 124 cases in arm A and 120 cases in arm B as of February 7, 2019. Treatment-related toxicities are summarized in Table 6. The worst-degree grade 3 or higher toxicity rate was 56% in arm A and 69% in arm B. There were 4 grade 5 AEs in arm A and 1 in arm B. These cases with at least possibly treatment related grade 5 AEs are listed in Table 7. There are 12 grade 5 AEs reported via CTEP-AERS system. They include: case 16010 (arm A) Dyspnea, 16011 (arm A) neoplasms progression, 16058 (arm A) GI disorder, 16064 (arm A) respiratory failure, 16078 (arm A) deaths NOS, 16121 (arm A) aspiration, 16216 (arm B) Neoplasm, 16196 (arm A) cardiac disorder, 16232 (arm B) multiorgan failure, 16233 (arm A) Deaths NOS, 16242 (arm A), 16245 (arm A) deaths NOS. Of these, cases 16010, 16064, 16121, 16196, 16126, 16233 were reviewed at ECOG-ACRIN and considered as not treatment-related. Secondary primary tumor is listed in Table 8.


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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 4 Never Started Assigned Therapy 3

Reason for ineligibility (n=4): High Bilirubin (16226); No measurable disease (16242, 16062); Use of Immunosuppressant (16710). Reason for not starting therapy (n=3): Withdrawal/refusal before beginning protocol therapy (16014); Death before therapy (16143); Ineligible (16170).

Table 3. Demographics

Variable Level Arm A

(n=126) Arm B

(n=124) Total

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

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

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

Ethnicity Hispanic 3 (2.6) 3 (2.6) 6 (2.6) Non-Hispanic 111 (97.4) 113 (97.4) 224 (97.4) Unknown/Missing 12 8 20



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Table 4. Record Status - Phase II

Form Name Forms

Due Forms

Received % Demography 250 250 100.0 Patient Characteristics 250 249 99.6 Treatment Agent: Ipilimumab 810 810 100.0 Treatment Agent: Nivolumab 2722 2721 100.0 Treatment Agent: Sargramostim 1677 1675 99.9 Adverse Events 2902 2902 100.0 Hematology/Chemistry 250 248 99.2 Late Adverse Events 15 15 100.0 Disease Follow-Up Status Form 2 2 100.0 Disease Follow-Up Status Form (RECIST 1.1) 3238 3232 99.8 Off Treatment 210 210 100.0

Table 5. Reasons Off Treatment - Phase II

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

Reasons N %

Adverse event/side effects/complications 100 46.7 Alternative therapy 5 2.3 Death on study 7 3.3 Disease progression- relapse during active treatment 51 23.8 Other 17 7.9 Patient off-treatment for other complicating disease 3 1.4 Patient withdrawal/refusal after beginning protocol therapy 13 6.1 Treatment completed per protocol criteria 18 8.4 Total off treatment 214 100.0


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Table 6. Toxicity Incidence - Phase II

Step 1

Toxicity Type



(%) (%) (%) (%) (%) (%) Anemia 1 - - 2 - - Blood and lymphatic system disorders - Other, specify 1 - - 1 - - Leukocytosis 1 - - - - - Atrioventricular block complete 1 - - - - - Myocarditis 1 - - - - - Hearing impaired 1 - - - 1 - Adrenal insufficiency 4 - - 3 - - Endocrine disorders - Other, specify 5 - - 3 - - Hyperthyroidism 1 - - - - - Hypothyroidism 1 - - - - - Uveitis 1 - - - - - Abdominal pain 2 - - 2 - - Colitis 2 - - 10 - - Constipation 1 - - - - - Dental caries 1 - - - - - Diarrhea 6 2 1 15 - - Duodenal ulcer 1 - - - - - Dysphagia - - - 1 - - Enterocolitis 1 - - 1 - - Gastrointestinal disorders - Other, specify 1 - - - - - Mucositis oral - - - 2 - - Nausea 1 - - 3 - - Vomiting 2 - - 2 - - Lower gastrointestinal hemorrhage 1 - - - - - Death NOS - - 1 - - - Fatigue 5 - - 4 - - Fever - - - 1 - - Multi-organ failure - - - - - 1 Pain 1 - - - - - Non-cardiac chest pain 1 - - - - - Hepatobiliary disorders - Other, specify - - - 1 1 - Allergic reaction 1 - - - - - Immune system disorders - Other, specify - - - 3 - - Autoimmune disorder 2 - - 1 - - Infections and infestations - Other, specify 1 - - - - - Skin infection 1 - - - - - Lung infection 1 - - 1 - - Fall 1 - - - - - Alanine aminotransferase increased 10 - - 11 - - Alkaline phosphatase increased 2 - - 2 - - Aspartate aminotransferase increased 4 1 - 10 - - Blood bilirubin increased 1 - - - - - Cardiac troponin I increased - - - 1 - -


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Toxicity Type



(%) (%) (%) (%) (%) (%) CPK increased - - - 1 1 - Creatinine increased - - - 2 - - Investigations - Other, specify - - - 1 - - Lipase increased 8 4 - 11 6 - Lymphocyte count decreased 1 1 - 2 - - Neutrophil count decreased - - - 1 - - Platelet count decreased 1 1 - - - - Serum amylase increased 5 - - 3 1 - Urine output decreased - 1 - - - - Acidosis - - - 1 1 - Anorexia 4 - - - - - Dehydration 2 - - 3 - - Hypercalcemia - - - - 1 - Hyperglycemia 1 1 - 3 3 - Hyperkalemia 1 - - - - - Hyperuricemia - 2 - 1 2 - Hypokalemia - 2 - 2 - - Hyponatremia 2 1 - 4 - - Hypophosphatemia - - - 1 - - Metabolism and nutrition disorders - Other, specify - - - 1 - - Back pain - - - 1 - - Bone pain 1 - - - - - Joint effusion - - - 1 - - Myalgia 1 - - - - - Pain in extremity - - - 1 - - Generalized muscle weakness 4 - - - - - Muscle weakness lower limb 2 - - - - - Muscle weakness right-sided - - - 1 - - Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify - - 1 - - - Dizziness 1 - - - - - Dysphasia - - - 1 - - Headache 3 - - 1 - - Nervous system disorders - Other, specify 1 - - - - - Peripheral motor neuropathy - - - 1 - - Peripheral sensory neuropathy - - - 1 - - Seizure 1 - - 1 - - Syncope 2 - - 1 - - Anxiety - - - 1 - - Confusion - - - 1 - - Renal and urinary disorders - Other, specify 1 - - - - - Chronic kidney disease - 1 - - - - Acute kidney injury - - - 2 - - Aspiration - - 1 - - - Dyspnea 1 - - 5 2 - Hypoxia 1 - - 1 - -


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Toxicity Type



(%) (%) (%) (%) (%) (%) Pneumonitis 2 - - 4 - - Respiratory failure - - - - 1 - Respiratory, thoracic and mediastinal disorders - Other, specify - - - - 1 - Pruritus 2 - - 1 - - Rash maculo-papular 8 - - 9 - - Hypertension - - - 1 - - Hypotension 2 1 - 1 - - Thromboembolic event - - - 1 - - WORST DEGREE 39 14 3 53 15 1

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

Case Arm Description of Event 16058 A Diarrhea 16242 A Aspiration 16245 16078

A A

Neoplasms Death NOS

16232 B Multi-organ failure

Table 8. Second Primary Cancers

Site Arm A Arm B

Breast 1 - Liver, Gall Bladder, Bile Duct 1 -

MELANOMA COMMITTEE - SWOG 2019/Melanoma.pdfT-VEC + MK-3475 (Pembrolizumab) 11 7 1 19 S1616 MELAN, Adv, Ipilimumab ± Nivolumab Randomization Ipilimumab 4 3 4 12 Nivolumab + Ipilimumab

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