MELANOMA COMMITTEE - SWOG 2018/Melanoma.pdf · melanoma. Patients must have BRAF mutation-positive...

OCTOBER 3 - 6, 2018 SWOG MELANOMA 1

MELANOMA COMMITTEE


CONTENTS

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

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

S1404 Phase III ............................................................................................................................................................ 18

S1512 Phase II ............................................................................................................................................................. 28

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

S1609 Phase II ............................................................................................................................................................. 34

S1614 Phase III ............................................................................................................................................................ 36

S1616 Phase II ............................................................................................................................................................. 38

S1801 Phase II ............................................................................................................................................................. 42

EAY131 Master Protocol / Phase II ............................................................................................................................ 44


S1204

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

192 193

89

277

1040

308

0

100

200

300

400

500

600

700

800

900

1000

1100

Time of Registration

Jul 2012Jun 2013

Jul 2013Jun 2014

Jul 2014Jun 2015

Jul 2015Jun 2016

Jul 2016Jun 2017

Jul 2017Jun 2018

108 97

6555

107

141

198

224

477

59

63

150


S1204

Patient Registrations by Study and Arm MELANOMA COMMITTEE

Jan 2018

Jun 2018

Jul 2017

Dec 2017

Jan 2017

Jun 2017

All

Patients

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

Lead In Registration

Lead-in Continuous Dosing 28 31 35 219

Randomization

Continuous Dosing 15 13 12 91

Intermittent Dosing 13 10 12 87

28 23 24 178

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

Tissue Submission

Tissue for PD-L1 testing 0 185 527 1,426

Randomization

FDA approved regimen 0 110 265 678

MK-3475 (Pembrolizumab) 0 102 260 667

0 212 525 1,345

S1512 Adv, Desmoplastic, MK-3475 (Pembrolizumab)

Registration

MK-3475 (Pembrolizumab) 6 4 1 11

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

Registration

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

S1616 Adv, Ipilimumab ± Nivolumab

Randomization

Ipilimumab 4 1 0 5

Nivolumab + Ipilimumab 7 3 0 10

11 4 0 15


S1204

Non-SWOG Studies with SWOG-Credited Registrations MELANOMA COMMITTEE

Studies with Accrual from January 2017 - June 2018

SWOG Accrual

SWOG

Champion

Jan 2018

Jun 2018

Jul 2017

Dec 2017

SWOG

Total

Total

Accrued

E3612 Adv, Ipilimumab ± Bevacizumab 0 1 6 169

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

Most Recent Progress Report

EA6134 Adv, BRAF mut, Dabrafenib + Trametinib/Ipilimumab

+Nivolumab vs Ipilimumab + Nivolumab/Dabrafenib + Trametinib

B Chmielowski 2 8 26 150

Date Activated: 12/15/15


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

Date Activated: 03/01/16



S1204

S1204 Surveillance

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

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

Hepatitis C Virus (HCV) Among Newly Diagnosed Cancer Patients

Study Chairs:

S Ramsey, D Hershman

Statisticians:

J Unger, K Arnold

Data Coordinator:

M Yee

Date Activated:

08/29/2013

Date Closed:

02/15/2017

Objectives Among newly diagnosed cancer patients presenting

to SWOG-affiliated community and academic

oncology clinics, estimate the prevalence of human

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

and hepatitis C (HCV) infection.

Evaluate known sociodemographic, clinical, and

behavioral factors that are significantly associated

with previously undiagnosed HIV, HBV, and/or

HCV infection in a population of people with newly

diagnosed cancer.

Among patients who are identified as having HIV,

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

treatments received (if any), both for the viral

infections and the cancers.

Describe type of adverse events possibly attributable

to the patient's viral status in patients with HIV,

HBV, and/or HCV infection.

Using simulation modeling that is directly informed

by the data obtained from this study, determine the

cost-effectiveness (expressed as cost per infection

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

routine, universal screening and (2) risk factor-

directed screening of newly diagnosed cancer

patients for HIV, HBV and/or HCV versus current

care.

Patient Population Patients must be presenting for evaluation or

treatment for the first diagnosis of a new solid or

hematologic cancer malignancy. Confirmed diagnosis

date must be within 120 days prior to first clinic visit

as a newly diagnosed cancer patient at the registering

clinic. Patients presenting for "second opinions" of

confirmed malignancies are eligible, including those

who have started cancer treatment at other facilities.

Patients must be registered within 90 days after their

first clinic visit. Patients must not have been

diagnosed with a malignancy other than the current

malignancy within the past five years, with the

exception of basal cell or squamous cell skin cancer,

in situ cervical cancer, or in situ breast cancer.

Patients must have no evidence of disease for a prior

malignancy for at least five years prior to

randomization except as noted above.

Patients must be 18 years of age or older. Patients

must have had their blood drawn for viral status

testing for HIV, HBV and HCV or provide

acceptable viral status documentation prior to

registration, as defined in the protocol. Note that

patients must have blood drawn for testing prior to

registration for any of the three viruses not covered

by the documentation. Patients are allowed to

participate in other clinical trials.


S1204

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

3,000 eligible patients.

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

Cancer Care Delivery chapter.


S1320/II

S1320 Phase II

Coordinating Group: SWOG

A Randomized Phase II Trial of Intermittent versus Continuous Dosing of

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

Mutant Melanoma

Participants:

SWOG, CTSU (Supported by ECOG-ACRIN)

Study Chairs:

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

Statisticians:

M Othus, J Moon

Data Coordinator:

J Hayward

Date Activated:

07/22/2014

SCHEMA

Objectives To compare progression-free survival with

intermittent dosing versus continuous dosing of

dabrafenib and trametinib among patients with

metastatic BRAFV600E/K mutant melanoma.

To compare the response rate (complete and partial

response, confirmed and unconfirmed), overall

survival, and survival after progression between the

two dosing schedules.

To compare the frequency and severity of fever

greater than Grade 1 per CTCAE 4.0 of 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 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 must not

have brain metastases unless brain metastases have

been treated and 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 226 eligible patients. An interim

analysis testing for harm will be performed when 78

progression events have occurred.

Summary Statement Accrual to this study has been slower than

anticipated. In an effort to increase accrual, a

protocol amendment has been proposed that would

allow patients with a history of untreated brain

metastases as long as the patient is asymptomatic.

As of June 30, 2018, 219 patients have been

registered. Six patients are currently ineligible for the

following reasons: not having a V600E or V600K

BRAF mutation (1), inadequate cardiac function (2),

inadequate bone marrow function (1), untreated brain

metastases (1), and baseline disease scans out of

window (1). In addition, one eligible patient who

refused protocol treatment and was never randomized

is not evaluable for any of the study endpoints and is

coded as a major deviation. One patient was never

randomized and remained on continuous dosing off

protocol (coded as Reason Off Treatment = “Other –

not protocol specified”).

A total of 207 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

five patients experienced Grade 4 adverse events;

CPK increased and MS/ connective tissue disorder –

Rhabdomolysis (1), hypocalcaemia (1), neutrophil


S1320/II

count decreased (1), hyponatremia (1), and the other

due to hypocalcaemia and pneumonitis (1).

A total of 178 patients have been randomized

between intermittent and continuous dosing. Six

patients are currently ineligible for the following

reasons: ineligible for the trial at the initial

registration (4), disease progression during the lead-

in continuous dosing phase (1), and treatment start

date out of window (1). 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, 84 patients have been

assessed for adverse events. Three patients have

experienced Grade 4 treatment-related adverse

events; anemia and increases in ALT and AST (1),

dyspnea (1), and creatinine increase (1). On the

intermittent dosing arm, 84 patients have been

assessed for adverse events. Three patients have

experienced Grade 4 treatment-related adverse

events; fever (1), lipase increased (1), and acute

kidney injury (1).

Initial Registrations By 3 Month IntervalsDivisions by ARM

Lead-in Continuous Dosing

0

10

20

30


JulSep2014

OctDec2014

JanMar

2015

AprJun

2015

JulSep2015

OctDec2015

JanMar

2016

AprJun

2016

JulSep2016

OctDec2016

JanMar

2017

AprJun

2017

JulSep2017

OctDec2017

JanMar

2018

AprJun

2018

23

9

20

8

16

6

15

20

1

27

11

13

5

15

12

18


S1320/II

Registration by Institution

Lead-In Continuous Dosing

Registrations ending June 30, 2018

Institutions

Total

Reg Institutions

Total

Reg

Kaiser Perm NCORP 27 Colorado, U of 2

Kansas, U of 17 CRC West MI NCORP 2

Ohio State Univ 15 Ozarks NCORP 2

Loyola University 8 PCRC NCORP 2

San Francisco, U-CA 8 Bay Area NCORP 1

Utah, U of 8 Boston Medical Ctr 1

Southeast COR NCORP 7 CORA NCORP 1

Arkansas, U of 6 Dayton NCORP 1

Heartland NCORP 5 Hawaii MU-NCORP 1

Michigan, U of 5 Lahey Hosp & Med Ctr 1

Los Angeles, U of CA 4 UF Cancer Center/Arkansas, U of 1

Nevada CRF NCORP 4 Wisconsin NCORP 1

Rochester, Univ of 4 ECOG-ACRIN 42

Wichita NCORP 4 NRG 18

Columbus NCORP 3 ALLIANCE 13

KaiserPermanenteSCAL/Kaiser Perm NCORP 3 Total (32 Institutions) 219

Arizona MC, U of 2

Registration, Eligibility, and Evaluability


Registrations ending June 30, 2018; Data as of July 20, 2018

Lead-in

Continuous Dosing

NUMBER REGISTERED 219

INELIGIBLE 6

ELIGIBLE 213

Analyzable, Pend. Elig. 13

Not Analyzable 1

ADVERSE EVENT ASSESSMENT

Evaluable 207

Too Early 5


S1320/II

Treatment Summary



Lead-in

Continuous Dosing

NUMBER ON PROTOCOL TREATMENT 5

NUMBER OFF PROTOCOL TREATMENT

REASON OFF TREATMENT

207

Treatment completed as planned 172

Adverse Event or side effects 13

Refusal unrelated to adverse event 1

Progression/relapse 10

Death 2

Other - not protocol specified 1

Reason under review 8

MAJOR PROTOCOL DEVIATIONS 1

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=207)

Grade

ADVERSE EVENTS <=2 3 4 5

AST increased 201 6 0 0

Abdominal pain 206 1 0 0

Acute kidney injury 205 1 1 0

Anemia 203 4 0 0

Anorexia 205 2 0 0

Arthralgia 206 1 0 0

Blood bilirubin increased 206 1 0 0

Blood/lymph disorder-Other 206 1 0 0

CPK increased 206 0 1 0

Cardiac troponin T increased 206 1 0 0

Constipation 206 1 0 0

Dehydration 200 7 0 0

Diarrhea 204 3 0 0

Dyspnea 206 1 0 0

ECG QT corrected int prolong 206 1 0 0

Ejection fraction decreased 206 0 1 0

Epistaxis 206 1 0 0

Erythema multiforme 206 1 0 0

Fatigue 202 5 0 0

Febrile neutropenia 204 3 0 0


S1320/II

Lead-in Continuous

Dosing

(n=207)

Grade

ADVERSE EVENTS <=2 3 4 5

Fever 204 3 0 0

Fracture 206 1 0 0

Gastric hemorrhage 206 1 0 0

Generalized muscle weakness 205 2 0 0

Headache 205 2 0 0

Hyperglycemia 206 1 0 0

Hypertension 203 4 0 0

Hypoalbuminemia 206 1 0 0

Hypocalcemia 205 0 2 0

Hypokalemia 206 1 0 0

Hyponatremia 196 10 1 0

Hypophosphatemia 206 1 0 0

Hypotension 203 4 0 0

Hypoxia 206 1 0 0

Leukocytosis 206 1 0 0

Lipase increased 205 2 0 0

Lung infection 206 1 0 0

Lymphocyte count decreased 201 6 0 0

MS/connective tissue disorder 205 1 1 0

Metab/nutrition disorders-Oth 206 1 0 0

Mucositis oral 206 1 0 0

Nausea 205 2 0 0

Neutrophil count decreased 198 8 1 0

Platelet count decreased 206 1 0 0

Pneumonitis 206 0 1 0

Proteinuria 206 1 0 0

Rash acneiform 204 3 0 0

Rash maculo-papular 203 4 0 0

Retinopathy 206 1 0 0

Sepsis 205 0 1 1

Skin infection 206 1 0 0

Skin/subq tissue ds-Other 206 1 0 0

Thromboembolic event 206 1 0 0

Tx related secondary malig 205 2 0 0

Upper GI hemorrhage 206 1 0 0

Urinary tract infection 205 2 0 0

Vasc disorders-Other, spec 206 1 0 0

Vomiting 205 2 0 0

White blood cell decreased 203 4 0 0

MAX. GRADE ANY ADVERSE EVENT 146 54 6 1


S1320/II


Randomization


TOTAL

Continuous

Dosing

Intermittent

Dosing

NUMBER REGISTERED 178 91 87

INELIGIBLE 6 5 1

ELIGIBLE 172 86 86

Analyzable, Pend. Elig. 8 5 3

RESPONSE ASSESSMENT

Determinable 139 74 65

Not Determinable 1 1 0

Too Early 32 11 21


Evaluable 168 84 84

Too Early 4 2 2

Patient Characteristics

Randomization


Continuous

Dosing

(n=86)

Intermittent

Dosing

(n=86)

AGE

Median 59.3 64.5

Minimum 22.7 20.9

Maximum 88.6 88.8

SEX

Males 52 60% 59 69%

Females 34 40% 27 31%

HISPANIC

Yes 2 2% 4 5%

No 82 95% 82 95%

Unknown 2 2% 0 0%

RACE

White 85 99% 83 97%

Native American 1 1% 0 0%

Multi-Racial 0 0% 1 1%

Unknown 0 0% 2 2%

PERFORMANCE STATUS

0 47 55% 53 62%

1 37 43% 32 37%

Data pending 1 1% 0 0%


S1320/II

Continuous

Dosing

(n=86)

Intermittent

Dosing

(n=86)

PRIMARY TYPE

Cutaneous 74 86% 66 77%

Unknown primary 10 12% 19 22%


STAGE

III 11 13% 13 15%

IV 75 87% 73 85%

SITE(S) OF DISTANT DISEASE

Bone 18 21% 18 21%

Brain/CNS 9 10% 5 6%

Liver 25 29% 22 26%

Lymph node, skin, soft tissue 53 62% 44 51%

Lung 43 50% 44 51%

Other, visceral 16 19% 18 21%

Other non-visceral 13 15% 15 17%


LDH

Elevated (>IULN) 32 37% 31 36%

Normal 54 63% 55 64%

PRIOR IMMUNE CHECKPOINT INHIBITOR

Yes 24 28% 23 27%

No 62 72% 63 73%

PRIOR BIOLOGIC THERAPY

No 45 52% 50 58%

Yes 4 5% 7 8%


PRIOR CHEMOTHERAPY

No 50 58% 49 57%

Yes 3 3% 5 6%


PRIOR IMMUNOTHERAPY

No 36 42% 36 42%

Yes 17 20% 24 28%


PRIOR RADIATION THERAPY

No 67 78% 60 70%

Yes 19 22% 26 30%

PRIOR SURGERY

No 19 22% 13 15%

Yes 67 78% 73 85%


S1320/II

Treatment Summary

Randomization


Total




127




Progression/relapse 72

Death 2





Randomization




Continuous Dosing

(n=84)

Grade

Intermittent Dosing

(n=84)

Grade

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

ALT increased 82 1 1 0 84 0 0 0

AST increased 80 3 1 0 83 1 0 0

Acute kidney injury 84 0 0 0 83 0 1 0

Alkaline phosphatase increased 83 1 0 0 84 0 0 0

Anemia 81 2 1 0 83 1 0 0

Arthralgia 83 1 0 0 83 1 0 0

Back pain 83 1 0 0 84 0 0 0

Blood bilirubin increased 83 1 0 0 84 0 0 0

Chills 83 1 0 0 83 1 0 0

Confusion 84 0 0 0 83 1 0 0

Creatinine increased 83 0 1 0 84 0 0 0

Dehydration 83 1 0 0 84 0 0 0

Diarrhea 82 2 0 0 84 0 0 0

Dry skin 83 1 0 0 84 0 0 0

Dyspnea 83 0 1 0 84 0 0 0

ECG QT corrected int prolong 83 1 0 0 83 1 0 0

Ejection fraction decreased 81 3 0 0 81 3 0 0

Fatigue 77 7 0 0 82 2 0 0

Fever 80 4 0 0 83 0 1 0


S1320/II

Continuous Dosing

(n=84)

Grade

Intermittent Dosing

(n=84)

Grade

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

Flu like symptoms 82 2 0 0 84 0 0 0

Gastric hemorrhage 83 1 0 0 84 0 0 0

Generalized muscle weakness 82 2 0 0 82 2 0 0

Glucose intolerance 83 1 0 0 84 0 0 0

Hand-Foot syndrome 83 1 0 0 84 0 0 0

Hypercalcemia 84 0 0 0 83 1 0 0

Hyperglycemia 81 3 0 0 82 2 0 0

Hypertension 78 6 0 0 82 2 0 0

Hypoalbuminemia 83 1 0 0 84 0 0 0

Hyponatremia 80 4 0 0 82 2 0 0

Hypotension 83 1 0 0 83 1 0 0

Hypothyroidism 83 1 0 0 84 0 0 0

Infections/infestations-Other 84 0 0 0 83 1 0 0

LV systolic dysfunction 83 1 0 0 83 1 0 0

Lipase increased 82 2 0 0 81 2 1 0

Localized edema 83 1 0 0 84 0 0 0

Lung infection 83 1 0 0 84 0 0 0

Lymphocyte count decreased 80 4 0 0 83 1 0 0

Mucositis oral 83 1 0 0 84 0 0 0

Myalgia 84 0 0 0 83 1 0 0

Neutrophil count decreased 81 3 0 0 84 0 0 0

Pain in extremity 83 1 0 0 84 0 0 0

Platelet count decreased 83 1 0 0 84 0 0 0

Rash acneiform 82 2 0 0 84 0 0 0

Rash maculo-papular 83 1 0 0 84 0 0 0

Resp/thoracic/mediastinal ds 83 1 0 0 84 0 0 0

Retinal detachment 84 0 0 0 82 2 0 0

Serum amylase increased 84 0 0 0 82 2 0 0

Skin/subq tissue ds-Other 83 1 0 0 84 0 0 0

Syncope 83 1 0 0 84 0 0 0

Thromboembolic event 82 2 0 0 84 0 0 0

Tx related secondary malig 84 0 0 0 82 2 0 0

Urinary tract infection 84 0 0 0 83 1 0 0

Urinary tract obstruction 83 1 0 0 84 0 0 0

White blood cell decreased 81 3 0 0 83 1 0 0

MAX. GRADE ANY ADVERSE EVENT 46 35 3 0 60 21 3 0


S1404/III

S1404 Phase III


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

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

Patients with High Risk Resected Melanoma

Participants:

SWOG, CTSU (Supported by CCTG and ECOG-

ACRIN)

Study Chairs:

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

T Petrella (CCTG)

Statisticians:

M Othus, H Li, J Moon

Data Coordinators:

J Jardine, L Kingsbury, V Kim, S O'Bryan, J Sanchez, B

Zeller

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. Forty-seven

patients are currently ineligible for the following

reasons: incorrect stage of disease (18),

inadequate/incomplete resection of disease (13),

radiologic or clinical evidence that patient was not

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

testing (2), inadequate renal function (1), concurrent


S1404/III

radiation therapy (1), recurrent satellite metastases

(1), recurrent distant metastases (1).

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

six are currently ineligible, including 25 who were

ineligible at the screening step and one patient due to

a positive pregnancy test. Ninety-nine patients, 91 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.

Thirty-two patients have discontinued protocol

treatment for reasons coded as “other - not protocol

specified", which include: other primary cancer,

pregnancy, insurance, and a change in treatment plan

by the medical team.

On the control arm, 574 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 34 patients have experienced treatment-

related Grade 4 adverse events. These included 14

patients who received high-dose interferon:

hematologic adverse events (8), increased AST and

ALT (2), hypertriglyceridemia (2), increased CPK

(1), and febrile neutropenia (1); and 20 patients who

received ipilimumab: hyponatremia (4), ALT

increase (2), pancreatitis, colitis and an autoimmune

disorder (autoimmune colitis) (1), hyperthyroidism

(1), sepsis and respiratory failure (1), adrenal

insufficiency (1), lipase increase (1), diarrhea (1),

encephalitis infection (1), CPK and creatinine

increase (1), peripheral sensory neuropathy (1),

colitis (1), autoimmune disorder (1), dyspnea (1),

ALT and AST increase (1), and AIDP (coded as

"Nervous system disorders - Other) (1).

On the pembrolizumab arm, 645 patients have been

assessed for adverse events. There has been one

treatment-related death due to myocarditis. One

additional death, due to a secondary leukemia, is

possibly related to protocol treatment; however, this

case is still under review. An additional 12 patients

have experienced treatment-related Grade 4 adverse

events: hyperglycemia (3), dyspnea, wheezing and

bronchospasm (1), acidosis (1) , CPK increase (1),

sepsis (1), blood bilirubin increase (1),

hyperglycemia and type 1 diabetes (coded as

"Endocrine disorders-Other") (1), diabetic

ketoacidosis (coded as Metabolic/nutrition disorders -

Other) (1), myasthenia gravis (coded as "Nervous

system disorders, Other") (1), and episcleritis (coded

as "Eye disorders, other") (1).

Sites are encouraged to submit all outstanding data

and resolve all outstanding queries in order to meet

upcoming deadlines.

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 MC, U of 11 All Other SWOG Institutions 22

Mt Sinai Med Ctr 11 ECOG-ACRIN 323

Northwest NCORP 11 ALLIANCE 150

CORA NCORP 10 CCTG 130

New Mexico MU-NCORP 10 NRG 113

Southeast COR NCORP 10 Total (61 Institutions) 1426

Wayne State Univ 10


Initial Registration

Data as of August 1, 2018

Tissue for

PD-L1 testing

NUMBER REGISTERED 1426

INELIGIBLE 47

ELIGIBLE 1379

Analyzable, Pend. Elig. 205


S1404/III


Randomization

Institutions

Total

Reg Institutions

Total

Reg

Kaiser Perm NCORP 74 Wayne State Univ 9

H Lee Moffitt CC 52 Cedars-Sinai Med Ctr 8

MD Anderson CC 43 City of Hope Med Ctr 8

Ohio State Univ 33 Michigan CRC NCORP 8

Utah, U of 31 Wisconsin NCORP 8

Colorado, U of 29 Dayton NCORP 7

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

Cleveland Clinic OH 25 Rochester, Univ of 6

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

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

Georgia NCORP 20 Yale University 6

PCRC NCORP 17 Arkansas, U of 5

Northwestern Univ 16 Sutter Cancer RC 5

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

Wichita NCORP 13 Columbus NCORP 4

Baylor Univ Med Ctr 12 Gulf South MU-NCORP 4

Michigan, U of 12 Montana NCORP 4

Oregon Hlth Sci Univ 12 Ozarks NCORP 4

Arizona MC, U of 11 All Other SWOG Institutions 24

Northwest NCORP 11 ECOG-ACRIN 302

Mt Sinai Med Ctr 10 ALLIANCE 144

Southeast COR NCORP 10 CCTG 122

CORA NCORP 9 NRG 106

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

Randomization By 3 Month IntervalsDivisions by ARM

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


TOTAL

FDA approved

regimen

MK-3475

(Pembrolizumab)


INELIGIBLE 26 12 14

ELIGIBLE 1319 666 653



Evaluable 1219 574 645

Not Evaluable 99 91 8

Too Early 1 1 0


Randomization


FDA approved

regimen

(n=666)

MK-3475

(Pembrolizumab)

(n=653)

AGE

Median 56.9 56.3

Minimum 18.3 20.0

Maximum 86.4 82.6

SEX

Males 402 60% 386 59%

Females 264 40% 267 41%

HISPANIC

Yes 18 3% 26 4%

No 629 94% 610 93%

Unknown 19 3% 17 3%

RACE

White 633 95% 626 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%


S1404/III

FDA approved

regimen

(n=666)

MK-3475

(Pembrolizumab)

(n=653)

STAGE

IIIA 69 10% 76 12%

IIIB 327 49% 313 48%

IIIC 228 34% 223 34%

IV 42 6% 41 6%

PLANNED CONTROL REGIMEN

High Dose Interferon 159 25% 153 25%

Ipilimumab 470 75% 460 75%

PERFORMANCE STATUS

0 558 84% 546 84%

1 108 16% 107 16%

Treatment Summary

Randomization


Total




1175








S1404/III


Randomization




FDA approved regimen

(n=574)

Grade


(n=645)

Grade

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

ALT increased 530 39 5 0 626 19 0 0

AST increased 541 30 3 0 632 13 0 0

Abdominal pain 568 6 0 0 643 2 0 0

Acidosis 573 1 0 0 643 1 1 0

Acute kidney injury 572 2 0 0 643 2 0 0

Adrenal insufficiency 566 7 1 0 641 4 0 0


Anemia 573 1 0 0 644 1 0 0

Anorexia 571 3 0 0 644 1 0 0

Anxiety 572 2 0 0 645 0 0 0

Arthralgia 572 2 0 0 642 3 0 0

Arthritis 573 1 0 0 644 1 0 0

Atelectasis 573 1 0 0 645 0 0 0

Atrial fibrillation 573 1 0 0 645 0 0 0

Atrial flutter 574 0 0 0 644 1 0 0

Autoimmune disorder 572 0 2 0 644 1 0 0

Back pain 571 3 0 0 645 0 0 0

Blood bilirubin increased 573 1 0 0 643 1 1 0

Blood/lymph disorder-Other 573 1 0 0 645 0 0 0

Blurred vision 573 1 0 0 645 0 0 0

Bone pain 573 1 0 0 645 0 0 0

Bronchospasm 574 0 0 0 644 0 1 0

CPK increased 569 3 2 0 643 1 1 0

Cardiac disorder-Other, spec 573 1 0 0 645 0 0 0

Cardiac troponin T increased 573 1 0 0 645 0 0 0

Colitis 543 29 2 0 633 12 0 0

Confusion 573 1 0 0 644 1 0 0

Cough 573 1 0 0 644 1 0 0

Creatinine increased 572 1 1 0 645 0 0 0

Cystitis noninfective 573 1 0 0 645 0 0 0

Dehydration 571 3 0 0 643 2 0 0

Delirium 573 1 0 0 645 0 0 0

Depression 570 4 0 0 645 0 0 0

Diarrhea 520 53 1 0 628 17 0 0

Dizziness 573 1 0 0 645 0 0 0

Duodenal ulcer 573 1 0 0 645 0 0 0

Dyspepsia 573 1 0 0 645 0 0 0

Dyspnea 562 11 1 0 641 3 1 0

Encephalitis infection 572 1 1 0 645 0 0 0

Encephalopathy 573 1 0 0 645 0 0 0

Endocrine disorders-Other 571 3 0 0 642 2 1 0

Enterocolitis 568 5 0 1 645 0 0 0

Enterocolitis infectious 572 2 0 0 644 1 0 0


S1404/III


(n=574)

Grade


(n=645)

Grade

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

Erectile dysfunction 573 1 0 0 645 0 0 0

Esophagitis 573 1 0 0 645 0 0 0

Eye disorders - Other, specify 573 1 0 0 644 0 1 0

Eye pain 574 0 0 0 644 1 0 0

FEV1 decreased 574 0 0 0 644 1 0 0

Facial nerve disorder 574 0 0 0 644 1 0 0

Fatigue 546 28 0 0 642 3 0 0

Febrile neutropenia 572 1 1 0 645 0 0 0

Flu like symptoms 573 1 0 0 644 1 0 0

GI disorders-Other, specify 571 3 0 0 645 0 0 0

Gastritis 572 2 0 0 645 0 0 0

Gen disorders/admin site cond 573 1 0 0 644 1 0 0

Generalized muscle weakness 570 4 0 0 644 1 0 0

Headache 561 13 0 0 642 3 0 0

Hepatic pain 574 0 0 0 644 1 0 0

Hepatitis viral 572 2 0 0 645 0 0 0

Hepatobil disorders-Other 573 1 0 0 645 0 0 0

Hiccups 574 0 0 0 644 1 0 0

Hyperglycemia 569 5 0 0 638 3 4 0

Hypersomnia 573 1 0 0 645 0 0 0

Hypertension 567 7 0 0 643 2 0 0

Hyperthyroidism 573 0 1 0 643 2 0 0

Hypertriglyceridemia 566 6 2 0 644 1 0 0

Hypoalbuminemia 573 1 0 0 645 0 0 0

Hypokalemia 572 2 0 0 645 0 0 0

Hyponatremia 559 11 4 0 636 9 0 0

Hypophosphatemia 571 3 0 0 642 3 0 0

Hypotension 571 3 0 0 645 0 0 0


Hypoxia 571 3 0 0 644 1 0 0

Immune sys disorders-Other 573 1 0 0 644 1 0 0

Infections/infestations-Other 573 1 0 0 645 0 0 0

Infusion related reaction 573 1 0 0 644 1 0 0

Insomnia 573 1 0 0 645 0 0 0

Joint effusion 574 0 0 0 644 1 0 0

Leukocytosis 573 1 0 0 645 0 0 0

Lipase increased 569 4 1 0 645 0 0 0

Lower GI hemorrhage 573 1 0 0 645 0 0 0

Lung infection 574 0 0 0 639 6 0 0


MS/connective tissue disorder 573 1 0 0 643 2 0 0

Meningitis 572 2 0 0 645 0 0 0

Metab/nutrition disorders-Oth 572 2 0 0 644 0 1 0

Mucositis oral 574 0 0 0 643 2 0 0

Muscle weakness lower limb 573 1 0 0 645 0 0 0

Myalgia 570 4 0 0 644 1 0 0

Myocardial infarction 574 0 0 0 644 1 0 0

Myocarditis 574 0 0 0 644 0 0 1

Myositis 573 1 0 0 644 1 0 0

Nausea 565 9 0 0 644 1 0 0

Nervous sys disorders-Other 570 3 1 0 643 1 1 0


S1404/III


(n=574)

Grade


(n=645)

Grade

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

Neuralgia 572 2 0 0 645 0 0 0

Neutrophil count decreased 522 45 7 0 644 1 0 0

Pain 573 1 0 0 645 0 0 0

Pain in extremity 572 2 0 0 645 0 0 0

Pain of skin 574 0 0 0 644 1 0 0

Pancreatitis 571 2 1 0 640 5 0 0

Papulopustular rash 573 1 0 0 645 0 0 0

Peripheral motor neuropathy 573 1 0 0 645 0 0 0

Peripheral sensory neuropathy 573 0 1 0 645 0 0 0

Pharyngitis 573 1 0 0 645 0 0 0

Pleural effusion 573 1 0 0 645 0 0 0

Pneumonitis 568 6 0 0 642 3 0 0

Proctitis 574 0 0 0 643 2 0 0

Proteinuria 574 0 0 0 644 1 0 0

Pruritus 566 8 0 0 645 0 0 0

Rash acneiform 574 0 0 0 643 2 0 0


Rash pustular 573 1 0 0 645 0 0 0

Resp/thoracic/mediastinal ds 574 0 0 0 644 1 0 0

Respiratory failure 572 0 1 1 645 0 0 0

Restrictive cardiomyopathy 573 1 0 0 645 0 0 0

Secondary Leukemia 574 0 0 0 644 0 0 1

Seizure 574 0 0 0 644 1 0 0

Sepsis 572 0 2 0 644 0 1 0

Serum amylase increased 573 1 0 0 644 1 0 0

Sinus tachycardia 572 2 0 0 645 0 0 0

Sinusitis 574 0 0 0 644 1 0 0

Skin infection 573 1 0 0 644 1 0 0


Syncope 568 6 0 0 644 1 0 0

Tremor 574 0 0 0 644 1 0 0

Vomiting 566 8 0 0 644 1 0 0

Weight loss 572 2 0 0 645 0 0 0

Wheezing 574 0 0 0 644 0 1 0

White blood cell decreased 553 19 2 0 645 0 0 0

MAX. GRADE ANY ADVERSE EVENT 266 272 34 2 527 104 12 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

Data Coordinator:

V Kim

Date Activated:

10/20/2016

Objectives This study will enroll two separate cohorts to assess

the efficacy of MK-3475 (pembrolizumab) in

desmoplastic melanoma (DM). Cohort A will

evaluate MK-3475 (pembrolizumab) as neoadjuvant

therapy for patients with DM that is deemed

resectable by the treating investigator; including

primary DM, locally advanced DM, and locally

recurrent DM. Cohort B will be a pilot study to

evaluate the use of MK-3475 (pembrolizumab) for

patients with DM that is deemed unresectable by the

treating investigator, including metastatic DM.

Cohort A

To evaluate the pathologic complete response rate in

patients with resectable desmoplastic melanoma

treated with neoadjuvant MK-3475 (pembrolizumab).

To estimate the nine week response rate

(unconfirmed complete and partial responses).

To estimate the median overall survival.

To evaluate safety and tolerability of MK-3475

(pembrolizumab) in the neoadjuvant setting.

Cohort B

To evaluate the complete response rate (confirmed

and unconfirmed) in patients with unresectable

desmoplastic melanoma treated with MK-3475

(pembrolizumab).

To estimate the median progression-free survival.

To estimate the median overall survival.

To evaluate safety and tolerability of MK-3475

(pembrolizumab) in this setting.

Patient Population Patients must have histologically or cytologically

confirmed primary desmoplastic melanoma. Patients

with disease that, in the judgment of the surgeon is

deemed completely resectable resulting in free

surgical margins, are eligible for Cohort A. Patients

with unresectable disease are eligible for Cohort B.

Patients must not have known brain metastases unless

brain metastases have been treated and patient is

asymptomatic with no residual neurological

dysfunction without receiving enzyme-reducing anti-

epileptic drugs or corticosteroids.


S1512/II

Patients must not have received prior systemic

therapy for desmoplastic melanoma. Patients must

not have received radiation therapy, non-cytotoxic

agents or investigational agents or systemic

corticosteroids within 14 days prior to registration.

Patients may have received prior surgery.

Patients must have adequate hematologic and hepatic

function with a Zubrod performance status of 0-2.

Patients must not have known, active non-infectious

pneumonitis, an active infection requiring systemic

therapy, or an active autoimmune disease that has

required systemic treatment in the past two years.

Patients must not have received live vaccines within

42 days prior to registration. Patients known to be

HIV positive must have stable and adequate CD4

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

must be on stable anti-viral therapy. Women of

childbearing potential must have a negative urine or

serum pregnancy test within 28 days prior to

registration.

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

B (unresectable).

Accrual Goals Accrual to this study will proceed in two independent

cohorts: A and B.

Cohort A will accrue approximately 51 patients to

achieve 41 eligible patients. Initially, 21 eligible

patients will be enrolled. If two or more pathologic

complete responses are observed, an additional 20

eligible patients will be enrolled.

Cohort B will accrue approximately 26 patients to

achieve 21 eligible patients.

Summary Statement As of June 30, 2018, eleven patients have been

registered. One eligible patient never started

treatment due to study and follow up consent

withdrawal and is therefore coded as not analyzable.

Eight patients have been assessed for adverse events,

two patients experienced Grade 3 adverse events:

dyspnea and hypoxia (1), Rash maculo-papular (1).



Institutions Total Reg

H Lee Moffitt CC 3

Ohio State Univ 3

Los Angeles, U of CA 2

Georgia NCORP 1

So Calif, U of 1

Southeast COR NCORP 1

Total (6 Institutions) 11


S1512/II

Registration, Eligibility, and Evaluability Classified by Cohort


TOTAL

Resectable

(Cohort A)

Unresectable

(Cohort B)


ELIGIBLE 11 7 4


Not Analyzable 1 1 0

RESPONSE ASSESSMENT

Determinable 4 1 3

Too Early 6 5 1


Evaluable 8 5 3

Too Early 2 1 1

Patient Characteristics Classified by Cohort


Resectable

(Cohort A)

(n=7)

Unresectable

(Cohort B)

(n=4)

AGE

Median 70.7 82.4

Minimum 49.2 80.2

Maximum 85.8 89.6

SEX

Males 6 86% 4 100%

Females 1 14% 0 0%

HISPANIC

No 7 100% 4 100%

RACE

White 7 100% 4 100%


S1512/II

Number of Patients with a Given Type and Grade of Adverse Event Classified by Cohort



Resectable

(Cohort A)

(n=5)

Grade

Unresectable

(Cohort B)

(n=3)

Grade

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


Anemia 5 0 0 0 3 0 0 0

Bullous dermatitis 5 0 0 0 3 0 0 0

Diarrhea 5 0 0 0 3 0 0 0

Dyspnea 5 0 0 0 2 1 0 0

Fatigue 5 0 0 0 3 0 0 0

Hypercalcemia 5 0 0 0 3 0 0 0

Hyperkalemia 5 0 0 0 3 0 0 0

Hypernatremia 5 0 0 0 3 0 0 0

Hypertension 5 0 0 0 3 0 0 0

Hyperthyroidism 5 0 0 0 3 0 0 0

Hyponatremia 5 0 0 0 3 0 0 0


Hypoxia 5 0 0 0 2 1 0 0


Pruritus 5 0 0 0 3 0 0 0



MAX. GRADE ANY ADVERSE

EVENT

5 0 0 0 1 2 0 0


S1607/II

S1607 Phase II


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

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

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

Participants:

SWOG, CTSU

Study Chairs:

S Hu-Lieskovan, A Ribas

Statisticians:

M Wu, J Moon

Data Coordinator:

V Kim

Date Activated:

10/02/2017

Objectives To evaluate the durable response rate of treatment

with talimogene laherparepvec (T-VEC) in

combination with MK-3475 (pembrolizumab)

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

L1 therapy alone or in combination with other agents

different from talimogene laherparepvec (T-VEC).

To estimate the response rate (confirmed and

unconfirmed, complete and partial responses) in the

injected lesions.

To estimate the response rate in the non-visceral,

non-injected lesions.

To estimate the response rate in the visceral lesions.

To estimate the overall objective response rate per

RECIST 1.1, progression-free survival, and overall

survival within each cohort.

To evaluate whether adding talimogene

laherparepvec (T-VEC) to PD1 blockade can increase

T-cell infiltration into tumors and whether change in

T-cell infiltration is associated with response.

To evaluate whether adding talimogene

laherparepvec (T-VEC) to PD1 blockade can increase

TCR clonality in tumors and in peripheral blood and

whether increased TCR clonality is associated with

response.

To evaluate whether intra-tumoral injection of

talimogene laherparepvec (T-VEC) is associated with

the tumor immune microenvironment.

To evaluate whether tumor mutational load and

mutations in the IFN pathway is associated with

response to talimogene laherparepvec (T-VEC) plus

MK-3475 (pembrolizumab) therapy in the anti-

PD1/L1 therapy refractory melanoma patients.

Patient Population Patients must have pathologically confirmed Stage

IV or unresectable Stage III melanoma with

cutaneous, mucosal or unknown primary. Patients

with uveal primary are not eligible. Patients will be

enrolled onto one of two independent cohorts: for

Cohort A, patients must have at least one measurable

visceral lesion, defined as any solid organ except for

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.

Patients 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.

Patients must have received anti-PD-1 or PD-L1

based therapy as the immediate previous line of

treatment and within 56 days prior to registration.

Patients must not have had surgery, chemotherapy,

biologic therapy, hormonal therapy, or radiation

therapy within 14 days prior to registration. Patients

must not have had an investigational agent or

monoclonal antibodies, except anti-PD1/L1

antibodies, within 28 days prior to registration.

Patients must not have received prior treatment with

talimogene laherparepvec (T-VEC) or other oncolytic

virus agents. Patients must not have had any

infectious disease vaccination within seven days prior

to registration.

Patients must have adequate hematologic, hepatic,

and renal function and a Zubrod performance status

of 0-2. Patients must not have severe autoimmune

disease requiring systemic corticosteroids or ongoing

immunosuppression. Patients must not have a known

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

pneumonitis. Patients must not have an active

infection requiring systemic therapy nor a viral-

infection requiring intermittent treatment with an

antiherpatic drug, and must not have active herpatic

skin lesions or prior complications of herpatic

infection which require treatment with an anti-

herpatic drug. Patients must not have organ

allografts, or a history of autoimmune disease, or

clinically significant immunosuppression. Women of

reproductive potential must have a negative serum

pregnancy test within seven days prior to registration.

Patients must have tissue available and must be

willing to submit blood and tissue specimens for the

translational medicine objectives. Patients must be

offered the opportunity to participate in specimen

banking.

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

visceral lesions: one or more vs none.

Accrual Goals The study will accrue to two independent cohorts.

Cohort A, patients with at least one visceral lesion,

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

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

an additional 14 patients will be enrolled for a total of

32 patients.

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

modified two-stage design. Initially 16 patients will

be enrolled. If two or more durable responses are

observed, then an additional nine patients will be

enrolled for a total of 25 patients.

Summary Statement This study was activated on October 2, 2017. As of

June 30, 2018, 1 patient has been registered by

UCLA.


S1609/II

S1609 Phase II


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

Participants:

SWOG, CTSU

Study Chairs:

S Patel, Y Chae

Statisticians:

M Othus, M Plets, E Mayerson

Data Coordinators:

C McLeod, J Hayward

Date Activated:

01/13/2017

Objectives To evaluate the RECIST 1.1 overall response rate

(ORR) in subsets of patients with advanced rare

cancers treated with ipilimumab plus nivolumab

combination immunotherapy.

To evaluate toxicities in each cohort.

To estimate overall survival (OS), progression-free

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

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

PFS (irPFS) by unidimensional immune-related

response criteria.

To collect specimens for banking for use in future

correlative biomarker research studies.

Patient Population Patients must have histologically confirmed rare

cancer and/or cancer of unknown primary specified

on the list of eligible rare cancer histologic cohorts in

the S1609 protocol. Patients who do not qualify for

one of the histologic cohorts may be considered for

registration in the "Not Otherwise Categorized"

(NOC) cohort with confirmation by one of the study

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

longer required to have been enrolled in EAY131

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

Patients must have measurable disease and have

progressed following at least one line of standard

systemic therapy and there must not be other

approved/standard therapy available that has been

shown to prolong overall survival. Patients are also

eligible if no standard treatment exists that has been

shown to prolong overall survival. Patients must not

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

anti-PD-L1 therapy. Other immunotherapy is

permitted, provided that it is completed at least seven

days prior to registration. Patients who had a prior

immune-related adverse event with prior

immunotherapy are not eligible. Patients with brain

metastases or primary brain tumors must have

completed treatment, surgery or radiation therapy ≥

28 days prior to registration and have stable disease

at time of registration. Patients with metastatic brain

parenchymal disease must have been treated and off

steroids for seven days prior to registration. Patients

must have been off all other systemic anti-cancer

therapy at least seven days prior to registration and

any therapy-induced toxicity must have recovered to

≤ Grade 1.


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


S1609/II

Hepatitis C Virus (HCV) infection at time of

registration. Patients with HBV or HCV that have an

undetectable viral load, or in the opinion of the

treating investigator is well controlled, are eligible.

Patients who are known to be HIV-positive at

registration are eligible if they meet the conditions

outlined in the protocol.

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

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

achieve 636 eligible patients. A two-stage design will

be used for all cohorts, with the exception of the

NOC and "Cancer of Unknown Primary" (CuP)

cohorts. Initially, six eligible patients will be

registered to each histologic cohort. If at least one

response is observed within a cohort, an additional 10

eligible patients will be registered to that cohort. Up

to 16 eligible patients will be registered to the CuP

cohort with no formal first stage response

assessment. Up to 60 eligible patients will be enrolled

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

additional cohorts.


Early Therapeutics and Rare Cancers chapter.


S1614/III

S1614 Phase III


A Phase III Randomized Trial of Prophylactic Antiviral Therapy in Patients

with Current or Past Hepatitis B Virus (HBV) Infection Receiving Anti-

Cancer Therapy for Solid Tumors

Participants:


Study Chairs:

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

Statisticians:

J Unger, E Mayerson

Data Coordinator:

K Carvalho

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 not be taking

antiviral medications active against HBV or

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 HIV test

within the past 365 days. Patients must have

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

lab tests as specified in the protocol. Patients must be

able to take oral medications.

Patients must be willing to submit specimens for

ongoing testing of HBV reactivation. Patients must

be offered the opportunity to participate in the

translational medicine studies.

Stratification/Descriptive Factors Patients with chronic HBV infection will be

randomized within Cohort 1, with randomization

stratified by planned cancer therapy type: any

cytotoxic therapy vs immunotherapy alone vs

targeted therapy alone vs immunotherapy and

targeted therapy.

Patients with past HBV infection will be randomized

within Cohort 2 with randomization stratified by the

following factors: (1) planned cancer therapy type:

any cytotoxic therapy vs immunotherapy alone vs

targeted therapy alone vs immunotherapy and

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

negative.

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

patients per cohort to achieve 200 eligible patients

per cohort. A single formal interim analysis for

efficacy for each cohort will be conducted when one

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


Symptom Control and QOL chapter.


S1616/II

S1616 Phase II


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

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

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

Participants:

SWOG, CTSU

Study Chairs:

A VanderWalde, A Ribas, E Buchbinder (ECOG-

ACRIN)

Statisticians:

J Moon, M Wu

Data Coordinator:

J Hayward

Date Activated:

07/17/2017

SCHEMA

R

A

N

D

O

M

I

Z

A

T

I

O

N

Ipilimumab + Nivolumab

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

three will be randomized to receive the combination of ipilimumab and

nivolumab

Ipilimumab

Nivolumab


S1616/II

Objectives To compare progression free survival (PFS) of

patients with advanced melanoma refractory to an

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

combination therapy ipilimumab plus nivolumab

versus ipilimumab alone.

To estimate difference in T-cell infiltrate between on-

study biopsy samples of patients who respond to

combination therapy (including confirmed and

unconfirmed, complete and partial response per

RECIST 1.1) as compared to those who do not

respond.

To evaluate the objective response rate (ORR)

(confirmed and unconfirmed complete or partial

responses) in each treatment arm.

To evaluate overall survival in each treatment arm.

To evaluate the toxicity profile of patients in each

treatment arm.

Patient Population Patients must have pathologically confirmed

melanoma that is either Stage IV or unresectable

Stage III. Patients may have primaries of cutaneous,

mucosal, or unknown origin. Patients with uveal

(ocular) primary are not eligible. Patients must have

measurable disease. If the only measurable disease is

cutaneous or subcutaneous, lesions must be at least

10 mm in greatest dimension and able to be serially

recorded using calipers and photographs. Patients

must not have central nervous system metastases

unless adequately treated and patient is asymptomatic

without requiring steroids for at least 14 days prior to

registration.

Patients must have had prior treatment with anti-PD-

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

progression either while on these agents or after

stopping therapy with these agents without

intervening therapy. Patients must not have achieved

a confirmed partial or complete response to the anti-

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

Patients must not have had any systemic therapy

within 21 days prior to registration. Patients must not

have had prior radiation therapy within 14 days prior

to registration. Patients must not have had prior

treatment with ipilimumab or other CTLA-4

antagonists.

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

Zubrod performance status of 0-2 with adequate

hepatic, renal, and hematologic function. Patients

with a known history of HIV must have an adequate

CD4 count. Patients must not have a known active

Hepatitis B, or Hepatitis C infection. Patients must

not have received systemic treatment with

corticosteroids or other immunosuppressive

medications within 14 days prior to registration.

Patients must not have organ allografts or a history of

immune-mediated pneumonitis or colitis that required

steroid treatment. Women of reproductive potential

must have a negative serum pregnancy test within

two days prior to registration.

Patients must be willing to undergo biopsies and

submit tissue and blood for the translational medicine

objectives.

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

receive combination therapy ipilimumab and

nivolumab versus single therapy ipilimumab. In other

words, 63 patients will be randomized to receive the

combination regimen and 21 will be randomized to

receive the single agent regimen. Assuming an

ineligibility rate of 10% the total accrual goal is 94

patients to achieve 84 eligible patients.

Summary Statement As of June 30, 2018, 15 patients have accrued. Three

patients are currently ineligible due to insufficient

baseline documentation. Eight patients have been

assessed for adverse events; one patient has

experienced a Grade 3 adverse event, Rash maculo-

papular.


S1616/II



Institutions Total Reg

Tennessee, U of 3

Los Angeles, U of CA 2

New Mexico MU-NCORP 2

Northwestern Univ 2

ALLIANCE 3

NRG 3

Total (6 Institutions) 15



TOTAL Ipilimumab

Nivolumab +

Ipilimumab


INELIGIBLE 3 0 3

Insufficient Documentation 3 0 3

Irreversible 3 0 3

ELIGIBLE 12 5 7


RESPONSE ASSESSMENT

Determinable 1 1 0

Too Early 11 4 7


Evaluable 8 3 5

Too Early 4 2 2



Ipilimumab

(n=5)

Nivolumab +

Ipilimumab

(n=7)

AGE

Median 60.1 63.5

Minimum 50.7 50.1

Maximum 69.3 86.9

SEX

Males 1 20% 5 71%

Females 4 80% 2 29%


S1616/II

Ipilimumab

(n=5)

Nivolumab +

Ipilimumab

(n=7)

HISPANIC

Yes 1 20% 0 0%

No 4 80% 6 86%

Unknown 0 0% 1 14%

RACE

White 5 100% 6 86%

Unknown 0 0% 1 14%

Number of Patients with a Given Type and Grade of Adverse Event Adverse Events Unlikely or Not Related to Treatment Excluded


Ipilimumab

(n=3)

Grade

Nivolumab + Ipilimumab

(n=5)

Grade

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

ALT increased 2 1 0 0 0 0 5 0 0 0 0 0

AST increased 2 1 0 0 0 0 4 1 0 0 0 0

Abdominal pain 2 0 1 0 0 0 4 1 0 0 0 0

Alkaline phosphatase increased 2 1 0 0 0 0 4 1 0 0 0 0

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

Blurred vision 2 1 0 0 0 0 5 0 0 0 0 0

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

Creatinine increased 3 0 0 0 0 0 4 1 0 0 0 0

Diarrhea 2 1 0 0 0 0 4 1 0 0 0 0

Dry mouth 3 0 0 0 0 0 4 1 0 0 0 0

Dry skin 3 0 0 0 0 0 4 1 0 0 0 0

Dysgeusia 3 0 0 0 0 0 4 1 0 0 0 0

Dyspnea 3 0 0 0 0 0 4 0 1 0 0 0

Fatigue 0 2 1 0 0 0 4 0 1 0 0 0

Fever 3 0 0 0 0 0 4 1 0 0 0 0

GERD 2 0 1 0 0 0 5 0 0 0 0 0

GI disorders-Other, specify 3 0 0 0 0 0 4 0 1 0 0 0

Hyperglycemia 3 0 0 0 0 0 4 1 0 0 0 0

Hypertension 3 0 0 0 0 0 4 1 0 0 0 0

Hyponatremia 3 0 0 0 0 0 4 1 0 0 0 0

Localized edema 3 0 0 0 0 0 4 1 0 0 0 0

Lymphocyte count decreased 3 0 0 0 0 0 4 0 1 0 0 0

Metab/nutrition disorders-Oth 3 0 0 0 0 0 4 0 1 0 0 0

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

Pruritus 3 0 0 0 0 0 3 2 0 0 0 0

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

Skin/subq tissue ds-Other 3 0 0 0 0 0 4 1 0 0 0 0

Weight loss 2 1 0 0 0 0 5 0 0 0 0 0

MAX. GRADE ANY ADVERSE

EVENT

0 2 0 1 0 0 2 1 2 0 0 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:

SWOG, CTSU

Study Chairs:

S Patel, K Grossmann, M Tetzlaff, V Sondak

Statisticians:

M Othus, J Moon

Data Coordinator:

V Kim

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.

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

To describe the proportion of patients on each arm

who received the surgery planned at randomization.

Patient Population Patients must have clinically detectable Stage III or

Stage IV resectable melanoma. Patients with

melanoma of mucosal or acral origin are eligible.

Patients with melanoma of uveal origin or with a

history of brain metastases documented by CT or

MRI within 42 days are not eligible. Patients are

eligible at initial presentation or at the time of the

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, 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 have available and be willing to submit

surgical specimen if randomized to the neoadjuvant

arm. Patients must be offered the opportunity to

participate in specimen banking.

Stratification/Descriptive Factors Randomization will be stratified by the following

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

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

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

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

at randomization.

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

patients with a goal of 500 eligible patients. A futility

analysis will be performed at 50% of expected

events.


EAY131

EAY131 Master Protocol / Phase II

Coordinating Group: ECOG-ACRIN

NCI-MATCH: Molecular Analysis for Therapy Choice

Participants:

ECOG-ACRIN, CTSU NCI

Study Chairs:

K Flaherty (ECOG-ACRIN), B Conley (NCI),

P O'Dwyer (ECOG-ACRIN), V Villalobos (SWOG),

A Chen (NCI)

Date Activated:

08/12/2015

SCHEMA

Objectives To evaluate the proportion of patients with objective

response (OR) to targeted study agent(s) in patients

with advanced refractory cancers/lymphomas/

multiple myeloma.

To evaluate the proportion of patients alive and

progression free at six months of treatment with

targeted study agent in patients with advanced

refractory cancers/lymphomas/multiple myeloma.

To evaluate the time until death or disease

progression.

To identify potential predictive biomarkers beyond

the genomic alteration by which treatment is assigned

or resistance mechanisms using additional genomic,

RNA, protein and imaging-based assessment

platforms.

To assess whether radiomic phenotypes obtained

from pre-treatment imaging and changes from pre-

through post-therapy imaging can predict Objective

Response and Progression Free Survival and to

evaluate the association between pre-treatment

radiomic phenotypes and targeted gene mutation

patterns of tumor biopsy specimens.

Patient Population Patients must have histologically documented solid

tumors or histologically confirmed diagnosis of

lymphoma or multiple myeloma that has progressed

following at least one line of standard systemic

therapy and/or for whose disease no standard

treatment exists that has been shown to prolong

survival. Patients must have measurable disease and

meet one of the criteria in the protocol regarding

tissue procurement.

Patients must not currently be receiving any other

investigational agents. Any prior therapy,

radiotherapy (except palliative radiation therapy of

30 Gy or less), or major surgery must have been

completed at least four weeks prior to treatment on

NCI-MATCH and all adverse events due to prior

therapy must have resolved to a Grade 1 or better

(except alopecia and lymphopenia) by start of

Treatment for

Molecular Profile of

Interest

*As of May 1, 2017, patients must be screened via one of the outside laboratories listed in the

protocol and only those patients with an applicable rare variant mutation of interest are eligible

for subprotocol enrollment.

Toxicity or

Progression

Molecular Profiling

by Outside Lab


EAY131

treatment. Palliative radiation therapy must have been

completed at least two weeks prior to start of

treatment. Patients with brain metastases or primary

brain tumors must have completed treatment,

surgery, or radiation therapy at least four weeks prior

to start of treatment. Patients must have discontinued

steroids at least one week prior to registration and

remain off steroids thereafter, except as permitted in

the protocol. Patients with glioblastoma must have

been on a stable dose of steroids, or be off steroids,

for one week prior to registration to treatment step.

Patients must not require the use of full dose

coumarin-derivative anticoagulants. Low molecular

weight heparin is permitted for prophylactic or

therapeutic use. Factor X inhibitors are permitted.

Patients may receive non-protocol treatment after

biopsy (if clinically indicated) until they receive

notification of results, but patients may not enroll in

another investigational study during this time and the

therapy cannot be an arm in this trial.

Patients must be at least 18 years of age, have an

ECOG performance status of 0 or 1, must have a life

expectancy of at least three months, and must be able

to swallow tablets. Patients must have adequate

hematologic, hepatic, renal, cardiac and marrow

function. Patients must not have any uncontrolled

intercurrent illness. HIV-positive patients are eligible

provided they meet protocol criteria. Each

subprotocol will have additional eligibility criteria

that will be outlined in Section 2.0 of the agent-

specific subprotocol.

Only sites utilizing the CIRB as their IRB of record

are able to participate in the trial.

Accrual Goals The target screening accrual for this study is

approximately 6,452 patients, with the goal of

accruing 35 patients in each treatment subprotocol. If

after screening 500 patients the total number of

patients with actionable tumor alteration (therefore

qualifying for treatment) is below 50, results will be

presented to the steering committee for consideration

of trial termination. Within any given subprotocol, if

rate of enrollment is such that it is unlikely accrual

can reach 25 patients by the time the overall study

screening accrual goal is met, and if 13 patients have

been treated and no responses have been observed,

then the steering committee may consider terminating

accrual in that subgroup due to lack of feasibility.

After 500 patients are screened, the study design will

be reassessed to assure its appropriateness. An

interim analysis of the assay results will be

performed after biopsies from approximately the first

200 patients are processed.


Early Therapeutics and Rare Cancers chapter.

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

Page 1

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

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


Page 2

Purpose of Study Primary Endpoint (1) To compare overall survival for patients receiving ipilimumab plus bevacizumab versus ipilimumab alone. Secondary Endpoints (1) To evaluate the progression free survival, response rate and safety in patients receiving ipilimumab plus bevacizumab versus ipilimumab alone. (2) To evaluate the utility of immune related response criteria (irRC) in patients receiving ipilimumab plus bevacizumab versus ipilimumab alone. Study Population Patients with measurable metastatic melanoma, no more than one prior therapy for metastatic disease, no prior therapy with bevacizumab or ipilimumab. Summary of Study Design In this randomized phase II study, patients with advanced melanoma will be equally randomized to Arm A: Iplimumab (Ipi) or Arm B: Ipi + Bevacizumab using the stratification factors (Prior Therapy and BRAF mutation status). The stratified randomization will be based on the permuted block method. The primary objective is to compare overall survival between Arms A vs. B. The secondary objectives are to evaluate the progression-free survival, response rate, safety and utility of immune related response criteria (irRC) in patients in Arms A vs. B. The primary comparison will be OS in arms A vs. B. It will be an ITT analysis in all eligible patients. It is assumed that the median OS in patients treated in arm A will be around 11 months and the median OS will be improved to 16.5 months (50% improvement) in arm B. If the OS follows an exponential distribution, this difference corresponds to an improvement of one-year OS rate from 47% (in arm A) to 60% (in arm B). A comparison of arms A vs. B will be made using a stratified logrank test with one-sided type I error of 10%. One interim analysis will be performed at 50% information time (57 deaths), with the final analysis at 114 deaths. To preserve the overall type I error rate, critical values at the analyses will be determined using the O'Brien and Fleming boundary. Under the accrual and failure rate assumptions below, one interim and final analyses are expected to occur at 12 and 28 months after activation. The repeated confidence interval (RCI) of Jennison-Turnbull will also be evaluated at the interim analysis. This design will provide power of 80%. Progress to Date This study was open between December 13, 2013 and September 25, 2017. Final accrual was 169 patients. Table 1a summarizes accrual by institution and Table 1b has accrual by group. Expected cumulative accrual and actual cumulative accrual are shown in Figure 1. Patient status as of January 24, 2018 is displayed in Table 2. Demographics of patients by treatment arm are summarized in Table 3. Record status on clinical report form is summarized in Table 4. The distribution of the reasons for treatment discontinuation of protocol treatment is summarized in Table 5. Toxicities have been reported for 164 patients (82 in each arm) as of January 24, 2018. Treatment-related grade 3 or higher toxicities are summarized in Table 6. Table 7 summarizes 2 cases with (treatment-related) lethal toxicities reported via ECOG-ACRIN CRFs. Based on CTEP AERS reporting, there were 13 additional cases with lethal adverse events: 36005 (arm A) cardiac arrest, 36122 (arm A) death NOS, 36131 (arm A) neoplasms, 36143 (arm A) cardiac arrest, 36148 (arm A) heart failure, 36160 (arm A) neoplasms, 36169 (arm A) death NOS, 36017 (arm B) aspiration, 36113 (arm B) death, 36142 (arm B) neoplasms, 36155 (arm B) neoplasms, 36158 (arm B) cardiac arrest and 36163 (arm B) sepsis. All these cases have been reviewed using the data collected on ECOG-ACRIN CRFs. All of them were considered having lethal adverse events unrelated to the treatment. Table 8 summaries second primary cancers.


Page 3

Table 1a. Accrual by ECOG-ACRIN Institution

Institution Name Step 1

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

Table 1b. Accrual by Group

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


Page 4

Table 2. Patient Status as of January 24, 2018

Cases Entered 169 Ineligible 7 Never Started Assigned Therapy 4

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

Table 3. Demographics

Variable Level Arm A (n=85)

Arm B (n=84)

Total (n=169)

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

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

Ethnicity Hispanic 2 (2.4) 3 (3.7) 5 (3.0) Non-Hispanic 80 (97.6) 79 (96.3) 159 (97.0) Unknown/Missing 3 2 5

Age Median 65 65 65 Minimum 26 36 26 Maximum 91 87 91

Table 4. Record Status

Form Name Forms

Due Forms

Received % Demography 170 170 100.0 Patient Characteristics 169 169 100.0 Treatment Agent: Bevacizumab 810 809 99.9 Treatment Agent: Ipilimumab 731 729 99.7 Adverse Event Form 1526 1499 98.2 Hematology/Chemistry 1387 1384 99.8 Late Adverse Event Form 2 1 50.0 Other Adverse Event Form 1137 1136 99.9 Disease Follow-Up Status Form (RECIST 1.1) 1521 1518 99.8 Off Treatment 156 156 100.0


Page 5

Table 5. Reasons Off Treatment (Includes all patients who started treatment and

for whom off-treatment data have been received)

Reasons N % Adverse event/side effects/complications 37 23.7 Alternative therapy 1 0.6 Death on study 8 5.1 Disease progression- relapse during active treatment 94 60.3 Other 9 5.8 Patient withdrawal/refusal after beginning protocol therapy 6 3.8 Treatment completed per protocol criteria 1 0.6 Total off treatment 156 100.0

Table 6. Toxicity Incidence

Toxicity Type Treatment Arm A (n=82) B (n=82)

Grade Grade 3 4 5 3 4 5

(%) (%) (%) (%) (%) (%) Anemia 1 - - 4 - - Atrial fibrillation - - - 1 - - Fatigue 5 - - 10 - - Fever 1 - - - - - Gait disturbance - - - 1 - - Sudden death NOS - - - - - 1 Erythema multiforme - - - 1 - - Pruritus - - - 2 - - Rash maculo-papular 9 - - 6 - - Skin ulceration - - - - 1 - Adrenal insufficiency 2 1 - 2 - - Endocrine disorders - Other, specify 1 - - 1 - - Hypothyroidism - - - 1 - - Abdominal pain 4 - - - - - Colitis 6 - - 6 - - Colonic perforation 1 - - 1 - - Diarrhea 16 - - 7 - - Gastrointestinal disorders - Other, specify - - - 1 - - Mucositis oral - - - 1 - - Nausea - - - 2 - - Pancreatitis - - - 1 - - Proctitis - - - 1 - - Rectal fistula - - - 1 - - Vomiting - - - 1 - - Cholecystitis - - - 1 - - Autoimmune disorder 4 - - - - - Infections and infestations - Other, specify - - - 1 - - Sepsis - 1 - - - - Sinusitis - - - 1 - -


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(%) (%) (%) (%) (%) (%) Wound infection - - - 1 - - Alanine aminotransferase increased 5 1 - 2 - - Aspartate aminotransferase increased 4 - - 2 - - Blood bilirubin increased 1 - - - - - Investigations - Other, specify - - - 1 - - Lipase increased 4 1 - 2 1 - Lymphocyte count decreased - 1 - - - - Serum amylase increased 1 - - - 1 - Anorexia - - - 2 - - Dehydration 1 - - 9 - - Hyperuricemia - - - - 1 - Hypoglycemia - 1 - - - - Hypokalemia 2 - - 1 - - Hyponatremia 5 - - 1 2 - Hypophosphatemia - - - 1 - - Metabolism and nutrition disorders - Other, specify - - - 1 - - Arthralgia - - - 1 - - Myalgia - - - 1 - - Generalized muscle weakness 1 - - 4 - - Headache 1 - - 2 - - Peripheral motor neuropathy 1 - - - - - Reversible posterior leukoencephalopathy syndrome - - - 1 - - Confusion - - - 1 - - Cough - - - 1 - - Dyspnea 2 - - - - - Proteinuria - - - 1 - - Acute kidney injury - - 1 - - - Hypertension 1 - - 35 - - Thromboembolic event - - - 1 - - WORST DEGREE 30 6 1 50 7 1

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

Case Arm Description of Event 36064 36086

A B

Acute kidney injury Sudden death NOS

Table 8. Second Primary Cancers

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

ECOG-ACRIN Cancer Research Group EA6141 Study Progress and Safety Report Spring 2018

Page 1

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 Jenna Hansel 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 Suspended Date Proposed July 9, 2014 Date Activated September 10, 2015 Date Suspended June 23, 2017 Date Phase II Started June 30, 2017 Schema


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


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For the logistical issues of reopening a phase III part, it is assumed it will begin 3 months after the phase II analysis is completed. For the phase III part, interim analyses of OS will be performed for all semi-annual DSMC meetings beginning when approximately 50% of the planned full information (133 deaths among all patients) has occurred, continuing until either criteria for early stopping are met or full information is reached. To preserve the overall type I error rate, critical values at the interim analyses will be determined using the Lan-DeMets spending function corresponding to the O'Brien-Fleming boundary. Under the accrual rate, follow up time, and failure rate assumptions above, interim analyses would be expected to occur at 0.25, 0.75, 1.3, 1.8, 2.3, 2.8 years after phase III accrual begins, at information times of 50%, 63%, 75%, 86%, 95%, and 100%. It will take approximately 2 years of additional follow up time after the last patient is randomized in phase III part. This study will also be monitored for early stopping for inefficacy. The approach of this monitoring will be based on the method proposed by Freidlin et al. (2010). Inefficacy monitoring will start around 50% information time. The study will be stopped if there is not at least a small trend in favor of the alternative hypothesis starting at this time. Specifically, an inefficacy monitoring boundary will begin at this time at a hazard ratio greater than 1 and will gradually increase to 20% of the targeted benefit at full information, subject to the requirement that two-sided 95% confidence interval for the log hazard ratio does not contain the design-alternative log hazard ratio of 0.67. The immune response will be assessed using the utility of Immune related response criteria (irRC). Standard response criteria (based on the RECIST) will be applied to assess clinical response. Immune response rate and clinical response rate will be compared between the two treatment arms. Progress to Date This study was activated on September 10, 2015 and suspended on June 23, 2017 as it reached the first stage accrual goal. As of June 23, 2017, 250 patients have enrolled. Table 1a summarizes accrual by institution. Table 1b has accrual by group and Table 1c shows projected accrual status as of January 24, 2018. Patient status as of January 24, 2018 is displayed in Table 2. Demographics of patients by treatment arm are summarized in Table 3 Record status as on clinical report form is summarized in Table 4. The distribution of the reasons for treatment discontinuation is summarized in Table 5. Toxicity data were reported for 122 cases in arm A and 119 cases in arm B as of January 24, 2018. Treatment-related toxicities are summarized in Table 6. The worst-degree grade 3 or higher toxicity rate was 51.6% in arm A and 66.4% in arm B. There were 3 grade 5 AEs in arm A and 2 in arm B. These cases with at least possibly treatment related grade 5 AEs are listed in Table 7. There are additional grade 5 AEs reported via CTEP-AERS system. They are: case 16010 (arm A) Dyspnea,16011 (arm A) neoplasms progression, 16064 (Arm A) respiratory failure, 16078 (arm A) deaths NOS, 16121 (arm A) aspiration, 16196 (arm A) cardiac disorder, 16233 (arm A) Deaths NOS and 16126 (arm B) neoplasms progression. Of these, cases 16010, 16011, 16064, 16121, 16196, 16126 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 1 Never Started Assigned Therapy 3

Reason for ineligibility (n=1):

No measurable disease (16242). 16170? Reason for not starting therapy (n=3): Withdrawal/refusal before beginning protocol therapy (16014); Death before therapy (16143); Ineligible (16170).


Variable Level Arm A

(n=126) Arm B

(n=124) Total

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

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

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




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Form Name Forms

Due Forms

Received % Demography 250 250 100.0 Patient Characteristics 250 248 99.2 Treatment Agent: Ipilimumab 806 805 99.9 Treatment Agent: Nivolumab 1975 1954 98.9 Treatment Agent: Sargramostim 1178 1153 97.9 Adverse Events 2077 2077 100.0 Hematology/Chemistry 250 247 98.8 Late Adverse Events 11 10 90.9 Disease Follow-Up Status Form (RECIST 1.1) 2243 2212 98.6 Off Treatment 174 172 98.9

Table 5. Reasons Off Treatment

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

Reasons N %

Adverse event/side effects/complications 94 52.8 Alternative therapy 5 2.8 Death on study 6 3.4 Disease progression- relapse during active treatment 44 24.7 Other 15 8.4 Patient off-treatment for other complicating disease 3 1.7 Patient withdrawal/refusal after beginning protocol therapy 10 5.6 Treatment completed per protocol criteria 1 0.6 Total off treatment 178 100.0


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Toxicity Type Treatment Arm

A (n=122) B (n=119) Grade Grade

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

Hearing impaired 1 - - - 1 - Anemia 1 - - 2 - - Blood and lymphatic system disorders - Other, specify 1 - - 1 - - Leukocytosis 1 - - - - - Atrioventricular block complete 1 - - - - - Myocarditis 1 - - - - - Death NOS - - 1 - - 1 Fatigue 5 - - 4 - - Fever - - - 1 - - Multi-organ failure - - - - - 1 Pain 1 - - - - - Non-cardiac chest pain 1 - - - - - Pruritus 2 - - 1 - - Rash maculo-papular 8 - - 8 - - Adrenal insufficiency 3 - - 3 - - Endocrine disorders - Other, specify 5 - - 3 - - Hyperthyroidism 1 - - - - - Hypothyroidism 1 - - 1 - - Abdominal pain 2 - - 2 - - Colitis 2 - - 9 - - Constipation 1 - - - - - Diarrhea 7 1 1 13 - - Duodenal ulcer 1 - - - - - Dysphagia - - - 1 - - Gastrointestinal disorders - Other, specify 1 - - - - - Mucositis oral - - - 2 - - Nausea 1 - - 3 - - Vomiting 1 - - 2 - - Lower gastrointestinal hemorrhage 1 - - - - - Hepatobiliary disorders - Other, specify - - - 1 1 - Allergic reaction 1 - - - - - Immune system disorders - Other, specify - - - 3 - - Autoimmune disorder 2 - - 1 - - Infections and infestations - Other, specify 1 - - 1 - - Skin infection 1 - - - - - Lung infection 1 - - 2 - - Fall 1 - - - - - Alanine aminotransferase increased 9 - - 11 - - Alkaline phosphatase increased 2 - - 2 - - Aspartate aminotransferase increased 3 1 - 9 - - Blood bilirubin increased 1 - - - - - CPK increased - - - 1 - - Creatinine increased - - - 2 - -


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(%) (%) (%) (%) (%) (%) Investigations - Other, specify - - - 1 - - Lipase increased 7 4 - 10 6 - Lymphocyte count decreased 1 1 - 1 - - Platelet count decreased 1 1 - - - - Serum amylase increased 5 - - 3 1 - Urine output decreased - 1 - - - - Acidosis - - - 1 1 - Anorexia 4 - - - - - Dehydration 2 - - 3 - - Hypercalcemia - - - 1 1 - Hyperglycemia 2 1 - 3 2 - Hyperkalemia 1 - - - - - Hyperuricemia - 2 - 1 2 - Hypokalemia - 2 - 1 - - Hyponatremia 2 - - 4 - - Back pain - - - 1 - - Bone pain 1 - - - - - Joint effusion - - - 1 - - Pain in extremity - - - 1 - - Generalized muscle weakness 2 - - - - - Muscle weakness lower limb 1 - - - - - Muscle weakness right-sided - - - 1 - - Dizziness 1 - - - - - Dysphasia - - - 1 - - Headache 2 - - 1 - - Nervous system disorders - Other, specify 1 - - - - - Peripheral motor neuropathy - - - 1 - - Peripheral sensory neuropathy - - - 1 - - Seizure 1 - - 1 - - Syncope 1 - - 1 - - Uveitis 1 - - - - - Adult respiratory distress syndrome 1 - - - - - Aspiration - - 1 - - - Dyspnea 1 - - 4 2 - Hypoxia 1 - - 1 - - Pneumonitis 2 - - 3 - - Respiratory, thoracic and mediastinal disorders - Other, specify - - - - 2 - Renal and urinary disorders - Other, specify 1 - - 1 - - Chronic kidney disease - 1 - - - - Acute kidney injury - - - 2 - - Hypotension 2 1 - 1 - - Thromboembolic event - - - 1 - - Lymphocele 1 - - - - - WORST DEGREE 37 12 2 51 13 2


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Case Arm Description of Event 16058 A Diarrhea 16242 A Aspiration 16245 A Death NOS 16067 B Death NOS 16232 B Multi-organ failure

Table 8. Second Primary Cancers

Site Arm A Liver, Gall Bladder, Bile Duct 1


Page 1

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

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


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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 January 24, 2018, 123 patients enrolled to step 1, and 20 to step 2. Table 1a summarizes accrual by institution. Table 1b has accrual by group, an Table 1c shows projected accrual status as of January 24, 2018. Expected cumulative accrual and actual cumulative accrual are shown in Figure 1. This report is based on the data as of January 24, 2018. Patient status is displayed in Table 2 with patients accrued at that time. Demographics of patients by treatment arm are summarized in Table 3 for Steps 1 and 2. Record status on clinical report form is summarized in Table 4. The distribution of the reasons for treatment continuation of protocol treatment is summarized in Table 5. As of January 24, 2018 there were 110 cases (54 in arm A, 56 in arm B in step 1) and 16 cases (5 in arm C and 10 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 10 cases with lethal adverse events: 46007 (arm A) respiratory failure, 46021 (arm A) neoplasms, 46280 (arm A) general disorder, 46052 (arm A) thromboembolic event, 46070 (arm A) nervous system disorder, 46102 (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, 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 3 0 Case Western Reserve University 2 0 Colorado Cancer Research Program NCORP 1 0 Dayton NCORP 3 2 Froedtert and the Medical College of Wisconsin 1 0 Georgia Cares Minority Underserved NCORP 1 0 Georgia NCORP 3 0 Hackensack University Medical Center 1 0 Heartland Cancer Research NCORP 3 0 Indiana Univ/Melvin and Bren Simon Cancer Center 3 1 Johns Hopkins Univ/Sidney Kimmel Cancer Center 3 1 Medical University of South Carolina MU NCORP 1 0 Metro Minnesota Community Oncology Res Consortium 4 2 Michigan Ca Res Consortium NCORP 2 0 Nevada Cancer Research Foundation NCORP 3 0 New Mexico MU NCORP 1 0 New York Oncology Hematology PC -Albany Med Center 1 0 Northwest NCI Community Oncology Research Program 1 0 Northwestern University 5 2 Ohio State University Comprehensive Cancer Center 2 0 Pacific Cancer Research Consortium NCORP 6 0 Saint Luke's University Hospital-Bethlehem Campus 1 0 Stanford Cancer Institute Palo Alto 1 0 University of Alabama at Birmingham Cancer Center 3 1 University of Miami Miller Schl Med-SylvesterCaCtr 2 0 University of Michigan Comprehensive Cancer Center 2 0 University of Pittsburgh Cancer Institute (UPCI) 9 0 University of Wisconsin Hospital and Clinics 1 0 Vanderbilt University/Ingram Cancer Center 4 1 Wisconsin NCORP 4 0 Total 78 10


Step 1 Step 2 ECOG-ACRIN 78 10 SWOG 25 5 ALLIANCE 6 2 NRG 14 3 Total 123 20


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Table 1c. Projected Accrual

Step 1 Step 2

Accrual goal 300 Planned accrual rate 192/yr Accrual to date 123 20 Annual accrual rate

Overall 52/yr 9/yr Last 6 months 66/yr 8/yr Projected date of closure September 2020


Step 1 Step 2 Cases Entered 123 20 Ineligible 0 0 Never Started Assigned Therapy 0 0


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Step 1

Variable Level Arm A (n=61)

Arm B (n=62)

Total (n=123)

Sex Male 32 (52.5) 40 (64.5) 72 (58.5) Female 29 (47.5) 22 (35.5) 51 (41.5)

Race White 59 (98.3) 60 (100.0) 119 (99.2) Asian 1 (1.7) 0 (0.0) 1 (0.8) Unknown/Unreported 1 2 3



Step 2

Variable Level Arm C

(n=9) Arm D (n=11)

Total (n=20)

Sex Male 3 (33.3) 7 (63.6) 10 (50.0) Female 6 (66.7) 4 (36.4) 10 (50.0)

Race White 9 (100.0) 11 (100.0) 20 (100.0) Ethnicity Non-Hispanic 8 (100.0) 10 (100.0) 18 (100.0)

Unknown/Missing 1 1 2 Age Median 58 54 55

Minimum 31 34 31 Maximum 79 70 79


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Form Name Forms

Due Forms

Received % Demography 122 122 100.0 Patient Characteristics 137 136 99.3 Treatment Agent: Dabrafenib 298 291 97.7 Treatment Agent: Ipilimumab - Induction 109 107 98.2 Treatment Agent: Nivolumab - Induction 109 107 98.2 Treatment Agent: Nivolumab - Maintenance 117 117 100.0 Treatment Agent: Trametinib 298 290 97.3 Adverse Event Form 524 497 94.9 Hematology/Chemistry 137 136 99.3 Other Adverse Event Form 396 394 99.5 Disease Follow-Up Status Form (RECIST 1.1) 584 569 97.4 Off Treatment 10 10 100.0 Off-Treatment with Intent to Reg Next Step 65 65 100.0

Table 5. Reasons Off Treatment Step 1

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


Reasons N % Adverse event/side effects/complications 19 40.4 Death on study 5 10.6 Disease progression- relapse during active treatment 16 34.0 Other 2 4.3 Patient withdrawal/refusal after beginning protocol therapy 4 8.5 Treatment completed per protocol criteria 1 2.1 Total off treatment 47 100.0

Step 2 (Includes all patients who started treatment and


Reasons N % Adverse event/side effects/complications 1 10.0 Disease progression- relapse during active treatment 8 80.0 Treatment completed per protocol criteria 1 10.0 Total off treatment 10 100.0


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Step 1

Toxicity Type

Treatment Arm A (n=54) B (n=56)


(%) (%) (%) (%) (%) (%) Anemia - - - 4 - - Disseminated intravascular coagulation - 2 - - - - Febrile neutropenia - - - 4 - - Leukocytosis 4 - - - - - Cardiac disorders - Other, specify - 2 - - - - Myocarditis 2 - - - - - Fatigue 7 - - 7 - - Fever - - - 7 - - Pain - - - 2 - - Edema limbs 4 - - - - - Infusion related reaction 2 - - - - - Rash maculo-papular 11 - - 2 - - Endocrine disorders - Other, specify - 2 - - - - Abdominal pain 2 - - - - - Colitis 4 - - - - - Diarrhea 24 2 - - - - Enterocolitis 2 - - - - - Gastrointestinal disorders - Other, specify 2 - - - - - Ileus 2 - - - - - Nausea 11 - - - - - Vomiting 6 - - 2 - - Hepatic failure 2 - - - - - Autoimmune disorder 2 - - - - - Sepsis - 2 - - 2 - Urinary tract infection 2 - - - - - Enterocolitis infectious 4 - - - - - Alanine aminotransferase increased 4 2 - - - - Aspartate aminotransferase increased 4 2 - - - - Blood bilirubin increased 2 4 - - - - Creatinine increased 4 - - 2 - - Lipase increased 4 11 - 4 - - Lymphocyte count decreased - - - 2 - - Neutrophil count decreased - - - 2 - - Serum amylase increased 2 2 - - 2 - Ejection fraction decreased - - - 2 - - Anorexia 4 - - - - - Dehydration 6 - - - - - Hypercalcemia 2 - - - - - Hyperglycemia 6 2 - - - - Hypoalbuminemia 7 - - - - - Hypokalemia 4 - - 2 - -

Toxicity Type

Treatment Arm A (n=54) B (n=56)


(%) (%) (%) (%) (%) (%) Hyponatremia 4 - - 4 2 - Hypophosphatemia 2 - - - - - Arthralgia 6 - - - - - Back pain 2 - - - - - Musculoskeletal and connective tissue disorder - Other, specify 2 - - - - - Myalgia 2 - - - - - Generalized muscle weakness 2 - - - - - Headache 2 - - - - - Hypersomnia 2 - - - - - Peripheral sensory neuropathy 2 - - - - - Syncope - - - 5 - - Retinal detachment - - - 2 - - Adult respiratory distress syndrome - 2 - - - - Pneumonitis 2 - - - - - Respiratory failure - - 2 - - - Acute kidney injury 4 - - - - - Hypertension 4 - - - - - Hypotension 2 - - 2 - - Thromboembolic event - - - 2 - - WORST DEGREE 48 20 2 34 5 -

Step 2

Toxicity Type

Treatment Arm C (n=5) D (n=11) Grade Grade

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

Anemia - - - 9 - - Fatigue - - - 18 - - Fever 20 - - 9 - - Rash maculo-papular 20 - - - - - Lipase increased - - - 9 - - Lymphocyte count decreased - - - 9 - - Dehydration - - - 9 - - Hypernatremia 20 - - - - - Hyponatremia - - - 9 - - Pneumonitis - - - 9 - - WORST DEGREE 40 - - 45 - -


Case Arm Description of Event 46007 A Respiratory failure

Table 8. QOL Table

QOL Timepoint

Patients Reaching

Timepoint % Forms

Completed Baseline Step 1 118 84.7 End of Cycle 1 in Step 1 - Arm A 50 50.0 End of Cycle 1 in Step 1 - Arm B 53 86.8 End of Cycle 2 in Step 1 - Arm A 47 38.3 End of Cycle 2 in Step 1 - Arm B 46 63.0 Disease stability or 6 Mos. Step 1-Arm A 36 22.2 Disease stability or 6 Mos. Step 1-Arm B 36 30.6 End of Step 1 Treatment 31 100.0 Baseline Step 2 19 73.7 End of Cycle 1 in Step 2 - Arm C 6 66.7 End of Cycle 1 in Step 2 - Arm D 10 60.0 End of Cycle 2 in Step 2 - Arm C 7 71.4 End of Cycle 2 in Step 2 - Arm D 10 40.0 Disease stability or 6 Mos. Step 2-Arm C 5 60.0 Disease stability or 6 Mos. Step 2-Arm D 9 33.3 End of Step 2 Treatment 6 100.0 12 Mos. from study entry - Arm B 22 0.0 12 Mos. from study entry - Arm A 23 13.0 18 Mos. from study entry - Arm B 11 0.0 18 Mos. from study entry - Arm A 11 9.1

MELANOMA COMMITTEE - SWOG 2018/Melanoma.pdf · melanoma. Patients must have BRAF mutation-positive...

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Transcript of MELANOMA COMMITTEE - SWOG 2018/Melanoma.pdf · melanoma. Patients must have BRAF mutation-positive...