Substudy 02C: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents or Pembrolizumab Alone in Participants With Stage III Melanoma Who Are Candidates for Neoadjuvant Therapy (MK-3475-02C/KEYMAKER-U02)

Sponsor

Merck Sharp & Dohme LLC (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04303169

Collaborator

(none)

Enrollment

Locations

Arms

117.2

Anticipated Duration (Months)

3.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Substudy 02C is part of a larger research study that is testing experimental treatments for melanoma, a type of skin cancer. The larger study is the umbrella study.

The goal of substudy 02C is to evaluate the safety and efficacy of investigational treatment arms in participants with Stage III melanoma who are candidates for neoadjuvant therapy to identify the investigational agent(s) that, when used in combination, are superior to the current treatment options/historical control available.

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Biological: Pembrolizumab Biological: Vibostolimab Biological: V937 Biological: MK-4830 Biological: Favezelimab + Pembrolizumab Drug: ATRA	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

90 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2 Open-Label Rolling-Arm Umbrella Platform Design of Investigational Agents With or Without Pembrolizumab or Pembrolizumab Alone in Participants With Melanoma (KEYMAKER-U02): Substudy 02C

Actual Study Start Date :

Jun 26, 2020

Anticipated Primary Completion Date :

Apr 3, 2030

Anticipated Study Completion Date :

Apr 3, 2030

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pembrolizumab + Vibostolimab Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab intravenously (IV) plus vibostolimab IV at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.	Biological: Pembrolizumab Administered via IV infusion at a specified dose on specified days Other Names: MK-3475 KEYTRUDA® Biological: Vibostolimab Administered via IV infusion at a specified dose on specified days Other Names: MK-7684
Experimental: Pembrolizumab + V937 Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV plus V937 intratumorally (IT) at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.	Biological: Pembrolizumab Administered via IV infusion at a specified dose on specified days Other Names: MK-3475 KEYTRUDA® Biological: V937 Administered via IT injection at a specified dose on specified days Other Names: Coxsackievirus A21 (CVA21) Formerly known as CAVATAK® CAV21
Experimental: Pembrolizumab Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.	Biological: Pembrolizumab Administered via IV infusion at a specified dose on specified days Other Names: MK-3475 KEYTRUDA®
Experimental: Pembrolizumab + MK-4830 Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV plus MK-4830 IV at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.	Biological: Pembrolizumab Administered via IV infusion at a specified dose on specified days Other Names: MK-3475 KEYTRUDA® Biological: MK-4830 Administered via IV infusion at a specified dose on specified days
Experimental: Favezelimab + Pembrolizumab Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive MK-4280A (favezelimab and pembrolizumab administered as a co-formulation) IV at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.	Biological: Favezelimab + Pembrolizumab Administered via IV infusion at a specified dose on specified days Other Names: MK-4280A
Experimental: Pembrolizumab + all-trans retinoic acid (ATRA) Prior to tumor resection surgery, in the neoadjuvant phase, participants will receive pembrolizumab IV plus ATRA orally at specified doses on specified days. After surgery, in the adjuvant phase, participants will receive pembrolizumab IV at a specified dose on specified days. Participants will receive treatments in the neoadjuvant and adjuvant phase for a total treatment duration of up to approximately 1 year.	Biological: Pembrolizumab Administered via IV infusion at a specified dose on specified days Other Names: MK-3475 KEYTRUDA® Drug: ATRA Administered via oral capsules at a specified dose on specified days Other Names: Tretinoin Vesanoid®

Outcome Measures

Primary Outcome Measures

Percentage of participants who experience an adverse event (AE) [Up to ~16 months]
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who experience an AE will be reported.
Percentage of participants who discontinue study treatment due to an AE [Up to ~12 months]
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who discontinue study treatment due to an AE will be reported.
Pathological complete response (pCR) rate [Up to ~1.5 months]
pCR rate is defined as the proportion of participants with complete absence of viable tumor in the treated tumor bed. Assessments are according to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) by central review of the pathology results. RECIST 1.1 has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

Secondary Outcome Measures

Near pathological complete response (near pCR) rate [Up to ~1.5 months]
Near pCR is defined as the proportion of participants with >0% but ≤10% of viable tumor cells in the treated tumor bed. Assessments are according to RECIST 1.1 by central review of the pathology results. RECIST 1.1 has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Pathological partial response (pPR) rate [Up to ~1.5 months]
pPR rate is defined as the proportion of participants with >10% but ≤50% of the treated tumor bed occupied by viable tumor cells. Assessments are according to RECIST 1.1 by central review of the pathology results. RECIST 1.1 has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
Recurrence-free survival (RFS) [Up to ~60 months]
RFS is defined as the time from the date of surgery to (1) any recurrence (local, regional, or distant) as assessed by the investigator or (2) death due to any cause (both cancer and noncancer causes of death). Assessments are according to RECIST 1.1 which has been modified for this study to include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Has histologically or cytologically confirmed melanoma
Has clinically detectable and resectable Stage IIIB or IIIC or IIID melanoma amenable to surgery
Has been untreated for Stage IIIB, IIIC or IIID melanoma
surgical resection of primary melanoma is allowed
prior radiotherapy to the primary melanoma is allowed
Has provided a baseline tumor biopsy
Male participants who receive V937 are abstinent from heterosexual intercourse or agree to use contraception during the intervention period and for at least 120 days after the last dose of V937
Male participants who receive ATRA are abstinent from heterosexual intercourse or agree to use contraception during the intervention period and for at least 7 days after the last dose of ATRA
Female participants are not pregnant or breastfeeding and are either not a woman of child-bearing potential (WOCBP) OR use a contraceptive method that is highly effective or are abstinent from heterosexual intercourse during the intervention period and for at least 120 days after the last dose of pembrolizumab, vibostolimab, V937, or MK-4830, favezelimab + pembrolizumab, or 30 days after the last dose of ATRA, whichever occurs last
Has adequate organ function
Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia)

Exclusion Criteria:

Has a diagnosis of immunodeficiency or is receiving immunosuppressive therapy within 7 days before the first dose of study intervention
Has a known additional malignancy that is progressing or requires active treatment within the past 2 years
Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
Has ocular or mucosal melanoma
Has known hypersensitivity including previous clinically significant hypersensitivity reaction to treatment with another monoclonal antibody (mAb)
Has an active autoimmune disease that has required systemic treatment in the past 2 years
Has an active infection requiring systemic therapy
Has known history of human immunodeficiency virus (HIV)
Has known history of hepatitis B
Has a history of (noninfectious) pneumonitis
Has a history of active tuberculosis (TB)
Has received prior systemic anticancer therapy within 4 weeks prior to randomization
Has received prior radiotherapy within 2 weeks of first dose of study intervention
Has had major surgery <3 weeks prior to first dose of study intervention
Has received a live or live-attenuated vaccine within 30 days before the first dose of study intervention
Has participated in a study of an investigational agent within 4 weeks prior to the first dose of study intervention
Has had an allogeneic tissue/solid organ transplant
Has only mucosal lesions
Is not naïve to Talimogene laherparepvec (TVEC) and other oncolytic viruses

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Angeles Clinic and Research Institute ( Site 3009)	Los Angeles	California	United States	90025
2	Providence Saint John's Health Center ( Site 3010)	Santa Monica	California	United States	90404
3	University of Colorado, Anschutz Cancer Pavilion ( Site 3012)	Aurora	Colorado	United States	80045
4	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ( Site 3022)	Baltimore	Maryland	United States	21287
5	NYU Clinical Cancer Center ( Site 3002)	New York	New York	United States	10016
6	Duke Cancer Institute ( Site 3005)	Durham	North Carolina	United States	27710
7	Oregon Health & Science University ( Site 3013)	Portland	Oregon	United States	97239
8	University of Pennsylvania Abramson Cancer Center ( Site 3008)	Philadelphia	Pennsylvania	United States	19104
9	West Cancer Center - East Campus ( Site 3014)	Germantown	Tennessee	United States	38138
10	Inova Schar Cancer Institute ( Site 3011)	Fairfax	Virginia	United States	22031
11	Melanoma Institute Australia ( Site 3402)	Wollstonecraft	New South Wales	Australia	2065
12	Tasman Oncology Research Pty Ltd ( Site 3403)	Southport	Queensland	Australia	4215
13	Fiona Stanley Hospital ( Site 3401)	Murdoch	Western Australia	Australia	6150
14	Hopital La Timone ( Site 3103)	Marseille	Bouches-du-Rhone	France	13005
15	Institut Claudius Regaud ( Site 3105)	Toulouse cedex 9	Haute-Garonne	France	31059
16	Gustave Roussy ( Site 3101)	Villejuif	Ile-de-France	France	94800
17	Centre Hospitalier Lyon Sud ( Site 3102)	Pierre Benite	Rhone	France	69495
18	A.P.H. Paris, Hopital Saint Louis ( Site 3107)	Paris		France	75010
19	HaEmek Medical Center ( Site 3703)	Afula		Israel	1834111
20	Rambam Health Care Campus-Oncology ( Site 3704)	Haifa		Israel	3109601
21	Hadassah Ein Karem Jerusalem ( Site 3702)	Jerusalem		Israel	9112001
22	Chaim Sheba Medical Center ( Site 3701)	Ramat Gan		Israel	5265601
23	Istituto Europeo di Oncologia ( Site 3301)	Milano		Italy	20141
24	Policlinico Le Scotte - A.O. Senese ( Site 3377)	Siena		Italy	53100
25	CHUV Centre Hospitalier Universitaire Vaudois ( Site 3602)	Lausanne	Vaud	Switzerland	1011
26	Universitaetsspital Zuerich ( Site 3601)	Zuerich Flughafen	Zurich	Switzerland	8058