Clinical trial NCT04305054: Substudy 02B: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents or Pembrolizumab Alone in Participants With First Line (1L) Advanced Melanoma (MK-3475-02B/KEYMAKER-U02)
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 02B
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Melanoma
Keywords: programmed cell death 1 (PD-1, PD1)
programmed cell death ligand 1 (PD-L1, PDL1)
T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine receptor motif domains (TIGIT)
Cytotoxic T lymphocyte associated protein 4 (CTLA4)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2020-03-12
Enrollment: 315
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Substudy 02B is part of a larger research study where researchers are looking for new ways to treat advanced melanoma that has not been treated before. The larger study is the umbrella study. Researchers want to know if adding other treatments to pembrolizumab can treat advanced melanoma. The goals of this study are to learn:

* About the safety and how well people tolerate pembrolizumab given with other treatments
* How many people have melanoma that responds (gets smaller or goes away) to treatment

Arm 1: Pembrolizumab + Vibostolimab was added in the base protocol on 13-Nov-2019, and enrollment into this arm has been completed. Arm 2: Pembrolizumab was added in the base protocol on 13-Nov-2019, and enrollment stopped prematurely on 15-Aug-2022. Arm 3: Coformulation Pembrolizumab/Quavonlimab was added in Amendment 01 on 20-Oct-2020, and enrollment stopped prematurely on 15-Aug-2022. Arm 4: Coformulation Pembrolizumab/Quavonlimab + Lenvatinib was added in Amendment 01 on 20-Oct-2020, and enrollment is ongoing. Arm 5: Coformulation Favezelimab/Pembrolizumab was added in Amendment 03 on 01-DEC-2022 and has paused enrollment, Arm 6: Coformulation Favezelimab/Pembrolizumab + All-trans Retinoic Acid (ATRA) was added in Amendment 03 on 01-DEC-2022 and has paused enrollment, and Arm 7: Coformulation Favezelimab/Pembrolizumab + Vibostolimab was added in Amendment 03 on 01-DEC-2022 and enrollment was stopped prematurely on 22-SEP-2023.

Detailed description: With Amendment 5, participants receiving vibostolimab (Arm 1 and Arm 7) will discontinue treatment with vibostolimab and will be transitioned within their arm to pembrolizumab monotherapy. Participants receiving favezelimab (Arm 5, Arm 6, and Arm 7) may continue on study therapy until the end of study or may transition within their arm to pembrolizumab monotherapy. Participants with access to approved standard of care (SOC, pembrolizumab plus chemotherapy) should be considered for discontinuation from the study. Those benefiting from pembrolizumab with chemotherapy, but unable to access it as SOC outside the study, may continue on study and receive treatment with pembrolizumab plus chemotherapy until discontinuation criteria are met.

Eligibility criteria: Inclusion Criteria:

* Has histologically or cytologically confirmed melanoma
* Has unresectable Stage III or Stage IV melanoma, not amenable to local therapy
* Has been untreated for advanced disease.
* Has provided a tumor biopsy
* If capable of producing sperm, male participants agree to the following during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention (7 days):

  * Abstains from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) and agrees to remain abstinent OR
  * Uses contraception unless confirmed to be azoospermic
* A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:

  * Is not a WOCBP OR
  * Is a WOCBP and Uses a contraceptive method that is highly effective, with low user dependency, or be abstinent from penile-vaginal intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) during the intervention period and for at least the time needed to eliminate each study intervention after the last dose of study intervention. The length of time required to continue contraception for each study intervention is:
  * MK-4280A: 120 days
  * MK-1308A: 120 days
  * MK-7684: 50 days
  * MK-3475: 120 days
  * Lenvatinib: 30 days
  * ATRA: 30 days
* Has adequate organ function
* Has resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia and Grade 2 neuropathy)

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 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 history of Hepatitis B or known Hepatitis C virus infection
* 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 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 a known psychiatric or substance abuse disorder that would interfere with requirements of the study
* Participants who receive lenvatinib have the following additional exclusion criteria:

  * Has a pre-existing Grade ≥3 gastrointestinal or non-gastrointestinal fistula
  * Has radiographic evidence of encasement of invasion of a major blood vessel, or of intratumoral cavitation
  * Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first dose of study intervention
  * Has clinically significant cardiovascular disease within 12 months from first dose of study intervention
  * Has urine protein ≥1 g/24-hour.
  * Has presence of gastrointestinal condition including malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of lenvatinib

Primary outcomes:
measure: Percentage of participants who experience a dose-limiting toxicity (DLT): Safety lead-in phase
timeFrame: Up to ~3 weeks
measure: Percentage of participants who experience an adverse event (AE): Safety lead-in
timeFrame: Up to ~3 weeks
measure: Percentage of participants who discontinue study treatment due to an AE: Safety lead-in
timeFrame: Up to ~3 weeks
measure: Percentage of participants who experience an adverse event (AE)
timeFrame: Up to ~28 months
measure: Percentage of participants who discontinue study treatment due to an AE
timeFrame: Up to ~24 months
measure: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1)
timeFrame: Up to ~30 months
Secondary outcomes:
measure: Duration of Response (DOR) per RECIST 1.1
timeFrame: Up to ~30 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: The Angeles Clinic and Research Institute ( Site 2009)
state: California
city: Los Angeles
country: United States
facility: UCLA Hematology & Oncology ( Site 2004)
state: California
city: Santa Monica
country: United States
facility: Providence Saint John's Health Center ( Site 2010)
state: California
city: Aurora
country: United States
facility: University of Colorado, Anschutz Cancer Pavilion ( Site 2012)
state: Colorado
city: Gainesville
country: United States
facility: University of Florida College of Medicine-UF Health Cancer Center/Clinical Trials Office ( Site 2026)
state: Florida
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ( Site 2022)
state: Maryland
city: Lake Success
country: United States
facility: R.J. Zuckerberg Cancer Center ( Site 2032)
state: New York
city: New York
country: United States
facility: NYU Clinical Cancer Center ( Site 2002)
state: New York
city: Durham
country: United States
facility: Duke Cancer Institute ( Site 2005)
state: North Carolina
city: Columbus
country: United States
facility: Martha Morehouse Tower ( Site 2020)
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University ( Site 2013)
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Abramson Cancer Center ( Site 2008)
state: Pennsylvania
city: Germantown
country: United States
facility: West Cancer Center - East Campus ( Site 2014)
state: Tennessee
city: San Antonio
country: United States
facility: Mays Cancer Center ( Site 2025)
state: Texas
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute ( Site 2011)
state: Virginia
city: Caba.
country: Argentina
facility: Clinica Adventista Belgrano-Oncology ( Site 2242)
state: Buenos Aires
city: Waratah
country: Australia
facility: Calvary Mater Newcastle-Medical Oncology ( Site 2404)
state: New South Wales
city: Wollstonecraft
country: Australia
facility: Melanoma Institute Australia ( Site 2402)
state: New South Wales
city: Southport
country: Australia
facility: Tasman Oncology Research Pty Ltd ( Site 2403)
state: Queensland
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital ( Site 2401)
state: Western Australia
city: Temuco
country: Chile
facility: CIDO SpA-Oncology ( Site 2256)
state: Araucania
city: Santiago
country: Chile
facility: Bradfordhill ( Site 2252)
state: Region M. De Santiago
city: Bogota
country: Colombia
facility: Clinica Colsanitas S.A, Sede Clínica Universitaria Colombia-Center Investigator ( Site 2261)
state: Distrito Capital De Bogota
city: Cali
country: Colombia
facility: Fundación Valle del Lili ( Site 2265)
state: Valle Del Cauca
city: Marseille
country: France
facility: Hopital La Timone ( Site 2103)
state: Bouches-du-Rhone
city: Bordeaux
country: France
facility: CHU de Bordeaux- Hopital Saint Andre ( Site 2108)
state: Gironde
city: Toulouse cedex 9
country: France
facility: Institut Claudius Regaud ( Site 2105)
state: Haute-Garonne
city: Villejuif
country: France
facility: Gustave Roussy ( Site 2101)
state: Ile-de-France
city: Pierre Benite
country: France
facility: C.H. Lyon Sud ( Site 2102)
state: Rhone
city: Paris
country: France
facility: A.P.H. Paris, Hopital Saint Louis ( Site 2107)
city: Athens
country: Greece
facility: General Hospital of Athens "Laiko"-First Department of Internal Medicine ( Site 2212)
state: Attiki
city: Thessaloniki
country: Greece
facility: European Interbalkan Medical Center-Oncology Department ( Site 2211)
city: Szeged
country: Hungary
facility: Szegedi Tudományegyetem Szent-Györgyi Albert Klinikai Központ ( Site 2221)
state: Csongrad
city: Afula
country: Israel
facility: HaEmek Medical Center ( Site 2703)
city: Haifa
country: Israel
facility: Rambam Health Care Campus-Oncology ( Site 2704)
city: Jerusalem
country: Israel
facility: Hadassah Ein Karem Jerusalem ( Site 2702)
city: Petah-Tikva
country: Israel
facility: Rabin Medical Center-Oncology ( Site 2705)
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center ( Site 2701)
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano ( Site 2399)
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia ( Site 2301)
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Fondazione Pascale ( Site 2302)
city: Padova
country: Italy
facility: Istituto Oncologico Veneto IRCCS ( Site 2355)
city: Siena
country: Italy
facility: Policlinico Le Scotte - A.O. Senese ( Site 2377)
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy w Warszawie ( Site 2233)
state: Mazowieckie
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 2231)
state: Pomorskie
city: Port Elizabeth
country: South Africa
facility: CANCERCARE LANGENHOVEN DRIVE ONCOLOGY CENTRE ( Site 2865)
state: Eastern Cape
city: Pretoria
country: South Africa
facility: LIFE GROENKLOOF-Mary Potter Cancer Centre ( Site 2861)
state: Gauteng
city: Sandton
country: South Africa
facility: Sandton Oncology Medical Group (Pty) Ltd-Research ( Site 2863)
state: Gauteng
city: Tshwane
country: South Africa
facility: Steve Biko Academic Hospital-Medical Oncology ( Site 2862)
state: Gauteng
city: Cape Town
country: South Africa
facility: Cape Town Oncology Trials ( Site 2864)
state: Western Cape
city: Barcelona
country: Spain
facility: HOSPITAL CLÍNIC DE BARCELONA-ICHMO- Clinic Institut of Haematological and Oncological diseases ( Site 2801)
state: Cataluna
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal ( Site 2802)
state: Madrid, Comunidad De
city: Genève
country: Switzerland
facility: Hôpitaux Universitaires de Genève (HUG)-Oncology ( Site 2603)
state: Geneve
city: Lausanne
country: Switzerland
facility: CHUV Centre Hospitalier Universitaire Vaudois ( Site 2602)
state: Vaud
city: Zuerich Flughafen
country: Switzerland
facility: Universitaetsspital Zuerich ( Site 2601)
state: Zurich
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: