Clinical trial NCT04305041: Substudy 02A: Safety and Efficacy of Pembrolizumab in Combination With Investigational Agents in Participants With Programmed Cell-death 1 (PD-1) Refractory Melanoma (MK-3475-02A/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 02A
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Melanoma
Keywords: receptor tyrosine kinase inhibitor
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)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2020-03-12
Enrollment: 200
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 02A 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 02A is to evaluate the safety and efficacy of investigational treatment arms in participants with PD-1 refractory melanoma to identify the investigational agent(s) that, when used in combination, are superior to the current treatment options/historical control available.

As of Amendment 4 (effective date: 05JAN2022), a third arm has been opened to participant enrollment, treatment with pembrolizumab and all-trans retinoic acid (ATRA). Enrollment into the first two arms, treatment with pembrolizumab + quavonlimab+ vibostolimab and treatment with pembrolizumab + quavonlimab + lenvatinib has been completed per protocol as of September 2021.


Eligibility criteria: Inclusion Criteria:

* Has histologically or cytologically confirmed melanoma
* Has unresectable Stage III or Stage IV melanoma, not amenable to local therapy
* Has progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other therapies
* Has imaging documenting progression per RECIST 1.1 and iRECIST after initiation of an anti-PD-1/L1 agent, or by RECIST 1.1 if progression occurred on adjuvant therapy or in the setting of rapid progression.
* Has not received more than 3 lines of therapy for their advanced melanoma
* Has provided a tumor biopsy
* Male participants who receive lenvatinib or 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 lenvatinib or ATRA; for male participants who only receive pembrolizumab, quavonlimab, vibostolimab, or a combination, no contraception measures are needed
* Female participant 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, quavonlimab, vibostolimab or 30 days after the last dose of lenvatinib or 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 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 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 pre-existing Grade ≥3 gastrointestinal fistula or nongastrointestinal fistula
* Has radiographic evidence of encasement of invasion of 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

Primary outcomes:
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 1009)
state: California
city: Los Angeles
country: United States
facility: UCLA Hematology & Oncology ( Site 1004)
state: California
city: Santa Monica
country: United States
facility: Providence Saint John's Health Center ( Site 1010)
state: California
city: Aurora
country: United States
facility: University of Colorado, Anschutz Cancer Pavilion ( Site 1012)
state: Colorado
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ( Site 1022)
state: Maryland
city: New York
country: United States
facility: NYU Clinical Cancer Center ( Site 1002)
state: New York
city: Durham
country: United States
facility: Duke Cancer Institute ( Site 1005)
state: North Carolina
city: Columbus
country: United States
facility: Martha Morehouse Tower ( Site 1020)
state: Ohio
city: Portland
country: United States
facility: Oregon Health & Science University ( Site 1013)
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Abramson Cancer Center ( Site 1008)
state: Pennsylvania
city: Germantown
country: United States
facility: West Cancer Center - East Campus ( Site 1014)
state: Tennessee
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center ( Site 1006)
state: Texas
city: Fairfax
country: United States
facility: Inova Schar Cancer Institute ( Site 1011)
state: Virginia
city: Waratah
country: Australia
facility: Calvary Mater Newcastle-Medical Oncology ( Site 1404)
state: New South Wales
city: Wollstonecraft
country: Australia
facility: Melanoma Institute Australia ( Site 1402)
state: New South Wales
city: Southport
country: Australia
facility: Tasman Oncology Research Pty Ltd ( Site 1403)
state: Queensland
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital ( Site 1401)
state: Western Australia
city: Marseille
country: France
facility: Hopital La Timone ( Site 1103)
state: Bouches-du-Rhone
city: Bordeaux
country: France
facility: Hopital Saint Andre ( Site 1108)
state: Gironde
city: Toulouse cedex 9
country: France
facility: Institut Claudius Regaud ( Site 1105)
state: Haute-Garonne
city: Villejuif
country: France
facility: Gustave Roussy ( Site 1101)
state: Ile-de-France
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud ( Site 1102)
state: Rhone
city: Paris
country: France
facility: A.P.H. Paris, Hopital Saint Louis ( Site 1107)
city: Afula
country: Israel
facility: HaEmek Medical Center ( Site 1703)
city: Haifa
country: Israel
facility: Rambam Health Care Campus-Oncology ( Site 1704)
city: Jerusalem
country: Israel
facility: Hadassah Ein Karem Jerusalem ( Site 1702)
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center ( Site 1701)
city: Milano
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori di Milano ( Site 1399)
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia ( Site 1301)
city: Napoli
country: Italy
facility: Istituto Nazionale Tumori Fondazione Pascale ( Site 1302)
city: Padova
country: Italy
facility: Istituto Oncologico Veneto IRCCS ( Site 1355)
city: Siena
country: Italy
facility: Policlinico Le Scotte - A.O. Senese ( Site 1377)
city: Port Elizabeth
country: South Africa
facility: CANCERCARE LANGENHOVEN DRIVE ONCOLOGY CENTRE-Clinical Trials Unit ( Site 1865)
state: Eastern Cape
city: Genève
country: Switzerland
facility: Hôpitaux Universitaires de Genève (HUG)-Oncology ( Site 1603)
state: Geneve
city: Lausanne
country: Switzerland
facility: CHUV Centre Hospitalier Universitaire Vaudois ( Site 1602)
state: Vaud
city: Zuerich Flughafen
country: Switzerland
facility: Universitaetsspital Zuerich ( Site 1601)
state: Zurich
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: