Clinical trial NCT04626518: Substudy 03B: A Study of Immune and Targeted Combination Therapies in Participants With Second Line Plus (2L+) Renal Cell Carcinoma (MK-3475-03B/KEYMAKER-U03)
Official title: A Phase 1b/2 Study of Immune and Targeted Combination Therapies in Participants With RCC (KEYMAKER-U03): Substudy 03B in Second-Line Metastatic Participants
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Carcinoma, Renal Cell
Keywords: receptor tyrosine kinase inhibitor
programmed cell death 1 (PD-1, PD1)
programmed cell death ligand 1 (PD-L1, PDL1)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2020-11-12
Enrollment: 370
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 03B is part of a larger research study that is testing experimental treatments for renal cell carcinoma (RCC). The larger study is the umbrella study (U03).

The goal of substudy 03B is to evaluate the safety and efficacy of experimental combinations of investigational agents in participants with advanced second line plus (2L+) clear cell renal cell carcinoma (ccRCC).

This substudy will have two phases: a safety lead-in phase and an efficacy phase. The safety lead-in phase will be used to demonstrate a tolerable safety profile for the combination of investigational agents. There will be no hypothesis testing in this study.


Eligibility criteria: Inclusion Criteria:

* Has a histologically confirmed diagnosis of locally advanced/metastatic clear cell renal cell carcinoma (ccRCC)
* Has experienced disease progression on or after having received systemic treatment for locally advanced or metastatic RCC with a programmed cell death ligand 1 (PD-(L)1) checkpoint inhibitor (in sequence or in combination with a vascular endothelial growth factor. - tyrosine kinase inhibitor \[VEGF-TKI\]) where PD-(L)1 checkpoint inhibitor treatment progression is defined by meeting ALL of the following criteria: (a) has received ≥2 doses of an anti-PD-(L)1 monoclonal antibody (mAb) (b) has shown radiographic disease progression during or after an anti-PD-(L)1 mAb as defined by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) by investigator (c) disease progression has been documented within 12 weeks from the last dose of an anti-PD-(L)1 mAb
* Has experienced disease progression on or after having received systemic treatment for locally advanced or metastatic RCC with a VEGF-TKI (in sequence or in combination with a PD-\[L\]1 checkpoint inhibitor) where VEGF-TKI treatment progression is defined by meeting the following criterion: has shown radiographic disease progression during or after a treatment with a VEGF-TKI as defined by RECIST 1.1 by investigator.
* Is able to swallow oral medication
* Has adequate organ function
* Participants receiving bone resorptive therapy must have therapy initiated at least 2 weeks before randomization/allocation
* Has resolution of toxic effects of prior therapy to ≤Grade 1
* Has adequately controlled blood pressure (BP ≤150/90 mm Hg) with no change in hypertensive medications within 1 week before randomization/allocation
* Male participants are abstinent from heterosexual intercourse or agree to use contraception during treatment with and for at least 7 days after the last dose of lenvatinib and /or belzutifan; 7 days after lenvatinib and/or belzutifan is stopped, if the participant is only receiving pembrolizumab, pembrolizumab/quavonlimab, favezelimab/pembrolizumab, MK-4830 or a combination of the aforementioned drugs, no contraception is needed
* Female participant is not pregnant or breastfeeding and is not a woman of childbearing potential (WOCBP) or is a WOCBP abstinent from heterosexual intercourse or using contraception during the intervention period and for at least 120 days after the last dose of pembrolizumab, pembrolizumab/quavonlimab, favezelimab/pembrolizumab, MK-4830 or 30 days after the last dose of lenvatinib or belzutifan, whichever occurs last and must abstain from breastfeeding during the study intervention period and for at least 120 days after study intervention

Exclusion Criteria:

* Has urine protein ≥1 g/24 hours and has any of the following: (a) a pulse oximeter reading \<92% at rest, or (b) requires intermittent supplemental oxygen, or (c) requires chronic supplemental oxygen (d) active hemoptysis within 3 weeks prior to the first dose of study intervention
* Has clinically significant cardiovascular disease within 12 months from the first dose of study intervention administration
* Has had major surgery within 3 weeks before first dose of study interventions
* Has a history of lung disease
* Has a history of inflammatory bowel disease
* Has preexisting gastrointestinal (GI) or non-GI fistula
* Has malabsorption due to prior GI surgery or disease
* Has previously received treatment with a combination of pembrolizumab plus lenvatinib
* Has received prior treatment with belzutifan
* Has received prior radiotherapy within 2 weeks of start of study intervention
* Has received a live or live attenuated vaccine within 30 days before the first dose of study intervention; killed vaccines are allowed
* Has received more than 4 previous systemic anticancer treatment regimens
* Has a diagnosis of immunodeficiency or is receiving any form of immunosuppressive therapy within 7 days prior to the first dose of study intervention
* Has known additional malignancy that is progressing or has required active treatment within the past 3 years
* Has known central nervous system (CNS) metastases and/or carcinomatous meningitis
* Has an active autoimmune disease that has required systemic treatment in the past 2 years; replacement therapy is not considered a form of systemic treatment and is allowed
* Has an active infection requiring systemic therapy
* Has a known history of human immunodeficiency virus (HIV) infection
* Has a known history of Hepatitis B
* Has had an allogenic tissue/solid organ transplant

Primary outcomes:
measure: Safety Lead-in Phase: Number of participants who experience one or more dose-limiting toxicities (DLTs)
timeFrame: Up to ~21 days
measure: Safety Lead-in Phase: Number of participants who experience one or more adverse events (AEs)
timeFrame: Up to ~21 days
measure: Safety Lead-in Phase: Number of participants who discontinue study treatment due to an AE
timeFrame: Up to ~21 days
measure: Efficacy Phase: Number of participants who experienced DLTs
timeFrame: Up to ~21 days
measure: Efficacy Phase: Number of participants who experience one or more AEs
timeFrame: Up to ~56 months
measure: Efficacy Phase: Number of participants who discontinue study treatment due to an AE
timeFrame: Up to ~56 months
measure: Efficacy Phase: Objective response rate (ORR)
timeFrame: Up to ~56 months
Secondary outcomes:
measure: Efficacy Phase: Duration of response (DOR)
timeFrame: Up to ~56 months
measure: Efficacy Phase: Progression-free survival (PFS)
timeFrame: Up to ~56 months
measure: Efficacy Phase: Overall survival (OS)
timeFrame: Up to ~56 months
measure: Efficacy Phase: Clinical benefit rate (CBR)
timeFrame: Up to ~56 months
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California at San Francisco ( Site 3008)
state: California
city: New Haven
country: United States
facility: Yale-New Haven Hospital-Yale Cancer Center ( Site 3011)
state: Connecticut
city: Chicago
country: United States
facility: University of Chicago ( Site 3013)
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa ( Site 3012)
state: Iowa
city: Detroit
country: United States
facility: Henry Ford Health System ( Site 3014)
state: Michigan
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center ( Site 3016)
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center ( Site 3002)
state: New York
city: Durham
country: United States
facility: Duke Cancer Institute ( Site 3015)
state: North Carolina
city: Pittsburgh
country: United States
facility: UPMC Cancer Center/Hillman Cancer Center ( Site 3017)
state: Pennsylvania
city: Nashville
country: United States
facility: Vanderbilt University Medical Center ( Site 3004)
state: Tennessee
city: Dallas
country: United States
facility: UTSW Medical Center ( Site 3003)
state: Texas
city: Blacktown
country: Australia
facility: Western Sydney Local Health District ( Site 3601)
state: New South Wales
city: Kogarah
country: Australia
facility: St George Hospital ( Site 3602)
state: New South Wales
city: Herston
country: Australia
facility: Royal Brisbane and Women s Hospital ( Site 3603)
state: Queensland
city: Melbourne
country: Australia
facility: Austin Health ( Site 3600)
state: Victoria
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre ( Site 3101)
state: Ontario
city: Montreal
country: Canada
facility: Jewish General Hospital ( Site 3100)
state: Quebec
city: Temuco
country: Chile
facility: James Lind Centro de Investigación del Cáncer ( Site 4108)
state: Araucania
city: Temuco
country: Chile
facility: CIDO SpA-Oncology ( Site 4106)
state: Araucania
city: Santiago
country: Chile
facility: FALP-UIDO ( Site 4100)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Bradfordhill-Clinical Area ( Site 4101)
state: Region M. De Santiago
city: Viña del Mar
country: Chile
facility: ONCOCENTRO APYS-ACEREY ( Site 4103)
state: Valparaiso
city: Vandoeuvre les Nancy
country: France
facility: Institut De Cancerologie De Lorraine ( Site 3204)
state: Ain
city: Strasbourg
country: France
facility: Institut de cancérologie Strasbourg Europe (ICANS) ( Site 3203)
state: Alsace
city: Toulouse Cedex 9
country: France
facility: Institut Claudius Regaud ( Site 3200)
state: Haute-Garonne
city: Villejuif
country: France
facility: Gustave Roussy ( Site 3202)
state: Val-de-Marne
city: Budapest
country: Hungary
facility: Országos Onkológiai Intézet-Urogenitális Tumorok és Klinikai Farmakológiai Osztály ( Site 4301)
state: Pest
city: Haifa
country: Israel
facility: Rambam Health Care Campus-Oncology Division ( Site 3500)
city: Jerusalem
country: Israel
facility: Hadassah Medical Center-Oncology ( Site 3504)
city: Petah Tiqwa
country: Israel
facility: Rabin Medical Center ( Site 3502)
city: Ramat Gan
country: Israel
facility: Sheba Medical Center - Oncology Division ( Site 3501)
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center ( Site 3503)
city: Songpagu
country: Korea, Republic of
facility: Asan Medical Center ( Site 3800)
state: Seoul
city: Seoul
country: Korea, Republic of
facility: Severance Hospital ( Site 3802)
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center ( Site 3801)
city: Amsterdam
country: Netherlands
facility: Nederlands Kanker Instituut - Antoni van Leeuwenhoek (NKI-AVL)-medical oncology ( Site 4402)
state: Noord-Holland
city: Rotterdam
country: Netherlands
facility: Erasmus Medisch Centrum ( Site 4401)
state: Zuid-Holland
city: Auckland
country: New Zealand
facility: Auckland City Hospital ( Site 3700)
city: Bydgoszcz
country: Poland
facility: Centrum Onkologii im. Prof. Franciszka Lukaszczyka-Ambulatorium Chemioterapii ( Site 4201)
state: Kujawsko-pomorskie
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - P-Oddzial Badan Wczesnych Faz ( Site 4200
state: Mazowieckie
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne-Early Clinical Trials Unit ( Site 4202)
state: Pomorskie
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d Hebron ( Site 3300)
state: Cataluna
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal ( Site 3301)
city: Southampton
country: United Kingdom
facility: Southampton General Hospital ( Site 3403)
state: England
city: Glasgow
country: United Kingdom
facility: The Beatson West of Scotland Cancer Centre ( Site 3405)
state: Glasgow City
city: Preston
country: United Kingdom
facility: Royal Preston Hospital ( Site 3406)
state: Lancashire
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary ( Site 3408)
state: Leicestershire
city: London
country: United Kingdom
facility: Barts Health NHS Trust ( Site 3401)
state: London, City Of
city: Edinburgh
country: United Kingdom
facility: Western General Hospital ( Site 3402)
state: Midlothian
city: Cardiff
country: United Kingdom
facility: Velindre Cancer Centre Hospital ( Site 3407)
state: Wales
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust ( Site 3400)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: