Clinical trial NCT05030506: A Study of Belzutifan (MK-6482) as Monotherapy and in Combination With Lenvatinib (E7080/MK-7902) With or Without Pembrolizumab (MK-3475) in China Participants With Advanced Renal Cell Carcinoma (MK-6482-010)
Official title: An Open-Label, Phase 1 Study of MK-6482 as Monotherapy and in Combination With Lenvatinib (MK-7902) With or Without Pembrolizumab (MK-3475) in China Participants With Advanced Renal Cell Carcinoma
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Renal Cell Carcinoma
Keywords: Belzutifan
Pembrolizumab
Programmed Cell Death-1 (PD1)
Hypoxia inducible factor 2 alpha (HIF-2 alpha)
Hypoxia inducible factor 2α (HIF-2α)
Renal Cell Carcinoma (RCC)
Kidney Cancer
MK-6482
MK6482
PT-2977
PT2977
MK-3475 KEYTRUDA®
MK-7902
E7080
LENVIMA®
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2021-09-01
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the safety, tolerability, pharmacokinetic and pharmacodynamic profiles, and preliminary efficacy of belzutifan as monotherapy followed by belzutifan+lenvatinib combination therapy, as well as belzutifan combined with lenvatinib and pembrolizumab in China participants with advanced renal cell carcinoma.


Eligibility criteria: Inclusion Criteria

* Has a histologically confirmed diagnosis of unresectable, locally advanced or metastatic clear cell renal cell carcinoma (RCC).
* Has measurable disease per RECIST 1.1.
* Has adequate organ function.
* Has adequately controlled blood pressure (BP).
* If participants received major surgery or radiation therapy of \>30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
* Has resolution of the toxic effect(s) of the most recent prior therapy.
* Participants receiving bone resorptive therapy must have therapy initiated at least 2 weeks prior to allocation.
* Is Chinese descent, defined as both biological parents and all biological grandparents are of Chinese descent.

Male Participants:

- Must be willing to use an adequate method of contraception.

Female Participants:

- Must be a woman of non-childbearing potential (WONCBP) or have a negative urine or serum pregnancy test and must be willing to use an adequate method of contraception.

For Belzutifan + Lenvatinib treatment:

* Has progressed on or after having received systemic treatment for locally advanced or metastatic RCC.
* Has no more than 3 prior systemic regimens for locally advanced or metastatic RCC.

For Belzutifan + Lenvatinib + Pembrolizumab treatment:

- Has received no prior systemic therapy for advanced RCC.

Exclusion Criteria

* Is a woman of childbearing potential (WOCBP) who has a positive urine pregnancy test within 24 hours prior to first dose of study intervention.
* Has any of the following: A pulse oximeter reading \<92%, or requires intermittent supplemental oxygen, or requires chronic supplemental oxygen.
* Has a 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 clinically significant cardiac disease.
* Has symptomatic pleural effusion.
* Has a history of inflammatory bowel disease.
* Has preexisting ≥Grade 3 gastrointestinal or non-gastrointestinal fistula.
* Has clinically significant hematuria, hematemesis or hemoptysis of red blood, or other history of significant bleeding within 3 months before administration of the first dose of study intervention.
* Has other clinically significant disorders such as: A serious active non-healing wound/ulcer/bone fracture, requirement for hemodialysis or peritoneal dialysis or a history of allogenic tissue/solid organ transplantation.
* Received colony-stimulating factors, granulocyte macrophage colony-stimulating factor (GMCSF) or recombinant EPO within 28 days prior to the first dose of study intervention.
* Has a known psychiatric or substance abuse disorder that would interfere with cooperation with the requirements of the study.
* Is unable to swallow orally administered medication or has a gastrointestinal disorder affecting absorption.
* Has received prior treatment with belzutifan.
* Has received prior treatment with lenvatinib.
* Has received any type of systemic anticancer antibody (including investigational antibody) ≤28 days prior to allocation.
* Has received / will be receiving any traditional Chinese medicines.
* Has received prior radiotherapy within 2 weeks prior to first dose of study intervention. Participants must have recovered from all radiation-related toxicities and not require corticosteroids.
* Is receiving concomitant treatment, in therapeutic doses, with anticoagulants.
* Is receiving chronic systemic steroids therapy (at doses \>10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study intervention.
* Is currently participating in a study of an investigational agent or is currently using an investigational device.
* Has an active infection requiring systemic therapy.
* Has a known history of Human Immunodeficiency Virus (HIV) infection.
* Has a known history of Hepatitis B or known active Hepatitis C virus infection.
* Has a known history of active tuberculosis.
* Has radiographic evidence of intratumoral cavitation, encasement or invasion of a major blood vessel.
* Has known hypersensitivity or allergy to the active pharmaceutical ingredient or any component of the study intervention (belzutifan or lenvatinib) formulations.
* Has had major surgery within 4 weeks prior to first dose of study intervention.

For Belzutifan + Lenvatinib + Pembrolizumab treatment:

* Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
* Has a history of hypersensitivity reaction to the active pharmaceutical ingredient or any component of pembrolizumab or monoclonal antibody (mAb).
* Has an active autoimmune disease that has required systemic treatment in the past 2 years.
* Has received a live vaccine within 30 days prior to the first dose of study intervention.

Primary outcomes:
measure: Number of participants who experienced dose-limiting toxicities (DLTs)
timeFrame: Up to approximately 21 days
measure: Number of participants who experienced an adverse event (AE)
timeFrame: Up to approximately 20 months
measure: Number of participants who discontinued study treatment due to an AE
timeFrame: Up to approximately 20 months
measure: Area under the concentration-time curve from 0-24 hours (AUC0-24) of belzutifan after single dose (Cohort 1)
timeFrame: Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose
measure: Maximum concentration (Cmax) of belzutifan after single dose (Cohort 1)
timeFrame: Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose
measure: Time at maximum concentration (Tmax) of belzutifan after single dose (Cohort 1)
timeFrame: Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose
measure: Steady state area under the concentration-time curve from 0-24 hours (AUC0-24,ss) of belzutifan after multiple doses (Cohort 1)
timeFrame: Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose
measure: Steady state maximum concentration (Cmax,ss) of belzutifan after multiple doses (Cohort 1)
timeFrame: Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose
measure: Time at maximum concentration (Tmax) of belzutifan after multiple doses (Cohort 1)
timeFrame: Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose
measure: Apparent t½ of belzutifan after multiple doses (Cohort 1)
timeFrame: Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose.
measure: Steady state trough concentration (Ctrough,ss) of belzutifan after multiple doses (Cohort 1)
timeFrame: Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose
measure: Accumulation ratio (RAC) of belzutifan after multiple doses (Cohort 1)
timeFrame: Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose
measure: Apparent oral clearance (CL/F) of belzutifan after multiple doses (Cohort 1)
timeFrame: Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose
measure: Apparent oral volume (Vz/F) of belzutifan after multiple doses (Cohort 1)
timeFrame: Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose
Secondary outcomes:
measure: Objective response rate (ORR)
timeFrame: Up to approximately 20 months
measure: Duration of response (DOR)
timeFrame: Up to approximately 20 months
measure: Progression-free survival (PFS)
timeFrame: Up to approximately 20 months
measure: Overall survival (OS)
timeFrame: Up to approximately 20 months
measure: Steady state trough concentration (Ctrough,ss) of belzutifan (Cohort 2)
timeFrame: Pre-dose, and 1, 2 and 4 hours postdose
measure: Percent change from baseline in erythropoietin (EPO) level
timeFrame: Baseline, up to approximately 6 weeks
measure: Cmax,ss of belzutifan for UGT2B17 and CYP2C19 phenotypes
timeFrame: Week 3 Day 7: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose
measure: AUCss of belzutifan for UGT2B17 and CYP2C19 phenotypes
timeFrame: Week 3 Day 7: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose
measure: Ctrough,ss of belzutifan for UGT2B17 and CYP2C19 phenotypes
timeFrame: Week 3 Day 7: pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Cancer hospital-Digestive Oncology ( Site 0001)
state: Beijing
city: Guangzhou
country: China
facility: SUN YAT-SEN UNIVERSITY CANCER CENTRE-Urology Surgery Department ( Site 0005)
state: Guangdong
city: Nanjing
country: China
facility: Nanjing Drum Tower Hospital The Affiliated Hospital of Nanjing University Medical School-Urology ( S
state: Jiangsu
city: Tianjin
country: China
facility: Tianjin Medical University Cancer Institute and Hospital ( Site 0003)
state: Tianjin
city: Hangzhou
country: China
facility: The Second Affiliated hospital of Zhejiang University school of medicine-Urology ( Site 0007)
state: Zhejiang
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: