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)

Study Overview
=================
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.

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

Conditions
-----------------
Renal Cell Carcinoma

Intervention / Treatment
-----------------
* Drug: Belzutifan
* Biological: Pembrolizumab
* Drug: Lenvatinib


Participation Criteria
=================
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. Have received / be receiving any traditional Chinese medicines or herbal supplements. 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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Belzutifan + Lenvatinib<br>Participants will receive a daily oral dose of 120 mg of belzutifan monotherapy for 3 weeks, followed by a combination of a daily oral dose of 120 mg of belzutifan with a daily oral dose of 20 mg of lenvatinib until progressive disease or discontinuation. | Drug: Belzutifan<br>* 40 mg tablet administered orally at a dose of 120 mg<br>* Other names: PT2977;Drug: Lenvatinib<br>* 10 mg capsule administered orally at a dose of 20 mg<br>* Other names: LENVIMA®;|
| Experimental: Belzutifan + Lenvatinib + Pembrolizumab<br>Participants will receive an intravenous dose of 400 mg of pembrolizumab once every six weeks for up to 18 infusions (up to 2 years) in combination with a daily oral dose of 120 mg of belzutifan and a daily oral dose of 20 mg of lenvatinib until progressive disease or discontinuation. | Drug: Belzutifan<br>* 40 mg tablet administered orally at a dose of 120 mg<br>* Other names: PT2977;Biological: Pembrolizumab<br>* 25 mg/mL solution for Infusion in a single-dose vial administered intravenously at a dose of 400 mg<br>* Other names: MK-3475 KEYTRUDA®;Drug: Lenvatinib<br>* 10 mg capsule administered orally at a dose of 20 mg<br>* Other names: LENVIMA®;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants who experienced dose-limiting toxicities (DLTs) | A DLT is defined as an event with toxicity including the type, severity, time of onset, time of resolution, and the probable association with study treatment that are not due to pre-existing conditions as defined by the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE 5.0). Number of participants who experience a DLT per CTCAE 5.0 will be reported. | Up to approximately 21 days | 
| Number of participants who experienced an adverse event (AE) | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who experience an AE in the study will be reported. | Up to approximately 20 months | 
| Number of participants who discontinued study treatment due to an AE | An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who discontinued from the study treatment due to an AE will be reported. | Up to approximately 20 months | 
| Area under the concentration-time curve from 0-24 hours (AUC0-24) after single dose | AUC is a measure of plasma drug concentration and time and is estimated as the area under the plot of plasma concentration against time after drug administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine AUC0-24 of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Maximum concentration (Cmax) after single dose | Cmax is the maximum concentration of the drug observed in plasma. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Cmax of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Time at maximum concentration (Tmax) after single dose | Tmax is the amount of time that a drug is present at the maximum concentration is observed in plasma. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the Tmax of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Apparent terminal half-life (t½) after single dose | Apparent t1/2 is a measure of how long it takes to clear 50% of the drug after reaching Cmax. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the t1/2 of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Apparent oral clearance (CL/F) after single dose | CL/F is the apparent total clearance of the drug from plasma after oral administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine CL/F of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Apparent oral volume of distribution (Vz/F) after single dose | Vz/F is the apparent volume of distribution of the drug during terminal phase after non-intravenous administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Vz/F of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Steady state area under the concentration-time curve from 0-24 hours (AUC0-24,ss) after multiple doses | AUC0-24,ss is a measure of plasma drug concentration and time and is estimated as the area under the plot of plasma concentration against time after drug administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine AUC0-24,ss of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Steady state maximum concentration (Cmax,ss) after multiple doses | Cmax,ss is the maximum concentration of the drug observed in plasma. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Cmax,ss of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Time at maximum concentration (Tmax) after multiple doses | Tmax is the amount of time that a drug is present at the maximum concentration is observed in plasma. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the Tmax of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Apparent t½ after multiple doses | T1/2 is a measure of how long it takes to clear 50% of the drug after reaching Cmax. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine t1/2 of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose. | 
| Steady state trough concentration (Ctrough,ss) after multiple doses | Ctrough,ss is the lowest concentration reached by a drug before the next dose is administered. Blood samples taken at predose and at specified times post dose will be used to determine Ctrough,ss of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Accumulation ratio (RAC) after multiple doses | RAC is the ratio of accumulation of a drug under steady state conditions after repeated administration as compared to a single dose. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine RAC of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Apparent oral clearance (CL/F) after multiple doses | CL/F is the apparent total clearance of the drug from plasma after oral administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine CL/F of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 
| Apparent oral volume (Vz/F) after multiple doses | Vz/F is the apparent volume of distribution of the drug during terminal phase after non-intravenous administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Vz/F of belzutifan. | Pre-dose, and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours postdose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | ORR is defined as the percentage of participants who have a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors 1.1 (RECIST 1.1.) The percentage of participants who experience a CR or PR as assessed by blinded independent central review based on RECIST 1.1 will be presented. | Up to approximately 20 months | 
| Duration of response (DOR) | For participants who demonstrate a confirmed Complete Response (CR: Disappearance of all target lesions) or confirmed Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1, DOR is defined as the time from first documented evidence of CR or PR until progressive disease (PD) or death. Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. The DOR as assessed by blinded independent central review will be presented. | Up to approximately 20 months | 
| Progression-free survival (PFS) | PFS is defined as the time from first dose of study treatment to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by blinded independent central review will be presented. | Up to approximately 20 months | 
| Overall survival (OS) | OS, defined as the time from first dose of study treatment to death due to any cause, will be presented. | Up to approximately 20 months | 
| Steady state minimum concentration (Cmin,ss) | Cmin,ss is the minimum plasma drug concentration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Cmin,ss of belzutifan. | Pre-dose, and 1, 2 and 4 hours postdose | 
| Percent change from baseline in erythropoietin (EPO) level | Percent change from baseline in EPO level will be measured and presented. | Baseline, up to approximately 6 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
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®