Phase 1/2 Multicenter, Open-label, Randomized Study of Belzutifan and Palbociclib Versus Belzutifan Monotherapy in Advanced Renal Cell Carcinoma

The primary objective of this study is to assess the **safety** and tolerability of belzutifan in combination with palbociclib, and to establish the recommended Phase 2 dose (RP2D) in participants with advanced renal cell carcinoma. Additionally, the study aims to evaluate the objective response rate (ORR) as assessed by investigators using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in each treatment arm. These objectives are clinically relevant as they provide critical information on the potential efficacy and safety profile of the combination therapy, which could inform future treatment strategies for advanced renal cell carcinoma.

Secondary objectives include:

• Evaluating the clinical benefit rate (CBR) as assessed by investigators using RECIST 1.1 in each arm.
• Assessing the duration of response (DOR) using RECIST 1.1 in each arm.
• Evaluating progression-free survival (PFS) as assessed by investigators using RECIST 1.1 in each arm.
• Assessing overall survival (OS) in each arm.
• Evaluating the safety and tolerability in each arm.

The clinical trial involves a total of **134 participants** diagnosed with **advanced clear-cell renal cell carcinoma (ccRCC)**. The study population includes both male and female subjects, with an age range corresponding to categories 3 and 4, which typically includes adults and older adults. Participants were selected based on specific criteria, including a histologically confirmed diagnosis of unresectable Stage IV renal cell carcinoma with a clear-cell component, and prior disease progression after receiving at least two systemic treatments. The trial does not include vulnerable populations. Participants are required to have measurable disease as per RECIST 1.1 criteria and must have recovered from all adverse events due to previous therapies. Lifestyle factors such as diet and physical activity are not specified in the trial data provided.

The clinical trial is designed as a **randomized**, open-label, Phase 1/2 study to evaluate the safety, tolerability, and efficacy of **belzutifan** in combination with **palbociclib** versus belzutifan monotherapy in participants with advanced renal cell carcinoma (RCC). The trial aims to establish the recommended Phase 2 dose (RP2D) and assess the objective response rate (ORR) using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The study is expected to commence recruitment on February 1, 2026, and conclude by September 16, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a histologically confirmed diagnosis of unresectable Stage IV RCC with a clear-cell component and prior treatment history. Following successful screening, participants will be randomized into one of the study arms. The trial will include multiple follow-up visits to monitor safety, tolerability, and treatment efficacy, with assessments conducted by investigators and verified by blinded independent central review (BICR).

The expected duration of participant involvement will vary depending on individual response and tolerance to the treatment. Conditions that may lead to early termination from the study include the occurrence of dose-limiting toxicities (DLTs), adverse events (AEs), or disease progression as determined by the investigator. The end-of-study visit will be conducted to gather final data on treatment outcomes and any long-term effects experienced by the participants.

The clinical trial involves the administration of **Belzutifan**, an experimental medication, in the form of a **film-coated tablet**. Belzutifan, also known by its sponsor product code MK-6482, is a chemical compound with the active substance name **belzutifan**. It is administered orally. The trial aims to evaluate the safety, tolerability, and efficacy of Belzutifan in participants with advanced renal cell carcinoma. The dosing schedule and frequency of administration are determined based on the study protocol, with compliance monitored throughout the trial. Belzutifan is not a pediatric formulation and is not classified as an orphan drug.

In addition to Belzutifan, the trial includes the administration of **Palbociclib**, another chemical compound, which is also administered orally. Palbociclib is identified by its active substance name **palbociclib** and is classified under the ATC code L01XE33. The pharmaceutical form of Palbociclib is denoted as PHF00006MIG. This medication is used in combination with Belzutifan in one arm of the study to assess the combined therapeutic effect. The trial does not involve any placebo or comparator treatment, focusing solely on the experimental medications. Participant compliance with the dosing regimen is closely monitored to ensure adherence to the study protocol.

Efficacy in the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Objective Response Rate (ORR)** as assessed by the investigator using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. This will be evaluated in Part 2 of the study. Additionally, in Part 1, the number of participants who experience at least one dose-limiting toxicity (DLT), adverse event (AE), or discontinue study treatment due to an AE will be recorded.

Secondary endpoints in Part 2 include the **Clinical Benefit Rate (CBR)**, **Duration of Response (DOR)**, and **Progression-Free Survival (PFS)**, all assessed per RECIST 1.1 by the investigator. Overall Survival (OS) will also be measured. Furthermore, the number of participants experiencing at least one AE and those discontinuing treatment due to an AE will be documented. These efficacy parameters will be collected and analyzed at specified intervals throughout the trial to determine the treatment's impact on participants with advanced renal cell carcinoma.