What side effects are associated with this type of intervention?

Common side effects of HIF-2α inhibitors like Belzutifan include anemia, fatigue, nausea, and dizziness. CDK 4/6 inhibitors such as Palbociclib often cause neutropenia, leukopenia, fatigue, nausea, and diarrhea. Both types of treatments may also lead to more general side effects like decreased appetite and increased risk of infections.

What prior FDA approvals exist?

The FDA has approved several drugs for the treatment of kidney cancer, particularly targeting advanced and metastatic renal cell carcinoma. Belzutifan, a HIF-2α inhibitor, is part of a newer class of drugs targeting hypoxia-inducible factors, which play a role in tumor growth under low oxygen conditions. While Palbociclib, a CDK 4/6 inhibitor, is primarily approved for breast cancer, its mechanism of inhibiting cell cycle progression is being explored in combination therapies for kidney cancer. Other FDA-approved treatments for kidney cancer include immune checkpoint inhibitors like nivolumab and pembrolizumab, and tyrosine kinase inhibitors such as sunitinib and axitinib, which target angiogenesis and tumor cell proliferation.

What other types of research exist?

Promising novel alternatives for kidney cancer treatment in 2024 include: <ol> <li>Nivolumab plus Ipilimumab: This combination of immune checkpoint inhibitors has shown significant efficacy in advanced RCC, particularly in patients with intermediate and poor risk.</li> <li>Pembrolizumab plus Axitinib: This combination has demonstrated improved survival outcomes and quality of life in patients with advanced RCC.</li> <li>Cabozantinib plus Atezolizumab: This combination targets both the VEGF pathway and the immune system, showing promising results in clinical trials.</li> <li>Lenvatinib plus Pembrolizumab: This combination has shown efficacy in both treatment-naive and previously treated metastatic RCC patients.</li> <li>Avelumab plus Axitinib: This combination has been effective as a first-line treatment for advanced RCC, offering an alternative to traditional therapies.</li> </ol>

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HIF-2 Alpha Inhibitor

Belzutifan + Palbociclib for Kidney Cancer

Phase 1 & 2

Recruiting

Research Sponsored by Merck Sharp & Dohme LLC

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Has a histologically confirmed diagnosis of unresectable Stage IV (per American Joint Committee on Cancer [AJCC], 8th Edition) RCC with clear-cell component

Has had disease progression on or after having received at least 2 systemic treatments for unresectable Stage IV RCC with prior anti-programmed cell death 1 ligand 1 (PD-1/L1) and a vascular endothelial growth factor-tyrosine kinase inhibitor (VEGF-TKI) in sequence or in combination

Must not have

Has a history of hepatitis B (HBV) or known active hepatitis C (HCV) infection

Has moderate to severe hepatic impairment

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to approximately 6 years

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing belzutifan alone and with palbociclib in patients with advanced kidney cancer who haven't responded to other treatments. Belzutifan helps starve cancer cells of oxygen, and palbociclib stops them from growing. Belzutifan (Welireg™) is an oral small molecule inhibitor of hypoxia-inducible factor (HIF)-2α, first approved in the USA for treating patients with von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC).

Who is the study for?

This trial is for adults with advanced kidney cancer who've seen their disease get worse after at least two treatments, including anti-PD-1/L1 and VEGF-TKI therapies. They should have measurable disease, be recovered from past treatment side effects, and not need oxygen therapy or have had major surgery within the last 3 weeks.

What is being tested?

The study tests belzutifan alone and combined with palbociclib in patients with advanced clear-cell renal cell carcinoma. It has two parts: first to find a safe dose of palbociclib for combination use, then to test the effectiveness and safety of this combo compared to just belzutifan.

What are the potential side effects?

Possible side effects include fatigue, nausea, liver issues, blood count changes that can lead to infections or bleeding problems. There may also be risks related to heart health or allergic reactions.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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My kidney cancer is at stage IV and cannot be surgically removed.

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My kidney cancer has worsened after 2 treatments including PD-1/L1 and VEGF-TKI.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I have had hepatitis B or currently have hepatitis C.

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My liver is not working well.

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My cancer has spread to my brain or its coverings.

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I have a serious heart condition.

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I have not had major surgery in the last 3 weeks.

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I have been treated with belzutifan or palbociclib before.

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I need extra oxygen sometimes or all the time.

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I had radiotherapy less than 2 weeks ago and have recovered from side effects without needing steroids.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to approximately 6 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to approximately 6 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to approximately 6 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Part 1 - Number of Participants Who Discontinue Study Treatment Due to an AE

Part 1 - Number of Participants Who Experience at Least One Adverse Event (AE)

Part 1 - Number of Participants Who Experience at Least One Dose-limiting Toxicity (DLT)

+1 more

Secondary study objectives

Part 2 - Clinical Benefit Rate (CBR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator

Part 2 - Duration of Response (DOR) Per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator

Part 2 - Number of Participants Who Discontinue Study Treatment Due to an AE

+3 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

5Treatment groups

Experimental Treatment

Group I: Part 2 - Beltuzifan 120 mg + PalbociclibExperimental Treatment2 Interventions

Participants receive beltuzifan 120 mg orally QD and palbociclib orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation. Palbociclib will be administered at a dosage level determined in Part 1.

Group II: Part 2 - Beltuzifan 120 mgExperimental Treatment1 Intervention

Participants receive beltuzifan 120 mg orally QD until progressive disease or discontinuation.

Group III: Part 1 - Beltuzifan 120 mg + Palbociclib 75 mgExperimental Treatment2 Interventions

Participants receive beltuzifan 120 mg orally once per day (QD) and palbociclib 75 mg orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation.

Group IV: Part 1 - Beltuzifan 120 mg + Palbociclib 125 mgExperimental Treatment2 Interventions

Participants receive beltuzifan 120 mg orally QD and palbociclib 125 mg orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation.

Group V: Part 1 - Beltuzifan 120 mg + Palbociclib 100 mgExperimental Treatment2 Interventions

Participants receive beltuzifan 120 mg orally QD and palbociclib 100 mg orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Palbociclib

2017

Completed Phase 3

~3790

Belzutifan

2018

Completed Phase 1

~50

0 / 10Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for kidney cancer often target specific pathways crucial for cancer cell survival and proliferation. Belzutifan, a HIF-2α inhibitor, disrupts the hypoxia-inducible factor pathway, which is essential for cancer cells to adapt to low oxygen levels, thereby inhibiting tumor growth and metastasis. Palbociclib, a CDK 4/6 inhibitor, interferes with the cell cycle by blocking cyclin-dependent kinases 4 and 6, leading to cell cycle arrest and reduced cancer cell proliferation. These targeted therapies are significant for kidney cancer patients as they offer more precise and potentially more effective treatment options by directly attacking the mechanisms that cancer cells rely on for growth and survival.

Changes in Renal Function of Patients with Metastatic Renal Cell Carcinoma During Treatment with Molecular-Targeted Agents.