What is the mechanism of action of this treatment?

Belzutifan, a HIF-2α inhibitor, targets hypoxia-inducible factors to hinder tumor growth under low oxygen conditions. Pembrolizumab, a PD-1 inhibitor, enhances the immune system's ability to attack cancer cells by blocking the PD-1 pathway. Lenvatinib, a multi-kinase inhibitor, targets multiple receptor tyrosine kinases involved in tumor angiogenesis and growth. These mechanisms are vital for colorectal cancer patients as they offer targeted approaches to disrupt cancer progression and improve treatment outcomes.

What side effects are associated with this type of intervention?

Common treatments for colorectal cancer, such as Pembrolizumab (PD-1 inhibitor) and Lenvatinib (multi-kinase inhibitor), are associated with a range of side effects. Pembrolizumab can cause immune-related adverse events including fatigue, rash, diarrhea, and endocrinopathies like hypothyroidism. Lenvatinib is known for causing hypertension, diarrhea, fatigue, and proteinuria. While specific data on Belzutifan (HIF-2α inhibitor) in colorectal cancer is limited, similar treatments often result in gastrointestinal issues, fatigue, and potential cardiovascular effects. Patients should discuss these potential side effects with their healthcare provider to manage and mitigate risks effectively.

What prior FDA approvals exist?

For the treatment of colorectal cancer, the FDA has approved several drugs that fall into the categories of immunotherapy and targeted therapy. Pembrolizumab, a PD-1 inhibitor, has been approved for use in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer. While there are no specific FDA approvals for HIF-2α inhibitors like Belzutifan in colorectal cancer, multi-kinase inhibitors such as Regorafenib have been approved for metastatic colorectal cancer after failure of standard therapies. These approvals highlight the ongoing efforts to utilize targeted and immunotherapeutic approaches in the management of colorectal cancer.

What other types of research exist?

Promising novel alternatives for colorectal cancer treatment in 2024 include: <ol> <li>Regorafenib: An orally active multikinase inhibitor targeting VEGFR1-3, c-KIT, TIE-2, PDGFR-β, FGFR-1, RET, RAF-1, BRAF, and p38 MAP kinase.</li> <li></li> </ol> Atezolizumab: A PD-L1 inhibitor that has shown efficacy in various solid tumors, including CRC. 3. Enfortumab Vedotin: An antibody-drug conjugate targeting Nectin-4, showing promise in urothelial carcinoma and being explored in other solid tumors. These alternatives offer different mechanisms of action and have shown potential in clinical trials.

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HIF-2alpha Inhibitor

Triple Drug Combo for Solid Cancers

Phase 2

Recruiting

Research Sponsored by Merck Sharp & Dohme Corp.

Eligibility Criteria Checklist

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

Must have

Be older than 18 years old

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to approximately 60 months

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a new treatment combining three drugs to help patients with difficult-to-treat cancers. The treatment aims to stop cancer growth, help the immune system fight the cancer, and cut off the blood supply to tumors.

Who is the study for?

This trial is for adults with certain advanced solid tumors, including liver, colorectal, pancreatic, biliary tract, endometrial, and esophageal cancers. Participants must have measurable disease progression and agree to contraceptive measures. Exclusions include active second malignancies within 3 years, severe lung or liver conditions, HIV/Hepatitis infections (with some exceptions), and prior treatments with specific drugs.

What is being tested?

The study tests the safety and effectiveness of combining belzutifan with pembrolizumab and lenvatinib in treating various solid tumors. It aims to see how well patients respond to this combination therapy without formal hypothesis testing.

What are the potential side effects?

Potential side effects may include high blood pressure that needs medication control; fatigue; digestive issues like nausea or diarrhea; skin reactions; immune-related complications affecting organs such as lungs or intestines; increased risk of infections.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to approximately 60 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to approximately 60 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to approximately 60 months for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

Arm 1: Number of Participants Who Discontinue Study Treatment Due to an AE

Arm 1: Number of Participants Who Experience at Least One Adverse Event (AE)

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

+1 more

Secondary study objectives

Arm 2: Number of Participants Who Discontinued Study Treatment Due to an AE

Arm 2: Number of Participants Who Experienced an Adverse Event (AE)

DCR Per mRECIST 1.1 for HCC as Assessed by BICR

+7 more

Awards & Highlights

No Placebo-Only Group

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

Trial Design

2Treatment groups

Experimental Treatment

Group I: Arm 2: Pembrolizumab + LenvatinibExperimental Treatment2 Interventions

Participants with IO resistant ESCC will receive pembrolizumab 400 mg PLUS lenvatinib 20 mg. Pembrolizumab will be administered via intravenous (IV) infusion once every 6 weeks (Q6W) for a maximum of 18 doses (approximately 2 years). Lenvatinib will be administered orally once daily (QD) until progressive disease or discontinuation.

Group II: Arm 1: Pembrolizumab + Belzutifan + LenvatinibExperimental Treatment3 Interventions

Participants will receive pembrolizumab 400 mg PLUS belzutifan 120 mg PLUS lenvatinib 20 mg (For HCC: 8 mg \[body weight \<60kg\] or 12 mg \[body weight ≥ 60 kg\]). Pembrolizumab will be administered via intravenous (IV) infusion once every 6 weeks (Q6W) for a maximum of 18 doses (approximately 2 years). Belzutifan and lenvatinib will be administered orally once daily (QD) until progressive disease or discontinuation.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Lenvatinib

2017

Completed Phase 4

~2070

Pembrolizumab

2017

Completed Phase 3

~3130

Belzutifan

2018

Completed Phase 1

~50

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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

Belzutifan, a HIF-2α inhibitor, targets hypoxia-inducible factors to hinder tumor growth under low oxygen conditions. Pembrolizumab, a PD-1 inhibitor, enhances the immune system's ability to attack cancer cells by blocking the PD-1 pathway. Lenvatinib, a multi-kinase inhibitor, targets multiple receptor tyrosine kinases involved in tumor angiogenesis and growth. These mechanisms are vital for colorectal cancer patients as they offer targeted approaches to disrupt cancer progression and improve treatment outcomes.

Receptor tyrosine kinase inhibitors for the treatment of osteosarcoma and Ewing sarcoma.New and emerging combination therapies for esophageal cancer.The long and winding road to useful predictive factors for anti-EGFR therapy in metastatic colorectal carcinoma: the KRAS/BRAF pathway.