Vorasidenib + Pembrolizumab for Brain Cancer

Recruiting in Palo Alto (17 mi)

+24 other locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Institut de Recherches Internationales Servier

Must not be taking: IDH inhibitors, PD1 inhibitors

Disqualifiers: Recent cancer therapy, Multiple radiation, others

No Placebo Group

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

Vorasidenib in combination with pembrolizumab in participants with recurrent or progressive isocitrate dehydrogenase-1 (IDH-1) mutant Glioma.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot have received certain cancer treatments or investigational agents recently, so it's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Pembrolizumab in treating brain cancer?

Pembrolizumab has shown effectiveness in treating various cancers, including non-small cell lung cancer and melanoma, and has been used in patients with brain metastases from melanoma, suggesting potential benefits for brain cancer treatment.

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What safety information is available for Pembrolizumab (KEYTRUDA) in humans?

Pembrolizumab (KEYTRUDA) has been studied in various clinical trials and is generally considered safe, but it can cause side effects like fatigue, cough, nausea, skin rash, and diarrhea. Some serious immune-related side effects include lung inflammation (pneumonitis), liver inflammation (hepatitis), and thyroid problems.

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What makes the drug Vorasidenib + Pembrolizumab unique for brain cancer?

This treatment combines Vorasidenib, which targets specific genetic mutations in cancer cells, with Pembrolizumab, an immunotherapy drug that helps the immune system attack cancer cells. This combination is novel because it targets both the genetic and immune aspects of brain cancer, potentially offering a new approach compared to standard treatments.

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Eligibility Criteria

This trial is for adults with Grade 2 or 3 astrocytoma brain tumors that have an IDH-1 mutation and no co-deletion of chromosomes 1p/19q. Participants must have had prior treatment, be in good physical condition (KPS ≥70%), and not need immediate surgery. They can't join if they've had certain recent treatments, multiple radiation therapies, or used drugs targeting similar cancer pathways.

Inclusion Criteria

My tumor has an IDH1 mutation but no 1p19q co-deletion, or it has lost ATRX or has an ATRX mutation.

Have expected survival of ≥ 3 months

I am able to care for myself and perform normal activities with minimal assistance.

Exclusion Criteria

I have not been treated with specific cancer drugs like IDH inhibitors or immunotherapies.

I haven't had cancer treatment or investigational drugs too close to starting the trial.

I have undergone at least 2 radiation therapy sessions.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Safety Lead-In

Participants receive vorasidenib in combination with pembrolizumab to determine the recommended combination dose (RCD)

21-day cycles until disease progression or unacceptable toxicity

Randomized Perioperative

Participants are randomized to receive pre-surgical treatment with vorasidenib and pembrolizumab, vorasidenib only, or no treatment

28-day cycle prior to surgery

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 55 months

Participant Groups

The study tests a combination of two drugs: Vorasidenib and Pembrolizumab in patients with recurrent or progressive astrocytomas. It aims to see how well these drugs work together against this type of brain tumor that has come back or worsened after initial treatment.

Group I: Safety Lead-In Phase: Vorasidenib + Pembrolizumab Experimental Treatment 2 Interventions

Participants will receive vorasidenib orally, once daily (QD) in combination with pembrolizumab 200 mg intravenous (IV) infusion, once every 3 weeks (Q3W) in each 21-day cycle until disease progression, unacceptable toxicity or other discontinuation criteria are met.

Group II: Randomized Perioperative Phase: Vorasidenib Only Experimental Treatment 1 Intervention

Participants will receive vorasidenib orally, QD from Day 1 to 28 of a 28-day cycle prior to surgery.

Group III: Randomized Perioperative Phase: Vorasidenib + Pembrolizumab Experimental Treatment 2 Interventions

Participants will receive vorasidenib recommended combination dose (RCD) determined in the Safety Lead-in phase, orally, QD from Day 1 to 28 in combination with pembrolizumab 200 mg IV infusion, Q3W on Days 1 and 22 of a 28-day cycle prior to surgery.

Group IV: Randomized Perioperative Phase: Untreated Control Group Active Control 1 Intervention

Participants will not receive any treatment prior to surgery.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

🇺🇸 Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

🇪🇺 Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

🇬🇧 Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

University of Colorado Aurora, CO

Cleveland Clinic Cleveland, OH

MD Anderson Cancer Center (Site: 840102) Houston, TX

Johns Hopkins University Baltimore, MD

More Trial Locations

Who Is Running the Clinical Trial?

Institut de Recherches Internationales Servier Lead Sponsor

Merck Sharp & Dohme LLC Industry Sponsor

References

1. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022] A phase II trial investigating the therapeutic effect of neoadjuvant programmed cell death 1 (PD-1) inhibitor pembrolizumab (MK-3475, KEYTRUDA®) administered prior to surgery for the treatment of non-small cell lung cancer (NSCLC) has been conducted (NCT03197467). We report the first clinical results of a planned interim safety analysis after 15 patients were enrolled.

2. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017] New insights into the interaction between the immune system and the tumor microenvironment have led to the development of checkpoint inhibitors that target the PD-1/PD-L1 pathway. Pembrolizumab (MK-3475, lambrolizumab, Keytruda(®)) is a PD-1 inhibitor that has shown clinical activity in a variety of solid tumors and is currently approved for the second-line treatment of PD-L1-positive non-small-cell lung cancer and for unresectable/metastatic melanoma. This article will discuss the results of early-phase trials of pembrolizumab in thoracic malignancies as well as ongoing studies aimed to confirm clinical benefit.

3. United States pubmed.ncbi.nlm.nih.gov

Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC. [2023] Data of first-line ramucirumab plus pembrolizumab treatment of programmed death-ligand 1 (PD-L1)-positive NSCLC (cohort E) are reported (NCT02443324).

4. United States pubmed.ncbi.nlm.nih.gov

Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. [2020] Pembrolizumab is active in melanoma, but activity in patients with untreated brain metastasis is less established. We present long-term follow-up of pembrolizumab-treated patients with new or progressing brain metastases treated on a phase II clinical trial ( ClinicalTrials.gov identifier: NCT02085070).

5. England pubmed.ncbi.nlm.nih.gov

Evaluation of efficacy and safety of different pembrolizumab dose/schedules in treatment of non-small-cell lung cancer and melanoma: a systematic review. [2018] Pembrolizumab is a fully humanized anti-PD-1 agent currently approved for the treatment of advanced melanoma and pretreated non-small-cell lung cancer (NSCLC).

6. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022] On December 18, 2015, the FDA granted regular approval to pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) for treatment of patients with unresectable or metastatic melanoma based on results of two randomized, open-label, active-controlled clinical trials. In trial PN006, 834 patients with ipilimumab-naïve metastatic melanoma were randomized (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 or 3 weeks until disease progression or ipilimumab 3 mg/kg every 3 weeks for up to four doses. In trial PN002, 540 patients with ipilimumab-refractory metastatic melanoma were randomized (1:1:1) to pembrolizumab 2 or 10 mg/kg i.v. every 3 weeks or to investigator's choice of chemotherapy. In trial PN006, patients randomized to pembrolizumab demonstrated a statistically significant improvement in overall survival compared with ipilimumab [every-2-week arm: hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.47-0.83; P < 0.001; every-3-week arm: HR = 0.69; 95% CI, 0.52-0.90; P = 0.004]. In both trials, patients receiving pembrolizumab demonstrated statistically significant improvements in progression-free survival. The most common (≥2%) immune-mediated adverse reactions in a pooled safety analysis were hypothyroidism, pneumonitis, and hyperthyroidism. Key considerations for approval were determination of pembrolizumab dose and interpretation of tumor response-based endpoints using RECIST or immune-related RECIST. Clin Cancer Res; 23(19); 5661-5. ©2017 AACR.

7. United States pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021] On September 4, 2014, the FDA approved pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) with a recommended dose of 2 mg/kg every 3 weeks by intravenous infusion for the treatment of patients with unresectable or metastatic melanoma who have progressed following treatment with ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on demonstration of objective tumor responses with prolonged response durations in 89 patients enrolled in a randomized, multicenter, open-label, dose-finding, and activity-estimating phase 1 trial. The overall response rate (ORR) by blinded independent central review per RECIST v1.1 was 24% (95% confidence interval, 15-34); with 6 months of follow-up, 86% of responses were ongoing. The most common (≥20%) adverse reactions were fatigue, cough, nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. Immune-mediated adverse reactions included pneumonitis, colitis, hepatitis, hypophysitis, and thyroid disorders. The benefits of the observed ORR with prolonged duration of responses outweighed the risks of immune-mediated adverse reactions in this life-threatening disease and represented an improvement over available therapy. Important regulatory issues in this application were role of durability of response in the evaluation of ORR for accelerated approval, reliance on data from a first-in-human trial, and strategies for dose selection. Clin Cancer Res; 23(19); 5666-70. ©2017 AACR.

8. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023] Pembrolizumab (Keytruda) is a monoclonal antibody against the programmed cell death-1 (PD-1) receptor on lymphocytes, which is one of the immune checkpoint inhibitors (ICIs) approved for multiple solid and hematologic malignancies. Although ICIs have proven to be more effective and less toxic compared to chemotherapy, there are reports of adverse side effects with ICIs. For example, pneumonitis is a potentially lethal side effect occurring in 1%-5% of patients who received ICIs in clinical trials, and there are case reports with clinical and radiological features of checkpoint inhibitor-pneumonitis (CIP).

9. England pubmed.ncbi.nlm.nih.gov

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. [2023] Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed.

10. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. [2021] We did a phase 2 trial of pembrolizumab in patients with non-small-cell lung cancer (NSCLC) or melanoma with untreated brain metastases to determine the activity of PD-1 blockade in the CNS. Interim results were previously published, and we now report an updated analysis of the full NSCLC cohort.

11. United States pubmed.ncbi.nlm.nih.gov

Pembrolizumab Is Safe and Effective in Kaposi Sarcoma. [2022] Antitumor activity was observed with pembrolizumab in classic and endemic Kaposi sarcoma.