Vorasidenib + Pembrolizumab for Brain Cancer

Recruiting at 25 trial locations

Overseen By Institut de Recherches Internationales Servier Clinical Studies Department

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Institut de Recherches Internationales Servier

Must not be taking: IDH inhibitors, PD1 inhibitors

Disqualifiers: Recent cancer therapy, Multiple radiation, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

72 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a combination of two drugs, vorasidenib (a potential new drug) and pembrolizumab (an immunotherapy drug), for treating glioma, a type of brain cancer with a specific genetic change known as an IDH-1 mutation. The trial aims to determine if this drug combo can help people with glioma that has returned or worsened after previous treatments like chemotherapy or radiation. Suitable participants are those diagnosed with grade 2 or grade 3 glioma, who have the specific genetic mutation, and have already undergone treatment. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug combination.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Studies have shown that vorasidenib is generally well-tolerated in patients with certain types of brain cancer. In research involving patients with IDH1/2-mutant glioma, vorasidenib improved outcomes with manageable side effects. Only 22.8% of patients experienced severe side effects, indicating that most handled the treatment well.

The safety of combining vorasidenib with pembrolizumab remains under investigation. An early study found that only one patient (14%) experienced moderate side effects, suggesting the combination might be manageable. Pembrolizumab alone is a well-known treatment for various cancers and is generally safe.

Overall, while more research is needed, early findings are promising for the safety of these treatments in brain cancer. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of vorasidenib and pembrolizumab for brain cancer because it introduces a novel approach to treatment. Unlike traditional therapies that often involve surgery, radiation, or chemotherapy, vorasidenib targets specific cancer cell mutations, potentially offering a more precise intervention. Pembrolizumab enhances the immune system's ability to fight cancer by blocking a protein that prevents immune cells from attacking tumors. The combination of these two drugs offers a dual approach: directly targeting cancer cells while also boosting the body's immune response, which could lead to more effective and less invasive treatment options for patients.

What evidence suggests that this trial's treatments could be effective for brain cancer?

Research has shown that vorasidenib can be helpful for brain cancers with IDH mutations. In studies, this drug helped people with certain brain tumors live longer without their cancer worsening. It also slowed tumor growth and helped control seizures. Pembrolizumab boosts the body's immune system to fight cancer. In this trial, some participants will receive vorasidenib alone, while others will receive a combination of vorasidenib and pembrolizumab. Early research suggests that combining vorasidenib with pembrolizumab might provide extra benefits, but more studies are needed to determine their effectiveness together for gliomas. ^{2 3 6 7 8}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Vorasidenib

Trial Overview 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.

How Is the Trial Designed?

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

Who Is Running the Clinical Trial?

Institut de Recherches Internationales Servier

Lead Sponsor

Trials

91

Recruited

67,100+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

In a phase 1a/b trial involving 26 patients with PD-L1-positive non-small cell lung cancer (NSCLC), the combination of ramucirumab and pembrolizumab showed a manageable safety profile, with 84.6% experiencing treatment-related adverse events, primarily hypertension.

The treatment demonstrated promising efficacy, with an objective response rate of 42.3%, and particularly strong results in patients with high PD-L1 expression (TPS ≥ 50%), who had a median progression-free survival that was not reached.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC. Herbst, RS., Arkenau, HT., Bendell, J., et al.[2023]

A systematic review of four trials involving 3425 patients found that lower doses of pembrolizumab (2 mg/kg every 3 weeks) are equally effective as higher doses (10 mg/kg) in treating advanced melanoma and non-small-cell lung cancer (NSCLC).

The safety profile of pembrolizumab was similar across different doses, suggesting that the lower dose may be sufficient for routine treatment without compromising efficacy.

NCBI (Pubmed)

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. Abdel-Rahman, O.[2018]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

In a phase 2 trial involving 42 patients with untreated brain metastases from non-small-cell lung cancer (NSCLC), pembrolizumab showed a 29.7% response rate in patients with PD-L1 expression of at least 1%, indicating its efficacy in treating brain metastases.

The treatment was generally safe, with serious adverse events occurring in 14% of patients, but no treatment-related deaths were reported, suggesting that pembrolizumab can be a viable option for selected patients with CNS involvement.

NCBI (Pubmed)

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. Goldberg, SB., Schalper, KA., Gettinger, SN., et al.[2021]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab demonstrated antitumor activity in patients with classic and endemic Kaposi sarcoma, indicating its potential as a treatment option for this type of cancer.

The findings suggest that pembrolizumab, an immune checkpoint inhibitor, may effectively enhance the immune response against Kaposi sarcoma tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Is Safe and Effective in Kaposi Sarcoma. [2022]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

In a phase II clinical trial involving 23 melanoma patients with untreated brain metastases, pembrolizumab demonstrated a 26% response rate in brain metastases, indicating its potential efficacy in this challenging patient population.

The treatment was associated with acceptable toxicity, as 65% of patients experienced neurologic adverse events, mostly mild (grade 1 or 2), and nearly half of the patients (48%) were alive at 24 months, suggesting durable responses and a need for careful management of brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Survival of Patients With Melanoma With Active Brain Metastases Treated With Pembrolizumab on a Phase II Trial. Kluger, HM., Chiang, V., Mahajan, A., et al.[2020]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

In a study of 655 patients with advanced melanoma, pembrolizumab showed a 5-year overall survival rate of 34%, with even better outcomes (41%) for treatment-naive patients, indicating its long-term efficacy.

The treatment was generally well-tolerated, with 86% of patients experiencing treatment-related adverse events, but only 7.8% discontinued due to these effects, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Hamid, O., Robert, C., Daud, A., et al.[2023]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2304194

Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7025383/

Vorasidenib (AG-881): A First-in-Class, Brain-Penetrant Dual ... Furthermore, vorasidenib penetrates the brain of several preclinical species and inhibits 2-HG production in glioma tissue by >97% in an orthotopic glioma mouse ...

3. onclive.com onclive.com/view/vorasidenib-shows-consistent-efficacy-with-manageable-safety-in-idh1-2-mutant-diffuse-glioma

Vorasidenib Shows Consistent Efficacy With Manageable ... Updated INDIGO data reveal that vorasidenib continues to showcase improved efficacy over placebo in patients with IDH1/2-mutated diffuse glioma.

4. thelancet.com thelancet.com/journals/lanonc/article/PIIS1470-2045(25)00472-3/fulltext?rss=yes

Vorasidenib in IDH1-mutant or IDH2-mutant low-grade ... Vorasidenib reduced tumour growth rate and improved seizure control compared with placebo, with no observed negative effects on HRQOL or ...

5. voranigo.com voranigo.com/voranigo-results

Clinical Trial Results - VORANIGO® (vorasidenib) VORANIGO was shown to increase the length of time a person can live progression free with Grade 2 IDH-MUTANT Astrocytoma OR Oligodendroglioma.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12165550/

Toxicological insights and safety considerations of ... Vorasidenib, a dual inhibitor of isocitrate dehydrogenase 1 and 2 (IDH1/2), has shown promise as a therapeutic agent following its recent FDA ...

7. oncodaily.com oncodaily.com/drugs/vorasidenib-voranigo

Vorasidenib (Voranigo): Uses in Cancer, Side Effects ... Safety data revealed 22.8% of vorasidenib patients had grade 3 or ... Brain Cancer: Causes, Symptoms, Diagnosis, and 2025 Advances in Treatment.

8. aacrjournals.org aacrjournals.org/clincancerres/article-pdf/doi/10.1158/1078-0432.CCR-21-0611/2994631/1078-0432_ccr-21-0611v3.pdf

Vorasidenib, a Dual Inhibitor of Mutant IDH1/2, in Recurrent or ... Vorasidenib was associated with a favorable safety profile at doses <100 mg once daily in this previously treated glioma population, with many patients remain-.