Vorasidenib + Pembrolizumab for Brain Cancer

Recruiting at 24 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

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. ^{1 2 3 4 5}

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. ^{1 6 7 8 9}

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. ^{1 2 4 10 11}

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.

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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, 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]

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]

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]

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 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]

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]

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 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]

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 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]

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]

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

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

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

Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC. [2023]

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]

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]

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

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. [2022]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

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

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

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

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. [2023]

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]

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

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