Study of Vorasidenib and Pembrolizumab Combination in Recurrent or Progressive Enhancing IDH-1 Mutant Astrocytomas
Summary
This phase I study will evaluate the safety, dose-limiting toxicities, and preliminary efficacy of vorasidenib in combination with pembrolizumab in participants with recurrent or progressive enhancing isocitrate dehydrogenase-1 (IDH-1) mutant astrocytomas.
Vorasidenib is an orally administered drug that inhibits the mutated forms of both IDH1 and IDH2 proteins, which are both found in a variety of cancers. Mutant IDH1 and IDH2 proteins promote cell growth by blocking differentiation and inducing cell proliferation. Vorasidenib acts to counter those effects, specifically in tumor cells with IDH mutations.
Pembrolizumab is an antibody-based immunotherapy, administered intravenously, that targets the immune system and activates it to stop cancer growth and/or kill cancer cells. More specifically, pembrolizumab works by binding and inhibiting PD-1, a protein that normally protects the body from attacking itself. Normally, PD-1 works by detecting a molecular signal (called PDL-1) made by various cells across the body. Some cancer cells take advantage of this protection mechanism making the protective signal themselves. Blocking PD-1 with pembrolizumab allows the immune system to activate its T-cells and recognize these tumors as cells to be attacked.
The study is divided into two phases: a safety lead-in phase and a randomized perioperative phase. In the safety lead-in phase, the recommended combination dose (RCD) of vorasidenib will be determined. In the randomized perioperative phase, the lymphocyte infiltration in tumors will be evaluated following pre-surgical treatment with vorasidenib and pembrolizumab combination, compared to untreated control tumors. Prior to surgery, participants will be randomized to receive vorasidenib at the RCD in combination with pembrolizumab, or vorasidenib only, or no treatment (untreated control group). Following surgery, participants will have the option to receive treatment with vorasidenib in combination with pembrolizumab in 21-day cycles.
- Have Karnofsky Performance Status (KPS) of ≥ 70%.
- Have expected survival of ≥ 3 months.
- Have histologically confirmed Grade 2 or Grade 3 astrocytoma (per the 2016 World Health Organization [WHO] Classification of Tumors of the central nervous system).
- Have documented IDH1-R132H gene mutation and absence of 1p19q co-deletion (i.e., non-co-deleted, or intact) by local testing.
- Have measurable, magnetic resonance imaging (MRI)-evaluable, unequivocal contrast enhancing disease as determined by institutional radiologist/investigator at screening no either 2D T1 post-contrast weighted images or 3D T1 post-contrast weighted images. Per mRANO criteria, measurable lesion is defined as at least one enhancing lesion measuring ≥ 1 cm x ≥ 1 cm.
- Have recurrent or progressive disease and received prior treatment with chemotherapy, radiation, or both.
- Surgical resection is indicated for treatment, but surgery is not urgently indicated (e.g., for whom surgery within the next 6-9 weeks is appropriate). NOTE: This criterion only applies to participants enrolled in the preoperative phase of the study. Participants in the Safety Lead-In should not require surgery.
- Have received prior systemic anti-cancer therapy within 1 month of the first dose of IMP, radiation within 12 months of the first dose of IMP, or an investigational agent 14 days prior to the first dose of IMP. In addition, the first dose of IMP should not occur before a period of ≥ 5 half-lives of the investigational agent has elapsed.
- Have received two more courses of radiation.
- Have received any prior treatment with an isocitrate dehydrogenase (IDH) inhibitor; anti-programmed cell death 1 (PD1), anti-programmed cell death ligand 1 (PD-L1), or anti-PD-ligand 2 (L2) agent, or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137); any other checkpoint inhibitor; bevacizumab; or any prior vaccine therapy.
