This study will test the hypothesis that vorasidenib in combination with lomustine will be safe and tolerable. The overall goal of this study is to identify the optimal vorasidenib dose that can be tested in a subsequent phase 2 study to determine the efficacy of vorasidenib in combination with lomustine in patients with recurrent IDH mutant gliomas.
Age ≥18 years.
Karnofsky performance status score of ≥ 60%.
Be able to understand and willing to sign informed consent or assent as determined by local requirements.
Be willing to comply with scheduled visits, treatment plans, and laboratory tests, including serial peripheral blood sampling and during the study.
Patients who have not recovered to grade 0 or 1 or pre-treatment baseline from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia.
Presence of extracranial metastatic or leptomeningeal disease.
Have had any prior anticancer therapy within 28-days of treatment other than surgery (biopsy, sub-total resection, gross- total resection) for treatment of glioma including systemic chemotherapy, radiotherapy, vaccines, small-molecules, IDH inhibitors, investigational agents, laser ablation, etc.
Early progression prior to 3 months from completion of radiotherapy.
Single group
Vorasidenib
DrugOral targeted therapy for IDH1- or IDH2-mutant grade 2 astrocytoma or oligodendroglioma, approved for use after surgery.
Lomustine
DrugAn alkylating nitrosourea compound used in chemotherapy. It is highly lipid-soluble thus it crosses the blood-brain barrier. Primarily used in treating brain tumors.
Recommended Combination Dose (RCD)
Recommended combination dose (RCD) of vorasidenib in combination with lomustine in patients with recurrent Grades 2-4 oligodendroglioma and astrocytoma with an IDH1 or IDH2 mutation, determined using 3x3 dose de-escalation design with 3 dosing levels of vorasidenib. Initially, 3 patients are treated at Level 0. If # DLT≤1/3, treat 3 more patients at Level 0. If # DLT≤1/6, start the dose expansion part at Level 0. If # DLT≥2/6, treat 3-6 patients at dose Level -1. If # DLT≤1/6, start the dose expansion part at Level -1. If # DLT≥2/6, then 3-6 patients will be treated at dose Level -2. If #DLT≤1/6, start the dose expansion part at Level -2.
Adverse Events Related to Treatment
Adverse events, serious adverse events (SAEs), and AEs leading to discontinuation or death, and severity of AEs as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0 that are at least possibly related to study treatment. The analysis population will include all study eligible patients who received any dose of the study drug.
Progression Free Survival at 6 Months (PFS-6)
Percentage of patients with PFS at 6 months as defined as the time from initiation of cycle 1 to either disease progression or death, at the 6-month mark as assessed by RANO 2.0 criteria. Objective Progression: ≥25% increase in enhancing tumor volume from baseline.The analysis population will include patients who have received the treatment regimen and stayed on study long enough for at least one follow-up of response. Patients who never had a repeat tumor scan but clinically progressed will also be considered as evaluable for response, and the best response for these patients is progressive disease.
Progression Free Survival
Progression Free Survival (PFS) as defined as the time median between initiation of cycle 1 and first documentation of disease progression or death, whichever occurs first as assessed by RANO 2.0 criteria. Objective Progression: ≥25% increase in enhancing tumor volume from baseline. The analysis population will include patients who have received the treatment regimen and stayed on study long enough for at least one follow-up of response. Patients who never had a repeat tumor scan but clinically progressed will also be considered as evaluable for response, and the best response for these patients is progressive disease.
Clinical Benefit Rate (CBR)
For enhancing glioma, CBR is defined as complete response (CR), partial response (PR), or stable disease (SD) per study population as determined by the investigator on the basis of RANO 2.0 criteria. The analysis population will include patients who have received the treatment regimen and stayed on study long enough for at least one follow-up of response. For patients with non-enhancing glioma, CBR will be defined as CR, PR, minor response (mR), or SD as determined by the investigator on the basis of RANO2.0. Given the challenges associated with accurate representation of tumor response on MRI in LGG, the RANO working group considers a 25%-50% reduction in tumor size compared with baseline clinically meaningful, and several classifications now include mR as a measure of treatment effect. Therefore, mR will be included in the CBR for non-enhancing glioma.
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Megan Mantica
Lead sponsor
University of Pittsburgh
Sponsor institution
Institut de Recherches Internationales Servier
Collaborator
This trial is not recruiting at the moment. You can still explore other options:
