VorAsidenib With Lomustine In Patients With rEcurrent IDH-mutaNT Glioma Harboring IDH1 and/or IDH2 Mutations

NCT07629089 | Not Yet Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: HCC 25-076
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Brain Cancer

Keywords

isocitrate dehydrogenase (IDH); IDH mutations; glioma

Outcome Measures

Primary Outcomes (1)

• 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.

  Up to 48 months

Secondary Outcomes (6)

• Adverse Events Related to Treatment

  Up to 60 months

• Progression Free Survival at 6 Months (PFS-6)

  At 6 months from start of treatment

• Progression Free Survival

  Up to 60 months

• Clinical Benefit Rate (CBR)

  Up to 60 months

• Pharmacokinetics of vorasidenib in combination with lomustine

  Days 1, 15 and 22 of Treatment Cycle 1 (cycle is 28 days)

Study Arms (1)

Vorasidenib + Lomustine

EXPERIMENTAL

Dose Escalation: Dose level 0: (40mg) Vorasidenib + Lomustine 110mg/m\^2 (orally) on day 1 of each 42-day cycle Dose level -1: (20mg) Vorasidenib + Lomustine 110mg/m\^2 (orally) on day 1 of each 42-day cycle Dose level -2: (10mg) Vorasidenib + Lomustine 110mg/m\^2 (orally) on day 1 of each 42-day cycle

Drug: Vorasidenib; Drug: Lomustine

Interventions

Vorasidenib DRUG

Oral targeted therapy for IDH1- or IDH2-mutant grade 2 astrocytoma or oligodendroglioma, approved for use after surgery.

Also known as: VORANIGO

Vorasidenib + Lomustine

Lomustine DRUG

An alkylating nitrosourea compound used in chemotherapy. It is highly lipid-soluble thus it crosses the blood-brain barrier. Primarily used in treating brain tumors.

Also known as: Gleostine

Vorasidenib + Lomustine

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Must have recurrent IDH-mutant oligodendroglioma or astrocytoma grade 2-4 harboring IDH1 and/or IDH2 mutation per WHO 2021 criteria (Louis et al, 2021).
• Must have IDH1 (IDH1 R132H/C/G/S/L mutation variants tested) and/or IDH2 (IDH2 R172K/M/W/S/G mutation variants tested) mutation(s) as determined by standard of care local testing.
• Must have available 1p/19q and tumor O-6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) status available from a pathological report as per standard of care local testing.
• Have presence of measurable disease based on RANO2.0 criteria AND imaging review meeting definition of progression of disease as per RANO2.0 criteria (see Section 10.1.1 for more information).
• o Note: Contrast enhancing disease will be allowed.
• Participants must have received appropriate standard of care treatment options (in the opinion of the treating investigator) with at least 1 prior surgery (biopsy, subtotal resection, gross-total resection) and 1 prior treatment (radiation, chemotherapy).
• o Note: Prior exposure to IDH-inhibitors will be allowed.
• Have expected survival of ≥3 months.
• Sexually active fertile subjects and their partners must agree to use a highly effective method of contraception prior to study entry, during the course of the study, and for 90 days after the last dose of vorasidenib or 3.5 months after the last dose of lomustine, (whichever is later). Females of reproductive potential should be advised to use effective non-hormonal contraception during treatment with vorasidenib, since vorasidenib can redner some hormonal contraceptives ineffective. An additional contraceptive method, such as a barrier method (e.g., condom), is required. In addition, men must agree not to donate sperm and women must agree not to donate eggs (ova, oocyte) for the purpose of reproduction during these same periods.
• Female subjects of childbearing potential (FOCBP) must not be pregnant or breastfeeding at screening. Female subjects are considered to be of childbearing potential unless one of the following criteria is met:
• o Permanent sterilization (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined as 12 months of amenorrhea in a woman \> 45 years-of-age in the absence of other biological or physiological causes). Note: Documentation may include review of medical records, medical examination, or medical history interview by study site staff.

You may not qualify if:

• 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.
• Have features assessed as high-risk by the Investigator, including:
• Brainstem involvement either as primary location or by tumor extension
• Clinically relevant functional or neurocognitive deficits due to the tumor in the opinion of the Investigator (deficits resulting from surgery are allowed)
• Uncontrolled seizures (defined as persistent seizures interfering with activities of daily life AND failed 3 lines of antiepileptic drug regimens including at least 1 combination regimen).
• Concurrent active malignancy except for:
• Curatively resected non-melanoma skin cancer
• Curatively treated carcinoma in situ.
• Note: Subjects with previously treated malignancies are eligible provided they have been disease-free for 3 years at Screening.
• Are pregnant or breastfeeding.
• Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous.
• Have a known hypersensitivity to any of the components of vorasidenib or lomustine.

Sponsors & Collaborators

• Megan Mantica: lead
• Institut de Recherches Internationales Servier: collaborator

Study Sites (1)

UMPC Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

MeSH Terms

Conditions

Brain Neoplasms; Glioma

Interventions

vorasidenib; Lomustine

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Nitrosourea Compounds; Urea; Amides; Organic Chemicals; Nitroso Compounds

Study Officials

• Megan Mantica, MD

  UPMC Hillman Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Linda Elias, RN, BSN

CONTACT

(412) 623-6037; eliaslj@upmc.edu

Amy Rodger, RN, BSN

CONTACT

412-623-4036; rodgera@upmc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Assistant professor of Neurology and Medicine in the Division of Hematology/Oncology

Study Record Dates

• First Submitted: May 27, 2026
• First Posted: June 5, 2026
• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): June 30, 2030
• Study Completion (Estimated): June 30, 2035
• Last Updated: June 5, 2026

Record last verified: 2026-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)