Recurrent Glioma, IDH-mutant Gliomas
Conditions
Keywords
isocitrate dehydrogenase (IDH), IDH mutations, glioma
Brief summary
This phase I study will evaluate the safety and tolerability of vorasidenib in combination with lomustine and determine the recommended combination dose (RCD) of vorasidenib in adults with recurrent IDH1- or IDH2-mutant glioma. The study consists of a dose de-escalation phase followed by a dose-expansion cohort to further evaluate safety and preliminary clinical activity.
Detailed description
Isocitrate dehydrogenase (IDH)-mutant gliomas represent a molecularly distinct subset of diffuse gliomas and account for a substantial proportion of primary brain tumors diagnosed in young and middle-aged adults. Despite multimodality treatment approaches including surgery, radiotherapy, and chemotherapy, recurrent disease remains inevitable for most patients, and effective treatment options at recurrence are limited. Mutations in IDH1 and IDH2 result in production of the oncometabolite D-2-hydroxyglutarate, which contributes to gliomagenesis through epigenetic and metabolic dysregulation. Vorasidenib is an oral, brain-penetrant inhibitor of mutant IDH1 and IDH2 that has demonstrated clinical activity in patients with IDH-mutant glioma. Lomustine is an alkylating agent commonly used for recurrent gliomas and remains an established treatment option in this setting. The combination of vorasidenib and lomustine has not been previously evaluated in patients with recurrent IDH-mutant glioma. Given their distinct mechanisms of action and potential complementary antitumor effects, assessment of the safety and tolerability of this combination is warranted. VALIENT is a single-center, open-label, phase 1 study evaluating vorasidenib in combination with lomustine in adults with recurrent IDH1- or IDH2-mutant glioma. The study consists of two parts. Part 1 employs a dose de-escalation design to identify the recommended combination dose of vorasidenib when administered with standard-dose lomustine. Following determination of the recommended combination dose, Part 2 will enroll an expansion cohort to further characterize the safety profile of the combination and to evaluate preliminary antitumor activity. In addition to safety and tolerability assessments, the study will characterize the pharmacokinetic profile of vorasidenib and its circulating metabolite when administered in combination with lomustine. Clinical and radiographic outcomes will also be evaluated to inform the future development of this regimen and support subsequent studies in patients with recurrent IDH-mutant glioma.
Interventions
DRUGVorasidenib
Oral inhibitor of mutant IDH1 and IDH2 administered daily in combination with lomustine.
DRUGLomustine
Oral alkylating nitrosourea chemotherapy that penetrates the blood-brain barrier and is used for the treatment of brain tumors.
Sponsors
Megan Mantica
Institut de Recherches Internationales Servier
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Subjects must meet all of the following inclusion criteria to be eligible for enrollment: 1. Age ≥18 years. 2. Karnofsky performance status score of ≥ 60%. 3. Be able to understand and willing to sign informed consent or assent as determined by local requirements. 4. Be willing to comply with scheduled visits, treatment plans, and laboratory tests, including serial peripheral blood sampling during the study. 5. Must have recurrent IDH-mutant oligodendroglioma or astrocytoma grade 2-4 harboring IDH1 and/or IDH2 mutation per WHO 2021 criteria. 6. 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. 7. Availability of tumor 1p/19q codeletion status and MGMT promoter methylation status from prior pathology testing. 8. Have presence of measurable disease based on RANO2.0 criteria AND imaging review meeting definition of progression of disease as per RANO2.0 criteria. Note: Contrast enhancing disease will be allowed. 9. 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). Note: Prior exposure to IDH-inhibitors will be allowed. 10. Have expected survival of ≥3 months. 11. 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 render 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. 12. 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: 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. 13. Must have normal organ and marrow function as defined below: * Hemoglobin ≥ 9.0 g/dL * Absolute neutrophil count ≥ 1,500/mcL * Platelet count ≥ 100,000/mcL * Serum total bilirubin ≤1.5 × upper limit of reference range (ULN); if \>1.5 × ULN and due to Gilbert syndrome, total bilirubin ≤3×ULN with direct bilirubin ≤ULN * Aspartate aminotransferase (AST) at or below ULN * Alanine aminotransferase (ALT) at or below ULN * Alkaline phosphatase (ALP) ≤2.5 X institutional ULN * Serum creatinine ≤ 2.0 × ULN, OR Creatinine clearance \> 40 mL/min based on the Cockcroft-Gault glomerular filtration rate estimation: (140 - Age) × (Weight in kg) × (0.85 if female) / 72 × Serum Creatinine 14. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class II or better. 15. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within six (6) months are eligible for this trial. 16. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. 17. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
Exclusion criteria
1. 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. 2. Presence of extracranial metastatic or leptomeningeal disease. 3. 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. 4. Early progression prior to 3 months from completion of radiotherapy. 5. 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). 6. 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. 7. Are pregnant or breastfeeding. 8. Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make participation in this protocol unreasonably hazardous. 9. Have a known hypersensitivity to any of the components of vorasidenib or lomustine. 10. Have a heart-rate corrected QT interval using Fridericia's formula (QTcF) ≥450 msec or other factors that increase the risk of QT prolongation or arrhythmic events (eg, heart failure, hypokalemia, family history of long QT interval syndrome). Note: Subjects with bundle branch block and prolonged QTcF are permitted with approval of the principal investigator. 11. Are taking therapeutic doses of steroids at a dexamethasone equivalent of \> 4mg/day for signs/symptoms of glioma. Note: Subjects taking physiologic doses (defined as equivalent of ≤10 mg prednisone daily) for medical conditions not related to glioma will be permitted. 12. Are taking any medications that are cytochrome CYP2C19, or CYP3A substrates with a narrow therapeutic index or strong inhibitors of CYP1A2. (Subjects should be transferred to other medications before receiving the first dose of study drug.) 13. Are unable to swallow pills or have known active inflammatory gastrointestinal disease, chronic diarrhea, previous gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other condition that limits the ingestion or gastrointestinal absorption of drugs administered orally. Note: Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential). 14. Previous treatment with bevacizumab for the treatment of glioma with therapeutic intent, or with bevacizumab as supportive therapy (e.g., edema reduction) within six (6) weeks (42 days) of initiation of study treatment. 15. Have any other acute or chronic medical or psychiatric condition, including recent (within 12 months of C1D1) or active suicidal ideation or behavior, or a laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Recommended Combination Dose (RCD) | During Part 1, from Cycle 1 Day 1 through completion of the dose-limiting toxicity evaluation period for each cohort (42 days). The RCD will be determined after all Part 1 dose-escalation/de-escalation decisions are completed. | Recommended combination dose of vorasidenib administered with lomustine, determined during the dose de-escalation phase based on the occurrence of dose-limiting toxicities (DLTs). The RCD is defined as the highest dose level at which fewer than 2 of 6 evaluable participants experience a DLT during the first treatment cycle. DLTs are defined in the protocol and graded according to NCI CTCAE v5.0. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events | From first dose until 42 days after last study treatment (up to 60 months) | Incidence, severity, and relationship of treatment-emergent adverse events (AEs), serious adverse events (SAEs), and AEs leading to treatment discontinuation or death, graded according to NCI CTCAE version 5.0. |
| Progression-Free Survival at 6 Months (PFS-6) | 6 months after treatment initiation | Percentage of participants alive and progression-free 6 months after treatment initiation, as assessed using RANO 2.0 criteria. |
| Progression-Free Survival (PFS) | Up to 60 months | Time from treatment initiation until first documented disease progression or death from any cause, whichever occurs first, as assessed using RANO 2.0 criteria. |
| Clinical Benefit Rate (CBR) | Up to 60 months | Percentage of participants achieving clinical benefit according to RANO 2.0 criteria. For enhancing gliomas, clinical benefit is defined as complete response (CR), partial response (PR), or stable disease (SD). For non-enhancing gliomas, clinical benefit is defined as CR, PR, minor response (mR), or SD. |
| Plasma Concentration of Vorasidenib and AGI-69460 | Cycle 1 Days 1, 15, and 22 and Cycle 2 Day 1 (each cycle is 42 days; assessments occur over approximately 6 weeks from Cycle 1 Day 1 through Cycle 2 Day 1). | Plasma concentrations of vorasidenib and its circulating metabolite AGI-69460 following administration in combination with lomustine. |
Countries
United States
Contacts
CONTACTLinda Elias, RN, BSN
CONTACTAmy Rodger, RN, BSN
PRINCIPAL_INVESTIGATORMegan Mantica, MD
UPMC Hillman Cancer Center
Outcome results
None listed