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Testing Addition of an Anti-cancer Drug, Vorasidenib to Temozolomide, After Radiation for Advanced Brain Cancer

NCT07215910 · Alliance for Clinical Trials in Oncology
In plain English

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Official title
Phase III Trial of Radiotherapy Followed by Adjuvant Temozolomide in Combination With the IDH Inhibitor Vorasidenib vs Placebo in IDH-Mutated Newly-Diagnosed Grade 3 Astrocytomas
About this study
The primary and secondary objectives of the study: PRIMARY OBJECTIVE: I. To determine if vorasidenib citrate (vorasidenib) and adjuvant temozolomide following radiation therapy improves progression-free survival (PFS) per blinded independent review in patients with newly-diagnosed IDH-mutant astrocytoma (World Health Organization \[WHO\] grade 3) compared to placebo given with adjuvant temozolomide following radiation therapy. SECONDARY OBJECTIVES: I. To evaluate the safety and tolerability of vorasidenib versus (vs.) placebo in combination with temozolomide, following radiation therapy. II. To evaluate PFS associated with vorasidenib vs. placebo in combination with temozolomide following radiation therapy, defined by local institutional review. III. To evaluate the efficacy of vorasidenib vs. placebo in combination with adjuvant temozolomide, following radiation therapy, based on overall survival (OS). IV. To evaluate the efficacy of vorasidenib vs. placebo in combination with temozolomide, following radiation therapy, based on objective response rate (ORR), complete response (CR) + partial response (PR), time to response, time to CR+PR, duration of response, and duration of CR+PR, with response assessed per the blinded independent review using the Response Assessment in Neuro-Oncology (RANO) 2.0 criteria in patients with measurable tumor at baseline. V. To evaluate the efficacy of vorasidenib vs. placebo in combination with temozolomide, following radiation therapy, based on ORR, CR+PR, time to response, time to CR+PR, duration of response, and duration of CR+PR, with response assessed per local institutional review or investigator using the RANO 2.0 criteria. VI. To evaluate the efficacy of vorasidenib vs. placebo in combination with temozolomide, following radiation therapy, based on time to next intervention. VII. To evaluate vorasidenib vs. placebo in combination with temozolomide, following radiation, with respect to health-related quality of life (HRQoL) as assessed by the Functional Assessment of Cancer Therapy-Brain (FACT-Br) and symptom burden as assessed by the MD Anderson Symptom Inventory-Brain Tumor (MDASI-BT). EXPLORATORY OBJECTIVES: I. To correlate tumor genotype with PFS. II. To evaluate the effect of the addition of vorasidenib to adjuvant temozolomide on seizure control. OUTLINE: Patients are randomized 1:1 to 1 of 2 arms. ARM I (CONTROL): Patients receive intensity-modulated radiation therapy (IMRT)/volume modulated arc therapy (VMAT) or pencil beam scanning (PBS) or intensity-modulated proton therapy (IMPT) once daily (QD) on Monday-Friday for 33 fractions. Starting 4 weeks after radiotherapy, patients receive temozolomide orally (PO) QD on days 1-5 and placebo PO QD on days 1-28 of each cycle. Cycles of combination treatment repeat every 28 days for up to 12 months and placebo alone repeats every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and magnetic resonance imaging (MRI) throughout the study. ARM II (EXPERIMENTAL): Patients receive IMRT/VMAT or PBS or IMPT QD on Monday-Friday for 33 fractions. Starting 4 weeks after radiotherapy, patients receive temozolomide PO QD on days 1-5 and vorasidenib PO QD on days 1-28 of each cycle. Cycles of combination treatment repeat every 28 days for up to 12 months and vorasidenib alone repeats every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection and MRI throughout the study. After completion of study treatment, patients are followed up every 3 months for the first 2 years, every 4 months for the next 2 years, and then every 6 months for up to 10 years.
Eligibility criteria
Inclusion Criteria: * STEP 0: Histologic diagnosis of astrocytoma, IDH-mutant (central nervous system \[CNS\] WHO grade 3) * STEP 0: Available diagnostic slides (hematoxylin and eosin staining method \[H\&E\] and immunohistochemical stains for central review) * STEP 0: Tissue available for central biomarker testing (CDKN2A/B and1p/19q co-deletion \[all patients\], and IDH1/IDH2 \[if needed\]) * STEP 1: Centrally-confirmed diagnosis of astrocytoma, IDH-mutant (CNS WHO grade 3) * STEP 1: Presence of IDH1 p.R132 or IDH2 p.172 mutation, confirmed by central review of immunohistochemical stain or molecular testing results, with central confirmation of equivocal results * STEP 1: Absence of CDKN2A/B homozygous deletion by central testing * STEP 1: Absence of whole arm 1p/19q co-deletion (i.e. intact 1p/19q) by central testing * STEP 1: No evidence of spinal or leptomeningeal disease * STEP 1: No prior chemotherapy, cranial irradiation, IDH-inhibitor therapy, radiotherapy, vaccine therapy, small-molecule therapy, or laser ablation * STEP 1: Prior diagnostic surgery/resection/biopsy ≤ 6 months of registration * STEP 1: Planned radiotherapy and adjuvant chemotherapy * STEP 1: Age ≥ 12 years * STEP 1: Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (or Karnofsky performance status \[KPS\] ≥ 60%) * STEP 1: Absolute neutrophil count (ANC) ≥ 1,500/mm\^3 * STEP 1: Hemoglobin ≥ 9 g/dL * STEP 1: Platelet count ≥ 100,000/mm\^3 * STEP 1: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) \* For patients with Gilbert syndrome, total bilirubin ≤ 1.0 x ULN * STEP 1: Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase \[SGPT\]) ≤ 2.5 x ULN * STEP 1: Alkaline phosphatase ≤ 2.5 x ULN * STEP 1: Creatinine ≤ 2.0 x ULN or calculated (calc.) creatinine clearance \> 40 mL/min \* For patients ≥ 18 years of age, calculated using the Cockcroft-Gault equation. For patients \< 18 years of age, calculated using the Bedside Schwartz method: * Age: 10 to \< 13 years; Maximum Serum Creatinine (mg/dL): 1.2 (male) 1.2 (female) * Age: 13 to \< 16 years; Maximum Serum Creatinine (mg/dL): 1.5 (male) 1.4 (female) * Age: ≥ 16 years; Maximum Serum Creatinine (mg/dL): 1.7(male) 1.4 (female) * STEP 1: Not pregnant and not nursing, because this study involves agents whose genotoxic, mutagenic, and teratogenic effects on the developing fetus and newborn are unknown \* Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 14 days prior to registration is required * STEP 1: Women and men of reproductive potential should agree to abstain from sexual intercourse or use two highly effective methods of birth control, at least one of which must be a barrier method, throughout their participation in this study and for at least 90 days after the last dose of vorasidenib. Reproductive status and discussions about birth control measures should be documented in the patient's record. Abstinence is acceptable only as true abstinence when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of birth control. Highly effective forms of birth control are defined as hormonal oral contraceptives, injectables, patches, intrauterine devices, intrauterine hormone release systems, bilateral tubal ligation, condoms with spermicide, or male partner sterilization * STEP 1: No severe or intercurrent illness, no active infection that requires systemic anti-infective therapy, and no active infection with an unexplained fever \> 38.5°C within 7 days prior to registration * STEP 1: Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial * STEP 1: Patients must be able to tolerate or undergo an MRI * STEP 1: Patients with known HIV infection on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial * STEP 1: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * STEP 1: 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 * STEP 1: No significant active cardiac disease within 6 months prior to registration, including New York Heart Association Functional Classification class III or IV congestive heart failure, myocardial infarction, unstable angina, and/or stroke. To be eligible for this trial, patients should be class 2B or better * STEP 1: No history of significant (grade ≥ 2) intratumoral or peri-tumoral hemorrhage * STEP 1: No known active inflammatory gastrointestinal disease, chronic diarrhea, prior gastric resection or lap band dysphagia, short-gut syndrome, gastroparesis, or other condition causing an inability to swallow oral formulations of agents. Gastroesophageal reflux disease under medical treatment is allowed (assuming no drug interaction potential) * STEP 1: No known hypersensitivity to any of the components of vorasidenib or temozolomide * STEP 1: No other acute or chronic medical condition or laboratory abnormality that may increase the risk associated with study participation or protocol therapy administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study * STEP 1: No concurrent use of other investigational agents * STEP 1: No concurrent use of alternating tumor treating field (TTField) therapy * STEP 1: No concurrent use of therapeutic doses of steroids for glioma. Concurrent use of physiologic doses of steroids (defined as equivalent of ≤ 10 mg prednisone daily) for medical conditions unrelated to glioma is allowed. Corticosteroids administered for reasons related to glioma should be used in the smallest dose possible to control symptoms of cerebral edema and mass effect and discontinued whenever possible. * STEP 1: No concurrent use of warfarin sodium or any other Coumadin-derivative anticoagulant. Patients must be off Coumadin-derivative anticoagulants for at least 7 days prior to registration. Low molecular weight heparin (LMWH) and factor Xa inhibitors are allowed * STEP 1: No concurrent use of strong and moderate CYP1A2 inhibitors, moderate CYP1A2 inducers, or CYP3A substrates where a minimal concentration change can reduce efficacy. Patients should be transferred to other medications prior to registration Exclusion Criteria: \-
Study design
Enrollment target: 408 participants
Allocation: randomized
Masking: double
Age groups: child, adult, older_adult
Timeline
Starts: 2026-07-20
Estimated completion: 2040-01
Last updated: 2026-07-02
Interventions
Radiation: Intensity-Modulated Radiation TherapyRadiation: Volume Modulated Arc TherapyRadiation: Pencil Beam ScanningProcedure: Intensity-Modulated Proton TherapyDrug: TemozolomideDrug: VorasidenibDrug: Placebo AdministrationProcedure: Biospecimen CollectionProcedure: Magnetic Resonance ImagingOther: Questionnaire Administration
Primary outcomes
  • Progression free survival (PFS) by blinded independent central review (BICR) (assessed up to 10 years)
Sponsor
Alliance for Clinical Trials in Oncology · other
With: National Cancer Institute (NCI)
Contacts & investigators
ContactAlexandra Alexandra LeVasseur · contact · alevasseur@bsd.uchicago.edu · 773-834-4518
InvestigatorUgonma N Chukwueke, MD · study_chair, Alliance for Clinical Trials in Oncology
InvestigatorRifaquat M. Rahman, MD · study_chair, Alliance for Clinical Trials in Oncology
InvestigatorPatrick Y Wen, MD · study_chair, Alliance for Clinical Trials in Oncology
All locations (82)
City of Hope Comprehensive Cancer CenterRecruiting
Duarte, California, United States
UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory CareRecruiting
Irvine, California, United States
UC Irvine Health/Chao Family Comprehensive Cancer CenterRecruiting
Orange, California, United States
University of California Davis Comprehensive Cancer CenterRecruiting
Sacramento, California, United States
Yale UniversityRecruiting
New Haven, Connecticut, United States
Smilow Cancer Hospital Care Center-TrumbullRecruiting
Trumbull, Connecticut, United States
Smilow Cancer Hospital Care Center - WaterfordRecruiting
Waterford, Connecticut, United States
Helen F Graham Cancer CenterRecruiting
Newark, Delaware, United States
Medical Oncology Hematology Consultants PARecruiting
Newark, Delaware, United States
OSF Saint Joseph Medical CenterRecruiting
Bloomington, Illinois, United States
Illinois CancerCare-BloomingtonRecruiting
Bloomington, Illinois, United States
Illinois CancerCare-CantonRecruiting
Canton, Illinois, United States
Illinois CancerCare-CarthageRecruiting
Carthage, Illinois, United States
University of IllinoisRecruiting
Chicago, Illinois, United States
Illinois CancerCare-EurekaRecruiting
Eureka, Illinois, United States
NorthShore University HealthSystem-Evanston HospitalRecruiting
Evanston, Illinois, United States
Illinois CancerCare-GalesburgRecruiting
Galesburg, Illinois, United States
NorthShore University HealthSystem-Glenbrook HospitalRecruiting
Glenview, Illinois, United States
NorthShore University HealthSystem-Highland Park HospitalRecruiting
Highland Park, Illinois, United States
Illinois CancerCare-Kewanee ClinicRecruiting
Kewanee, Illinois, United States
Illinois CancerCare-MacombRecruiting
Macomb, Illinois, United States
Illinois CancerCare-Ottawa ClinicRecruiting
Ottawa, Illinois, United States
Illinois CancerCare-PekinRecruiting
Pekin, Illinois, United States
Illinois CancerCare-PeoriaRecruiting
Peoria, Illinois, United States
OSF Saint Francis Radiation Oncology at Peoria Cancer CenterRecruiting
Peoria, Illinois, United States
OSF Saint Francis Medical CenterRecruiting
Peoria, Illinois, United States
Illinois CancerCare-PeruRecruiting
Peru, Illinois, United States
Illinois CancerCare-PrincetonRecruiting
Princeton, Illinois, United States
Illinois CancerCare - WashingtonRecruiting
Washington, Illinois, United States
Midwestern Regional Medical CenterRecruiting
Zion, Illinois, United States
UI Health Care Mission Cancer and Blood - Ankeny ClinicRecruiting
Ankeny, Iowa, United States
UI Health Care Mission Cancer and Blood - West Des Moines ClinicRecruiting
Clive, Iowa, United States
Iowa Methodist Medical CenterRecruiting
Des Moines, Iowa, United States
UI Health Care Mission Cancer and Blood - Des Moines ClinicRecruiting
Des Moines, Iowa, United States
Broadlawns Medical CenterRecruiting
Des Moines, Iowa, United States
Mercy Medical Center - Des MoinesRecruiting
Des Moines, Iowa, United States
UI Health Care Mission Cancer and Blood - Laurel ClinicRecruiting
Des Moines, Iowa, United States
UI Healthcare Mission Cancer and Blood - PellaRecruiting
Pella, Iowa, United States
UI Health Care Mission Cancer and Blood - Waukee ClinicRecruiting
Waukee, Iowa, United States
West Jefferson Medical CenterRecruiting
Marrero, Louisiana, United States
East Jefferson General HospitalRecruiting
Metairie, Louisiana, United States
University Medical Center New OrleansRecruiting
New Orleans, Louisiana, United States
Children's Hospital New OrleansRecruiting
New Orleans, Louisiana, United States
MaineHealth Coastal Cancer Treatment CenterRecruiting
Bath, Maine, United States
MaineHealth Maine Medical Center - PortlandRecruiting
Portland, Maine, United States
MaineHealth Cancer Care Center of York CountyRecruiting
Sanford, Maine, United States
MaineHealth Maine Medical Center- ScarboroughRecruiting
Scarborough, Maine, United States
University of Michigan Rogel Cancer CenterRecruiting
Ann Arbor, Michigan, United States
University of Michigan - Brighton Center for Specialty CareRecruiting
Brighton, Michigan, United States
Memorial Sloan Kettering Basking RidgeRecruiting
Basking Ridge, New Jersey, United States
Memorial Sloan Kettering MonmouthRecruiting
Middletown, New Jersey, United States
Memorial Sloan Kettering BergenRecruiting
Montvale, New Jersey, United States
Northwell Health Imbert Cancer CenterRecruiting
Bay Shore, New York, United States
Memorial Sloan Kettering CommackRecruiting
Commack, New York, United States
Memorial Sloan Kettering WestchesterRecruiting
Harrison, New York, United States
Northwell Health/Center for Advanced MedicineRecruiting
Lake Success, New York, United States
Northern Westchester HospitalRecruiting
Mount Kisco, New York, United States
Memorial Sloan Kettering Cancer CenterRecruiting
New York, New York, United States
Stony Brook University Medical CenterRecruiting
Stony Brook, New York, United States
Memorial Sloan Kettering NassauRecruiting
Uniondale, New York, United States
University of Cincinnati Cancer Center-UC Medical CenterRecruiting
Cincinnati, Ohio, United States
Ohio State University Comprehensive Cancer CenterRecruiting
Columbus, Ohio, United States
University of Cincinnati Cancer Center-West ChesterRecruiting
West Chester, Ohio, United States
University of Oklahoma Health Sciences CenterRecruiting
Oklahoma City, Oklahoma, United States
Christiana Care Health System-Concord Health CenterRecruiting
Chadds Ford, Pennsylvania, United States
UPMC Hillman Cancer Center ErieRecruiting
Erie, Pennsylvania, United States
Forbes HospitalRecruiting
Monroeville, Pennsylvania, United States
Thomas Jefferson University HospitalRecruiting
Philadelphia, Pennsylvania, United States
Allegheny General HospitalRecruiting
Pittsburgh, Pennsylvania, United States
University of Pittsburgh Cancer Institute (UPCI)Recruiting
Pittsburgh, Pennsylvania, United States
UPMC-Shadyside HospitalRecruiting
Pittsburgh, Pennsylvania, United States
Wexford Health and Wellness PavilionRecruiting
Wexford, Pennsylvania, United States
University of Vermont Medical CenterRecruiting
Burlington, Vermont, United States
University of Vermont and State Agricultural CollegeRecruiting
Burlington, Vermont, United States
Froedtert Menomonee Falls HospitalRecruiting
Menomonee Falls, Wisconsin, United States
Medical College of WisconsinRecruiting
Milwaukee, Wisconsin, United States
ProHealth D N Greenwald CenterRecruiting
Mukwonago, Wisconsin, United States
Froedtert and MCW Moorland Reserve Health CenterRecruiting
New Berlin, Wisconsin, United States
Drexel Town Square Health CenterRecruiting
Oak Creek, Wisconsin, United States
ProHealth Oconomowoc Memorial HospitalRecruiting
Oconomowoc, Wisconsin, United States
UW Cancer Center at ProHealth CareRecruiting
Waukesha, Wisconsin, United States
Froedtert West Bend Hospital/Kraemer Cancer CenterRecruiting
West Bend, Wisconsin, United States
Testing Addition of an Anti-cancer Drug, Vorasidenib to Temozolomide, After Radiation for Advanced Brain Cancer · TrialPath