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NCT07215910PHASE3Recruiting

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

Alliance for Clinical Trials in Oncology

Start Date

6/24/2026

Completion Date

1/1/2040

Summary

This phase III trial compares the effect of vorasidenib to placebo in combination with usual treatment, temozolomide, in treating patients with newly diagnosed grade 3 astrocytoma after radiation. Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid and may kill tumor cells and slow down or stop tumor growth. Vorasidenib citrate blocks the proteins made by the mutated IDH1 and IDH2 genes, which may help keep tumor cells from growing. It is a type of enzyme inhibitor and a type of targeted therapy. Adding vorasidenib to the usual treatment, temozolomide, may be more effective than temozolomide alone in treating patients with newly diagnosed grade 3 astrocytoma after radiation therapy.

Detailed Description

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

Age Range: 12 years to No maximum

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: \-

Interventions

RADIATION

Intensity-Modulated Radiation Therapy

RADIATION

Volume Modulated Arc Therapy

RADIATION

Pencil Beam Scanning

PROCEDURE

Intensity-Modulated Proton Therapy

DRUG

Temozolomide

DRUG

Vorasidenib

DRUG

Placebo Administration

PROCEDURE

Biospecimen Collection

PROCEDURE

Magnetic Resonance Imaging

OTHER

Questionnaire Administration

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Conditions

Astrocytoma, IDH-Mutant, Grade 3

Locations

AIS Cancer Center at San Joaquin Community Hospital

Bakersfield, California 93301

United States

City of Hope Comprehensive Cancer Center

Duarte, California 91010

United States

Kaiser Permanente Dublin

Dublin, California 94568

United States

Kaiser Permanente-Fremont

Fremont, California 94538

United States

Kaiser Permanente Fresno Orchard Plaza

Fresno, California 93720

United States

Kaiser Permanente-Fresno

Fresno, California 93720

United States

UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care

Irvine, California 92612

United States

Kaiser Permanente- Modesto MOB II

Modesto, California 95356

United States

Kaiser Permanente-Oakland

Oakland, California 94611

United States

UC Irvine Health/Chao Family Comprehensive Cancer Center

Orange, California 92868

United States

Kaiser Permanente-Roseville

Roseville, California 95661

United States

Kaiser Permanente Downtown Commons

Sacramento, California 95814

United States

University of California Davis Comprehensive Cancer Center

Sacramento, California 95817

United States

Kaiser Permanente-South Sacramento

Sacramento, California 95823

United States

Kaiser Permanente-San Francisco

San Francisco, California 94115

United States

Kaiser Permanente-Santa Teresa-San Jose

San Jose, California 95119

United States

Kaiser Permanente San Leandro

San Leandro, California 94577

United States

Kaiser San Rafael-Gallinas

San Rafael, California 94903

United States

Kaiser Permanente Medical Center - Santa Clara

Santa Clara, California 95051

United States

Kaiser Permanente-Santa Rosa

Santa Rosa, California 95403

United States

Kaiser Permanente-South San Francisco

South San Francisco, California 94080

United States

Kaiser Permanente-Vallejo

Vallejo, California 94589

United States

Kaiser Permanente-Walnut Creek

Walnut Creek, California 94596

United States

John Muir Medical Center-Walnut Creek

Walnut Creek, California 94598

United States

Yale University

New Haven, Connecticut 06520

United States

Smilow Cancer Hospital Care Center-Trumbull

Trumbull, Connecticut 06611

United States

Smilow Cancer Hospital Care Center - Waterford

Waterford, Connecticut 06385

United States

Helen F Graham Cancer Center

Newark, Delaware 19713

United States

Medical Oncology Hematology Consultants PA

Newark, Delaware 19713

United States

UM Sylvester Comprehensive Cancer Center at Coral Gables

Coral Gables, Florida 33146

United States

UM Sylvester Comprehensive Cancer Center at Coral Springs

Coral Springs, Florida 33065

United States

UM Sylvester Comprehensive Cancer Center at Deerfield Beach

Deerfield Beach, Florida 33442

United States

UM Sylvester Comprehensive Cancer Center at Doral

Doral, Florida 33166

United States

UM Sylvester Comprehensive Cancer Center at Hollywood

Hollywood, Florida 33021

United States

University of Miami Miller School of Medicine-Sylvester Cancer Center

Miami, Florida 33136

United States

UM Sylvester Comprehensive Cancer Center at Kendall

Miami, Florida 33176

United States

University of Miami Sylvester Comprehensive Cancer Center at Sole Mia

North Miami, Florida 33181

United States

UM Sylvester Comprehensive Cancer Center at Plantation

Plantation, Florida 33324

United States

Augusta University Medical Center

Augusta, Georgia 30912

United States

OSF Saint Joseph Medical Center

Bloomington, Illinois 61701

United States

Illinois CancerCare-Bloomington

Bloomington, Illinois 61704

United States

Illinois CancerCare-Canton

Canton, Illinois 61520

United States

Illinois CancerCare-Carthage

Carthage, Illinois 62321

United States

University of Illinois

Chicago, Illinois 60612

United States

Illinois CancerCare-Eureka

Eureka, Illinois 61530

United States

NorthShore University HealthSystem-Evanston Hospital

Evanston, Illinois 60201

United States

Illinois CancerCare-Galesburg

Galesburg, Illinois 61401

United States

NorthShore University HealthSystem-Glenbrook Hospital

Glenview, Illinois 60026

United States

NorthShore University HealthSystem-Highland Park Hospital

Highland Park, Illinois 60035

United States

Illinois CancerCare-Kewanee Clinic

Kewanee, Illinois 61443

United States

Illinois CancerCare-Macomb

Macomb, Illinois 61455

United States

Illinois CancerCare-Ottawa Clinic

Ottawa, Illinois 61350

United States

Illinois CancerCare-Pekin

Pekin, Illinois 61554

United States

Illinois CancerCare-Peoria

Peoria, Illinois 61615

United States

OSF Saint Francis Radiation Oncology at Peoria Cancer Center

Peoria, Illinois 61615

United States

OSF Saint Francis Medical Center

Peoria, Illinois 61637

United States

Illinois CancerCare-Peru

Peru, Illinois 61354

United States

Illinois CancerCare-Princeton

Princeton, Illinois 61356

United States

Illinois CancerCare - Washington

Washington, Illinois 61571

United States

Midwestern Regional Medical Center

Zion, Illinois 60099

United States

UI Health Care Mission Cancer and Blood - Ankeny Clinic

Ankeny, Iowa 50023

United States

UI Health Care Mission Cancer and Blood - West Des Moines Clinic

Clive, Iowa 50325

United States

Iowa Methodist Medical Center

Des Moines, Iowa 50309

United States

UI Health Care Mission Cancer and Blood - Des Moines Clinic

Des Moines, Iowa 50309

United States

Broadlawns Medical Center

Des Moines, Iowa 50314

United States

Mercy Medical Center - Des Moines

Des Moines, Iowa 50314

United States

UI Health Care Mission Cancer and Blood - Laurel Clinic

Des Moines, Iowa 50314

United States

UI Healthcare Mission Cancer and Blood - Pella

Pella, Iowa 50219

United States

UI Health Care Mission Cancer and Blood - Waukee Clinic

Waukee, Iowa 50263

United States

University of Kansas Cancer Center

Kansas City, Kansas 66160

United States

Lawrence Memorial Hospital

Lawrence, Kansas 66044

United States

University of Kansas Cancer Center-Overland Park

Overland Park, Kansas 66210

United States

University of Kansas Hospital-Indian Creek Campus

Overland Park, Kansas 66211

United States

University of Kansas Hospital-Westwood Cancer Center

Westwood, Kansas 66205

United States

The James Graham Brown Cancer Center at University of Louisville

Louisville, Kentucky 40202

United States

UofL Health Medical Center Northeast

Louisville, Kentucky 40245

United States

West Jefferson Medical Center

Marrero, Louisiana 70072

United States

East Jefferson General Hospital

Metairie, Louisiana 70006

United States

University Medical Center New Orleans

New Orleans, Louisiana 70112

United States

Children's Hospital New Orleans

New Orleans, Louisiana 70118

United States

MaineHealth Coastal Cancer Treatment Center

Bath, Maine 04530

United States

MaineHealth Maine Medical Center - Portland

Portland, Maine 04102

United States

MaineHealth Cancer Care Center of York County

Sanford, Maine 04073

United States

MaineHealth Maine Medical Center- Scarborough

Scarborough, Maine 04074

United States

Tufts Medical Center

Boston, Massachusetts 02111

United States

Massachusetts General Hospital Cancer Center

Boston, Massachusetts 02114

United States

Dana-Farber Cancer Institute

Boston, Massachusetts 02215

United States

University of Michigan Rogel Cancer Center

Ann Arbor, Michigan 48109

United States

University of Michigan - Brighton Center for Specialty Care

Brighton, Michigan 48116

United States

Corewell Health Grand Rapids Hospitals - Butterworth Hospital

Grand Rapids, Michigan 49503

United States

Corewell Health Grand Rapids Hospitals - Helen DeVos Children's Hospital

Grand Rapids, Michigan 49503

United States

Trinity Health Grand Rapids Hospital

Grand Rapids, Michigan 49503

United States

University of Michigan Health - West

Wyoming, Michigan 49519

United States

Mercy Hospital

Coon Rapids, Minnesota 55433

United States

Fairview Southdale Hospital

Edina, Minnesota 55435

United States

Abbott-Northwestern Hospital

Minneapolis, Minnesota 55407

United States

Coborn Cancer Center at Saint Cloud Hospital

Saint Cloud, Minnesota 56303

United States

Regions Hospital

Saint Paul, Minnesota 55101

United States

United Hospital

Saint Paul, Minnesota 55102

United States

University of Mississippi Medical Center

Jackson, Mississippi 39216

United States

Siteman Cancer Center at Saint Peters Hospital

City of Saint Peters, Missouri 63376

United States

Siteman Cancer Center at West County Hospital

Creve Coeur, Missouri 63141

United States

University of Kansas Cancer Center - Briarcliff

Kansas City, Missouri 64116

United States

University of Kansas Cancer Center - North

Kansas City, Missouri 64154

United States

University of Kansas Cancer Center - Lee's Summit

Lee's Summit, Missouri 64064

United States

Mercy Hospital Springfield

Springfield, Missouri 65804

United States

Washington University School of Medicine

St Louis, Missouri 63110

United States

Siteman Cancer Center-South County

St Louis, Missouri 63129

United States

Siteman Cancer Center at Christian Hospital

St Louis, Missouri 63136

United States

Memorial Sloan Kettering Basking Ridge

Basking Ridge, New Jersey 07920

United States

Hackensack University Medical Center

Hackensack, New Jersey 07601

United States

Memorial Sloan Kettering Monmouth

Middletown, New Jersey 07748

United States

Memorial Sloan Kettering Bergen

Montvale, New Jersey 07645

United States

Northwell Health Imbert Cancer Center

Bay Shore, New York 11706

United States

NYU Langone Hospital - Brooklyn

Brooklyn, New York 11220

United States

Memorial Sloan Kettering Commack

Commack, New York 11725

United States

Memorial Sloan Kettering Westchester

Harrison, New York 10604

United States

Northwell Health/Center for Advanced Medicine

Lake Success, New York 11042

United States

NYU Langone Hospital - Long Island

Mineola, New York 11501

United States

Northern Westchester Hospital

Mount Kisco, New York 10549

United States

Laura and Isaac Perlmutter Cancer Center at NYU Langone

New York, New York 10016

United States

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

New York, New York 10032

United States

Memorial Sloan Kettering Cancer Center

New York, New York 10065

United States

Stony Brook University Medical Center

Stony Brook, New York 11794

United States

Memorial Sloan Kettering Nassau

Uniondale, New York 11553

United States

University of Cincinnati Cancer Center-UC Medical Center

Cincinnati, Ohio 45219

United States

Ohio State University Comprehensive Cancer Center

Columbus, Ohio 43210

United States

University of Cincinnati Cancer Center-West Chester

West Chester, Ohio 45069

United States

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma 73104

United States

Providence Portland Medical Center

Portland, Oregon 97213

United States

Providence Saint Vincent Medical Center

Portland, Oregon 97225

United States

Christiana Care Health System-Concord Health Center

Chadds Ford, Pennsylvania 19317

United States

UPMC Hillman Cancer Center Erie

Erie, Pennsylvania 16505

United States

Forbes Hospital

Monroeville, Pennsylvania 15146

United States

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania 19107

United States

Allegheny General Hospital

Pittsburgh, Pennsylvania 15212

United States

UPMC Hillman Cancer Center

Pittsburgh, Pennsylvania 15232

United States

UPMC-Shadyside Hospital

Pittsburgh, Pennsylvania 15232

United States

Wexford Health and Wellness Pavilion

Wexford, Pennsylvania 15090

United States

Medical University of South Carolina

Charleston, South Carolina 29425

United States

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah 84112

United States

University of Vermont Medical Center

Burlington, Vermont 05401

United States

University of Vermont and State Agricultural College

Burlington, Vermont 05405

United States

Swedish Medical Center-First Hill

Seattle, Washington 98122

United States

Froedtert Menomonee Falls Hospital

Menomonee Falls, Wisconsin 53051

United States

Medical College of Wisconsin

Milwaukee, Wisconsin 53226

United States

ProHealth D N Greenwald Center

Mukwonago, Wisconsin 53149

United States

Froedtert and MCW Moorland Reserve Health Center

New Berlin, Wisconsin 53151

United States

Drexel Town Square Health Center

Oak Creek, Wisconsin 53154

United States

ProHealth Oconomowoc Memorial Hospital

Oconomowoc, Wisconsin 53066

United States

UW Cancer Center at ProHealth Care

Waukesha, Wisconsin 53188

United States

Froedtert West Bend Hospital/Kraemer Cancer Center

West Bend, Wisconsin 53095

United States