BGB-290 and Temozolomide in Treating Isocitrate Dehydrogenase (IDH)1/2-Mutant Grade I-IV Gliomas (PNOC017)

• ClinicalTrials.gov Identifier: NCT03749187
• Recruitment Status: Recruiting
• First Posted: November 21, 2018
• Last Update Posted: April 6, 2023
• Sponsor: University of California, San Francisco
• Collaborators: BeiGene USA, Inc.; Pacific Pediatric Neuro-Oncology Consortium
• Information provided by (Responsible Party): Sabine Mueller, MD, PhD, University of California, San Francisco

Study Description

Brief Summary:

This phase I trial studies the side effects and best dose of BGB-290 and temozolomide in treating adolescents and young adults with IDH1/2-mutant grade I-IV glioma that is newly diagnosed or has come back. BGB-290 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving BGB-290 and temozolomide may work better in treating adolescents and young adults with IDH1/2-mutant grade I-IV glioma.

Condition or disease	Intervention/treatment	Phase
Glioblastoma; IDH1 Gene Mutation; IDH2 Gene Mutation; Low Grade Glioma; Malignant Glioma; Recurrent Glioblastoma; Recurrent WHO Grade II Glioma; Recurrent WHO Grade III Glioma; WHO Grade II Glioma; WHO Grade III Glioma	Drug: PARP Inhibitor BGB-290; Drug: Temozolomide	Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. Determine the safety and tolerability of the combination of Poly (ADP-Ribose) polymerase (PARP) inhibitor BGB-290 (BGB-290) and temozolomide (TMZ) in adolescent and young adult (AYA) subjects with IDH1/2-mutant glioma, including the maximum tolerated dose (MTD) and characterization of dose-limiting toxicities (DLTs) in both, newly diagnosed and recurrent treatment arms.

EXPLORATORY OBJECTIVES:

I. Evaluate the preliminary efficacy of BGB-290 and temozolomide in terms of progression free survival (PFS) and overall survival (OS) in Arm A and B stratified by tumor diagnosis, calculated using the Kaplan-Meier method with a goal of improving the historical high grade glioma progression free survival of 10% and overall survival of 20% at 2 years.

II. Assess the mutational landscape studies via whole-exome sequencing (WES). III. Assessment of gene expression patterns using ribonucleic acid (RNA) sequencing (RNAseq).

IV. Assess the methylation profiling with Infinium methylation assays. V. Assess the oncometabolite profiling via liquid chromatography (LC)/mass spectrometry (MS)-MS.

VI. Assess the intratumoral drug level assessments via LC/MS-MS.

OUTLINE: This is a dose-escalation study. Patients are assigned to 1 of 2 cohorts. After the MTD is established, additional patients will be enrolled into the efficacy component of the trial.

Arm A: Newly diagnosed IDH1/2-mutant high-grade glioma patients receive PARP inhibitor BGB-290 orally (PO) twice daily (BID) on days 1-28 and temozolomide PO daily on days 1-21. Courses repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

Arm B: Recurrent IDH1/2-mutant low-grade or high-grade glioma patients receive PARP inhibitor BGB-290 orally (PO) twice daily (BID) on days 1-28 and temozolomide PO daily on days 1-21. Courses repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

COHORT B0: Recurrent IDH1/2-mutant low-grade or high-grade glioma patients receive PARP inhibitor BGB-290 PO for 7 days pre-surgery at the MTD determined in the Phase I portion. After recovery from surgery (14-28 days), the patient will proceed to the efficacy component of the trial.

After completion of study treatment, patients are followed up for 5 years.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 78 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Target Validation/Phase1 Study of BGB-290 in Combination With Temozolomide in Adolescent and Young Adult IDH1/2 Newly Diagnosed and Recurrent Mutant Gliomas
• Actual Study Start Date: April 3, 2019
• Estimated Primary Completion Date: June 30, 2024
• Estimated Study Completion Date: July 30, 2029

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A (BGB-290, temozolomide); Patients with grades III-IV newly diagnosed IDH1/2 mutant glioma receive PARP inhibitor BGB-290 PO BID on days 1-28 and temozolomide PO daily on days 1-21. Courses repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.	Drug: PARP Inhibitor BGB-290; Given PO; Other Name: BGB-290; Drug: Temozolomide; Given PO; Other Names: CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Methazolastone; RP-46161; SCH 52365; Temcad; Temodal; Temodar; Temomedac
Experimental: Arm B (BGB-290, temozolomide); Patients with grades I-IV recurrent IDH1/2 mutant glioma receive PARP inhibitor BGB-290 PO BID on days 1-28 and temozolomide PO daily on days 1-21. Courses repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity. Cohort B0: Patients who are surgical candidates with grades I-IV recurrent IDH1/2 mutant glioma receive PARP inhibitor BGB-290 PO BID for 7 days, pre-surgery. After recovery from surgery, patients receive PARP inhibitor BGB-290 PO BID on days 1-28 and temozolomide PO daily on days 1-21. Courses repeat every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.	Drug: PARP Inhibitor BGB-290; Given PO; Other Name: BGB-290; Drug: Temozolomide; Given PO; Other Names: CCRG-81045; Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-; M & B 39831; M and B 39831; Methazolastone; RP-46161; SCH 52365; Temcad; Temodal; Temodar; Temomedac

Outcome Measures

Primary Outcome Measures :

1. Proportion of participants with Dose Limiting Toxicities (DLTs) [ Time Frame: Up to 28 days ]
   Events occurring on or after treatment on Day 1 will be classified using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Adverse events leading to treatment discontinuation will be listed.

Other Outcome Measures:

1. Progression free survival (PFS) [ Time Frame: Up to 5 years ]
   The analyses of PFS will include patients who have received any amount of study treatment. PFS is defined as the time from the first day of study treatment with until documented disease progression or death, whichever occurs first. For patients who do not have documented progressive disease (PD) or death before the end of the study or who are lost to follow-up, PFS will be censored at the day of the last clinical assessment. Data will be summarized by Kaplan-Meier method.
2. Overall survival (OS) [ Time Frame: Up to 5 years ]
   The analyses of OS will include patients who have received any amount of study treatment. OS is defined as the time from the first dose of study treatment to the time of death from any cause on study. For patients who do not die before the end of the study or who are lost to follow-up, OS will be censored at the date of last contact. Data will be summarized by Kaplan-Meier method.

Eligibility Criteria

• Ages Eligible for Study: 13 Years to 25 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Arm A Only: Subjects must have histologically confirmed World Health Organization (WHO) grade III-IV newly diagnosed IDH1/2-mutant glioma.
• Arm B Only: WHO grades I-IV recurrent IDH1/2 mutant glioma. Subjects in Arm B must have magnetic resonance imaging (MRI) confirming progressive disease; re-biopsy is encouraged, but not required at the time of recurrence for confirmation.
• Patients with a primary spinal tumor, secondary glioma, or multifocal disease in the brain, but without evidence of diffuse leptomeningeal spread, are eligible. In cases where there are questions about multifocality versus diffuse leptomeningeal spread, the study chair or co-chair must be contacted to make a final decision on eligibility.
• Subjects must have IDH1 or IDH2 mutation associated with neomorphic activity of the encoded proteins.
• Subjects must be willing to provide archival formalin-fixed embedded (FFPE) and frozen tissue specimens for biomarker studies if available.
• Subjects in Arm A must have been treated with maximal safe resection of primary tumor followed by adjuvant radiation therapy (RT). Treatment with TMZ during radiation is allowed but not required.

• Subjects in Arm B must have been treated with maximal safe resection of tumor.

  • Lower grade glioma (LGG) subjects who progressed after initial surgery alone are eligible. Any number of prior therapies are allowed.
  • High grade glioma (HGG) subjects enrolled on Arm B must have been treated with a minimum of maximal safe resection of primary tumor followed by adjuvant RT prior to recurrence. Any number of prior therapies are allowed.
• Subjects must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
• Myelosuppressive chemotherapy: subjects must have received their last dose of known myelosuppressive anticancer chemotherapy at least three weeks prior to study registration or at least six weeks if nitrosourea.

• Biologic agent: subjects must have recovered from any toxicity related to biologic agents and received their last dose >= 7 days prior to study registration.

  • For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval should be discussed with the study chair.
  • For biologic agents that have a prolonged half-life, the appropriate interval since last treatment should be discussed with the study chair prior to registration.
• Monoclonal antibody treatment: at least three half-lives must have elapsed prior to registration, and subjects on bevacizumab must have received their last dose >= 32 days prior to study registration.
• Subjects in Arm A should begin therapy with TMZ and BGB-290 after completion of radiation therapy and when all other eligibility criteria are met.
• For subjects in Arm B, patients must not have received radiation therapy within 4 weeks prior to the initiation of study treatment. Post-RT, the diagnosis of true progression versus ?pseudo-progression? can be challenging when imaging modalities are exclusively used, and thus an additional resection is encouraged if clinically indicated.
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3.
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
• Hemoglobin >= 9 g/dL.
• Serum creatinine =< 1.5 x upper limit of normal (ULN) or estimated creatinine clearance >= 50 mL/min (calculated using the institutional standard method).
• Total serum bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN).
• Aspartate and alanine aminotransferase (AST and ALT) =< 3 x ULN.
• Serum albumin >= 2 g/dL.
• Subjects with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and well controlled.
• Subjects who have neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration.
• Corticosteroids: Subjects who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to registration.
• The effects of BGB-290 on the developing human fetus are unknown. For this reason and because alkylating agents (such as TMZ) are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation and 4 months after completion of BGB-290 or TMZ administration. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately.
• Subjects must be able to swallow capsules.
• Subjects must have the ability to undergo serial MRI scans (computerized tomography [CT] cannot substitute for MRI).
• A legal parent/guardian or patient must be able to understand, and willing to sign, a written informed consent and assent document, as appropriate.
• Karnofsky >= 50 for subjects > 16 years of age and Lansky >= 50 for subjects =< 16 years of age. Subjects who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.

Exclusion Criteria:

• Subjects who are receiving any other investigational agents and/or subjects previously treated with small molecule inhibitors of mutant IDH1 or IDH2 proteins at any time may not be enrolled.
• Subjects who have received a PARP inhibitor previously.
• Subjects with active infection requiring antibiotics at time of therapy start.
• Subjects with other diagnosis of malignancy.
• Subjects with clinically significant active bleeding disorder, hemoptysis, or melena =< 6 months prior to day 1.

• Subjects on therapeutic anti-coagulation with heparin, warfarin, or other anticoagulants:

  • Use of low-dose aspirin and/or non-steroidal anti-inflammatory agents are allowed.
  • Use of thrombolytic to establish patency of indwelling venous catheters is allowed.
  • Prophylactic anticoagulation for venous access devices is allowed as long as institutional normalized ratio (INR) is =< 1.5 and partial thromboplastin time (aPTT) =< 1.5 x institutional ULN.
  • Use of low-molecular weight heparin is allowed.
• Subjects with known disseminated leptomeningeal disease.
• Subjects with diffuse intrinsic pontine glioma (DIPG) are not eligible for this study.
• Unresolved acute effects of any prior therapy of grade >= 2, except for adverse events (AEs) not constituting a safety risk by investigator judgement.
• Use =< 10 days (or =< 5 half-lives, whichever is shorter) prior to day 1 or anticipated need for food or drugs known to be strong or moderate Cytochrome P450, family 3, subfamily A (CYP3A) inhibitors or strong CYP3A inducers.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to TMZ or BGB-290.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Female subjects of childbearing potential must not be pregnant or breast-feeding. Female subjects of childbearing potential must have a negative serum or urine pregnancy test within 7 days of first dose.
• Human immunodeficiency virus (HIV)-positive subjects on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with BGB-290 and TMZ. In addition, these subjects are at increased risk of lethal infections when treated with marrow-suppressive therapy.
• Subjects with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.

Contacts and Locations

Contacts

Contact: Kelly Hitchner; 415-502-1600; PNOC017@ucsf.edu

Locations

United States, California

Children's Hospital Los Angeles; Recruiting

Los Angeles, California, United States, 90027

Contact: Ashley S. Margol, MD 323-361-8147 amargol@chla.usc.edu

Principal Investigator: Ashley S. Margol, MD

Sub-Investigator: Tom Davidson, MD

Rady Children's Hospital - San Diego; Not yet recruiting

San Diego, California, United States, 92123

Contact: Jennifer Elster, MD 858-966-4939 jelster@rchsd.org

Principal Investigator: Jennifer Elster, MD

University of California, San Francisco; Recruiting

San Francisco, California, United States, 94143

Contact: Elise Witham 415-502-1600 PNOC_Regulatory@ucsf.edu

Contact 877-827-3222 cancertrials@ucsf.edu

Principal Investigator: Sabine Mueller, MD, PhD

United States, Connecticut

Yale University; Recruiting

New Haven, Connecticut, United States, 06520

Contact: Asher M. Marks, MD 203-785-4640 asher.marks@yale.edu

Principal Investigator: Asher M. Marks, MD

United States, District of Columbia

Children's National Medical Center; Not yet recruiting

Washington, District of Columbia, United States, 20010

Contact: Lindsay B. Kilburn, MD 202-476-5973 lkilburn@cnmc.org

Principal Investigator: Lindsay B. Kilburn, MD

United States, Florida

University of Florida Health Science Center - Gainesville; Not yet recruiting

Gainesville, Florida, United States, 32610

Contact: Sridharan Gururangan 352-294-8347 Sridharan.Gururangan@neurosurgery.ufl.edu

Principal Investigator: Sridharan Gururangan

United States, Maryland

Johns Hopkins University/Sidney Kimmel Cancer Center; Recruiting

Baltimore, Maryland, United States, 21287

Contact: Kenneth J. Cohen, MD, MBA 410-614-5055 kcohen@jhmi.edu

Principal Investigator: Kenneth J. Cohen, MD, MBA

United States, Massachusetts

Dana-Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Contact: Tabitha Cooney, MD 617-632-2291 tabitha_cooney@dfci.harvard.edu

Principal Investigator: Tabitha Cooney, MD

United States, Missouri

Washington University School of Medicine; Recruiting

Saint Louis, Missouri, United States, 63110

Contact: Mohamed Abdelbaki, MD 314-286-2790 MohamedA@wustl.edu

Principal Investigator: Mohamed Abdelbaki, MD

United States, Ohio

Nationwide Children's Hospital; Not yet recruiting

Columbus, Ohio, United States, 43205

Contact: Margot Lazow, MD 614-722-4087 margot.lazow@nationwidechildrens.org

Principal Investigator: Margot Lazow, MD

United States, Oregon

Oregon Health and Science University; Recruiting

Portland, Oregon, United States, 97239

Contact: Linda Stork, MD 614-722-4087 storkl@ohsu.edu

Principal Investigator: Linda Stork, MD

United States, Pennsylvania

Children's Hospital of Philadelphia; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Cassie Kline, MD KlineC@EMAIL.CHOP.EDU

Principal Investigator: Cassie Kline, MD

United States, Tennessee

St. Jude Children's Research Hospital; Recruiting

Memphis, Tennessee, United States, 38105

Contact: Amar Gajjar, MD 901-595-2615 amar.gajjar@stjude.org

Principal Investigator: Amar Gajjar, MD

United States, Utah

Huntsman Cancer Institute/University of Utah; Not yet recruiting

Salt Lake City, Utah, United States, 84112

Contact: Nicholas S. Whipple, MD, MPH 801-662-4700 whipple@hsc.utah.edu

Principal Investigator: Nicholas S. Whipple, MD, MPH

Sponsors and Collaborators

University of California, San Francisco

BeiGene USA, Inc.

Pacific Pediatric Neuro-Oncology Consortium

Investigators

• Principal Investigator: Sabine Mueller, MD, PhD; University of California, San Francisco

More Information

• Responsible Party: Sabine Mueller, MD, PhD, Associate Professor, University of California, San Francisco
• ClinicalTrials.gov Identifier: NCT03749187
• Other Study ID Numbers: 18083; NCI-2018-02345 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); PNOC017 ( Other Identifier: Pacific Pediatric Neuro-Oncology Consortium )
• First Posted: November 21, 2018
• Last Update Posted: April 6, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:

Glioblastoma; Glioma; Recurrence; Disease Attributes; Pathologic Processes; Astrocytoma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Temozolomide; Pamiparib; Poly(ADP-ribose) Polymerase Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Enzyme Inhibitors