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

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ClinicalTrials.gov Identifier: NCT03749187
Recruitment Status : Recruiting
First Posted : November 21, 2018
Last Update Posted : April 5, 2019
Sponsor:
Collaborators:
BeiGene USA, Inc.
Pacific Pediatric Neuro-Oncology Consortium
Information provided by (Responsible Party):
Sabine Mueller, MD, PhD, University of California, San Francisco

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.


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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 2022
Estimated Study Completion Date : July 2027

Resource links provided by the National Library of Medicine


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




Primary Outcome Measures :
  1. Summary of Dose Limiting Toxicities Assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [ Time Frame: Up to 28 days ]
    Events occurring on or after treatment on Day 1 will be summarized by mapped term, appropriate thesaurus level, and CTCAE v5.0 grade. Adverse events leading to treatment discontinuation will be listed.


Other Outcome Measures:
  1. Progression free survival (PFS) Summarized by Kaplan-Meier Method [ Time Frame: Time from start of treatment to time of progression or death, whichever occurs first, assessed 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) Summarized by Kaplan-Meier Method [ Time Frame: Time from the first dose of study treatment to the time of death from any cause on study, assessed 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.



Information from the National Library of Medicine

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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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03749187


Contacts
Layout table for location contacts
Contact: Kelly Hitchner 415-502-1600 PNOC_Regulatory@ucsf.edu
Contact: Sabine Mueller 877-827-3222 cancertrials@ucsf.edu

  Show 21 Study Locations
Sponsors and Collaborators
University of California, San Francisco
BeiGene USA, Inc.
Pacific Pediatric Neuro-Oncology Consortium
Investigators
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Principal Investigator: Sabine Mueller UCSF Medical Center-Mount Zion

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Responsible Party: Sabine Mueller, MD, PhD, Associate Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03749187     History of Changes
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    Key Record Dates
Last Update Posted: April 5, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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