BGB-290 and Temozolomide in Treating Patients With Recurrent Gliomas With IDH1/2 Mutations

NCT03914742 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: ABTC-1801UM1CA137443
• Study Type: interventional
• Target: 67
• Locations: 1 country
• Sites: 12

Brief Summary

This phase I/II trial studies the side effects and how well BGB-290 and temozolomide work in treating patients with gliomas (brain tumors) with IDH1/2 mutations that have 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 patients with recurrent gliomas.

Conditions

IDH1 Mutation; IDH2 Mutation; Recurrent Glioblastoma; Recurrent WHO Grade II Glioma; Recurrent WHO Grade III Glioma

Outcome Measures

Primary Outcomes (3)

• Participants With Dose Limiting Toxicity (DLT) Rate Less Than or Equal to 33% (Dose Level 1)

  DLTS defined as the combination regimen that yields a dose limiting toxicity (DLT) rate less than, or equal to 33%. A DLT is defined as a clinically significant adverse event or abnormal laboratory value assessed as unrelated to disease progression, intercurrent illness, or concomitant medications and meets any of the criteria below. Any DLT must be a toxicity considered at least possibly related to pamiparib (BGB-290) or TMZ.

  up to 28 days

• Maximum Tolerated Dose

  Patients treated with TMZ 20mg Days 1-28, highest dose level/schedule. If DTL observed, dose level/schedule will de-escalated treatment schedule if necessary (days 1-21; days 1-14; days 1-7) BGG held constant at 60mg PO BID

  up to 28 days

• Phase II: Overall Best Response Rate for Arm A and Arm B

  Number of participants with response as defined by Response Assessment in Neuro-oncology (RANO) criteria: Complete Response (CR)= no change in size of T1-gadolinium-enhancing (T1-Gd+) disease, stable or reduced T2/FLAIR signal, no new lesion, no corticosteroid use, and stable or improved clinical status; Partial Response (PR)= ≥50% change in size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Stable Disease (SD)= \<50% reduction to \<25% increase size of T1-Gd+ disease, stable or reduced T2/FLAIR signal, no new lesion, stable or reduced corticosteroid use, and stable or improved clinical status; Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.

  up to 2 years

Secondary Outcomes (3)

• Phase II: Progression-free Survival (PFS) in Arm A and Arm B

  up to 2 years

• Phase II: Overall Survival (OS) for Arm A and Arm B

  up to 2 years

• Duration of Response Phase 2

  up to 2 years

Study Arms (5)

Phase 1: Dose Finding

EXPERIMENTAL

Recurrent IDH1/2-mutant grade II-III glioma: BGB290: Days 1-28, 60 mg PO BID TMZ: Days 1-28, 20 QD starting dose TMZ de-escalated treatment schedule if necessary (days 1-21; days 1-14; days 1-7) BGG held constant at 60mg PO BID

Drug: PARP Inhibitor BGB-290; Drug: Temozolomide

Phase 2: Arm A Alkylator-resistant

EXPERIMENTAL

Grade II-III: Recurrent IDH1/2-mutant glioma (WHO grades II/III) who have failed TMZ AND another alkylator BGB290 + TMZ at dose combination established in Phase 1

Drug: PARP Inhibitor BGB-290; Drug: Temozolomide

Phase 2: Arm B NOT Alkylator-resistant

EXPERIMENTAL

Grade II-III:Recurrent IDH1/2-mutant glioma (WHO grades II/III) Failed TMZ OR another alkylator; \>/=12 months since last treatment BGB290 + TMZ at dose combination established in Phase 1

Drug: PARP Inhibitor BGB-290; Drug: Temozolomide

GBM Arm

EXPERIMENTAL

Exploratory grade IV patients only BGB290 at Ph II dose for 7 days pre-surgery Progressed following RT + Chemo

Drug: PARP Inhibitor BGB-290; Drug: Temozolomide

Surgical Arm

EXPERIMENTAL

Recurrent IDH1/2-mutant glioma (WHO grade II-IV) eligible for re-resection BGB-290: 60mg PO BID for 6 days AND day once day of surgery (day 7)

Drug: PARP Inhibitor BGB-290; Drug: Temozolomide; Procedure: Therapeutic Conventional Surgery

Interventions

PARP Inhibitor BGB-290 DRUG

Given PO

Also known as: BGB-290, PARP, Inhibitor BGB-290

GBM Arm; Phase 1: Dose Finding; Phase 2: Arm A Alkylator-resistant; Phase 2: Arm B NOT Alkylator-resistant; Surgical Arm

Temozolomide DRUG

Given PO

Also known as: Temodar, Methazolastone

GBM Arm; Phase 1: Dose Finding; Phase 2: Arm A Alkylator-resistant; Phase 2: Arm B NOT Alkylator-resistant; Surgical Arm

Therapeutic Conventional Surgery PROCEDURE

resection surgery

Surgical Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• PHASE I: Patients must have histologically confirmed WHO grade II-III glioma that is progressive or recurrent following at least one prior chemotherapy regimen plus or minus radiation therapy regimen or (b) Grade IV disease in their recurrent resection or biopsy specimen or (c) Grade IV glioma at initial diagnosis, with recurrent disease. Phase I patients may have failed an unlimited number of prior systemic regimens.
• PHASE II: Patients must have histologically confirmed WHO grade II-IV glioma that is progressive or recurrent following therapy:
• Arm A patients must have WHO grade II-III glioma and have failed TMZ and another alkylator (e.g., carmustine, lomustine, procarbazine). Patients in Arm A may have failed an unlimited number of prior systemic regimens. Prior radiotherapy (RT) is not required for eligibility. There is no minimum time from the last antineoplastic treatment, except to allow for recovery: three weeks from last dose of TMZ and six weeks from last dose of nitrosourea.
• Arm B patients must have WHO grade II-III glioma and have experienced tumor progression after TMZ or another alkylator (maximum one prior chemotherapy regimen), and have gone \>= 12 months since last treatment (chemotherapy or RT). Prior radiation therapy (RT) is allowed but not mandated.
• GBM Arm patients must have WHO grade IV glioblastoma following radiotherapy (45-60 gray \[Gy\] in 1.8-2.0 Gy fractions) plus chemotherapy and may have failed an unlimited number of prior systemic regimens.
• Surgical portion patients must have histologically confirmed WHO grade II-IV glioma that is progressive or recurrent following therapy and must be undergoing repeat surgery that is clinically indicated as determined by their care providers. Surgical Portion patients may have had an unlimited number of prior therapy regimens.
• Recurrence in non-enhancing tumors will be defined as 25% or more increase in bi-dimensional product of FLAIR signal abnormality (measurable disease) per the low-grade glioma (LGG) RANO criteria. Contrast-enhancing tumors with measurable enhancing targets will be defined as recurrent based on standard RANO criteria.
• Patients with recurrent glioma \< 12 weeks after completion of radiotherapy must have new enhancement outside of the RT field (beyond the high-dose region or 80% isodose line), or evidence of viable tumor on histopathologic sampling.
• PHASE I AND PHASE II: Patients must have available at least 3 prior full sets of magnetic resonance imaging (MRI) scans (not including screening), each separated by at least 2 months.
• Patients must have IDH1/2-mutant glioma. IDH1/2-mutation status can be confirmed by immunohistochemistry (IHC) or direct deoxyribonucleic acid (DNA) sequencing, provided that it is performed in a Clinical Laboratory Improvement Amendments/College of American Pathologists (CLIA/CAP)-certified laboratory. IDH1/2 mutations must be associated with neomorphic activity of the encoded proteins (i.e. IDH1 R132, IDH2 R172, IDH2 R140, IDH1 R100, IDH1 G97, IDH1 Y139).
• Patients must have archival formalin-fixed paraffin-embedded (FFPE) specimens and mutations will be verified centrally, although this will not preclude patients with appropriate documentation of IDH1/2-mutant status from trial enrollment. Patients must have a tumor tissue form indicating availability of archived tissue from a previous surgery, completed and signed by a pathologist; sites must agree to provide this form within 14 days after treatment start.
• Patients must have measurable (defined by at least 1 cm x 1 cm) contrast-enhancing disease or measurable abnormal T2/FLAIR hyperintensity indicative of tumor by MRI imaging within 21 days of starting treatment.
• Patients must have documented molecular 1p/19q and MGMT testing. If either of these studies has not been performed previously, they can be done prior to enrollment.
• Patients must be able to undergo MRI of the brain with gadolinium. Patients must be maintained on a stable or decreasing dose of corticosteroid regimen (no increase for 5 days) prior to this baseline MRI.
• Patients must have recovered from severe toxicity of prior therapy. The following intervals from previous treatments are required to be eligible:

You may not qualify if:

• Patients receiving any other investigational agents are ineligible.
• Patients previously treated with a small molecule inhibitor of mutant IDH1/2 proteins are ineligible.
• Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to BGB-290 are ineligible.
• Patients who have received bevacizumab within the last 6 months are ineligible.
• Patients with a known hypersensitivity to TMZ are ineligible.
• Patients who have received a PARP inhibitor previously are excluded.
• Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for treatment on this protocol. Patients may be on non-enzyme inducing anti-epileptic drugs or not be taking any anti-epileptic drugs. Patients previously treated with EIAEDs may be enrolled if they have been off the EIAED for 10 days or more prior to the first dose of BGB-290.
• Patients who have not recovered to \< Common Terminology Criteria for Adverse Events (CTCAE) grade 2 toxicities apart from alopecia related to prior therapy are ineligible.
• Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, clinically significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible.
• Pregnant women are excluded from this study because the effects of BGB-290 on a fetus are unknown. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with BGB-290, breastfeeding should be discontinued if the mother is treated with BGB-290.
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible due to potential drug-drug interactions with BGB-290.

Sponsors & Collaborators

• Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins: lead
• National Cancer Institute (NCI): collaborator
• BeiGene: collaborator

Study Sites (12)

UAB Comprehensive Cancer Center

Birmingham, Alabama, 35294-3410, United States

Location

University of California, Los Angeles

Los Angeles, California, 90095, United States

Location

Yale University

New Haven, Connecticut, 06511, United States

Location

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Josephine Ford Cancer Center at Henry Ford Hospital

Detroit, Michigan, 48202, United States

Location

Washington University

St Louis, Missouri, 63110, United States

Location

Wake Forest University Comprehensive Cancer Center

Winston-Salem, North Carolina, 27157-1096, United States

Location

Cleveland Clinic Taussig Cancer Center

Cleveland, Ohio, 44195, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Hillman Cancer Center at University of Pittsburgh Cancer Institute

Pittsburgh, Pennsylvania, 15232, United States

Location

University of Virginia

Charlottesville, Virginia, 22908, United States

Location

MeSH Terms

Conditions

Glioblastoma

Interventions

pamiparib; Temozolomide

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

This study did finish enrollment for all arms (67 patients) however, due to mandated shut down by NCI/CTEP of our ABTC Consortium not all patients were able to complete treatment on study and/or have PFS or OS mature to use for outcomes (statistics). Additionally, many of the exploratory endpoints were not completed.

Results Point of Contact

• Title: Program Manager Adult Brain Tumor Consortium (ABTC) and Brain Cancer Program
• Organization: Johns Hopkins University

jfisher@jhmi.edu

410-955-8837

Study Officials

• Ranjit Bindra, MD

  ABTC/Yale University

  STUDY CHAIR

• David Schiff, MD

  ABTC/University of Virginia

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase 1: BGB-290 in combination with TMZ in patients w/ IDH1/2-mutant WHO grade II-IV recurrent glioma: Phase 2: Grade II-III patients in will be stratified into 2 arms based on the timing of prior alkylator chemotherapy exposure; a third arm will include the subset of glioblastoma (grade IV) patients

Study Record Dates

• First Submitted: April 11, 2019
• First Posted: April 16, 2019
• Study Start: February 16, 2020
• Primary Completion: October 31, 2023
• Study Completion: October 31, 2023
• Last Updated: January 14, 2025
• Results First Posted: December 16, 2024

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (12)