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IDH1 MutationPhase 1/2NCT03914742

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

A Phase 1/2 study testing PARP Inhibitor BGB-290, Temozolomide and Therapeutic Conventional Surgery in people with IDH1 Mutation and IDH2 Mutation, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 12 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
PARP Inhibitor BGB-290, Temozolomide and Therapeutic Conventional Surgery
Could I receive a placebo?
No, everyone receives an active treatment
How many people
67 participants
Where
12 sitesUnited States
Study dates
16 Feb 2020to 31 Oct 2023
Phase
Phase 1/2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
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  • 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:
  • 12 weeks from the completion of radiation
  • 6 weeks from a nitrosourea chemotherapy
  • 3 weeks from a non-nitrosourea chemotherapy
  • 4 weeks from any investigational (not Food and Drug Administration [FDA]-approved) agents
  • 2 weeks from administration of a non-cytotoxic, FDA-approved agent (e.g., erlotinib, hydroxychloroquine, etc.).
  • Patients must have a Karnofsky performance (KPS) status >= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others).
  • Absolute neutrophil count >= 1,500/ uL.
  • Platelets >= 100,000/ uL.
  • Hemoglobin >= 9 g/dL.
  • Total bilirubin =< institutional upper limit of normal.
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 4 × institutional upper limit of normal.
  • Creatinine =< institutional upper limit of normal OR creatinine clearance >= 60 ml/min/1.73m^2 for patients with creatinine levels above institutional normal.
  • Activated partial thromboplastin time (APTT) or PTT =< 1.5 × institutional upper limit of normal.
  • Patients must be able to provide written informed consent.
  • Women of childbearing potential must have a negative serum pregnancy test prior to study start. Women of childbearing 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 through 4 months after the last dose of study drug. 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. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and through 4 months after completion of BGB-290 or temozolomide administration.
  • Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder. Patients with prior malignancies must be disease-free for >= 5 years.
  • Patients must be able to swallow tablets and capsules.

Who cannot join

  • 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.
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  • 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.

Trial locations and contacts

12 sites in 1 country.

12 sites in 1 country

United States12 sites

  • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

    Baltimore, Maryland, 21231

  • UAB Comprehensive Cancer Center

    Birmingham, Alabama, 35294-3410

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

  • University of Virginia

    Charlottesville, Virginia, 22908

  • Cleveland Clinic Taussig Cancer Center

    Cleveland, Ohio, 44195

  • Josephine Ford Cancer Center at Henry Ford Hospital

    Detroit, Michigan, 48202

  • University of California, Los Angeles

    Los Angeles, California, 90095

  • Yale University

    New Haven, Connecticut, 06511

  • University of Pennsylvania

    Philadelphia, Pennsylvania, 19104

  • Hillman Cancer Center at University of Pittsburgh Cancer Institute

    Pittsburgh, Pennsylvania, 15232

  • Washington University

    St Louis, Missouri, 63110

  • Wake Forest University Comprehensive Cancer Center

    Winston-Salem, North Carolina, 27157-1096

Other trials in United States

About this study

Official title: Phase I/II Study of BGB-290 With Temozolomide in Recurrent Gliomas With IDH1/2 Mutations

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.

Read the detailed description

PRIMARY OBJECTIVES:

(Phase I) I. Determine the safety and tolerability of the combination of PARP inhibitor BGB-290 (BGB-290) and temozolomide (TMZ) in patients with recurrent IDH1/2 mutant glioma, including the maximum tolerated dose (MTD) and characterization of dose-limiting toxicities (DLTs) in the Phase I portion.

(Phase II) II. Determine the overall response rate of BGB-290 with TMZ in patients with recurrent IDH1/2-mutant gliomas that have progressed on TMZ and another alkylator (Arm A) in the Phase II portion.

III. Determine the overall response rate of BGB-290 with TMZ in patients with recurrent IDH1/2-mutant glioma that have failed one alkylator with >= 12 months since last treatment (Arm B) in the Phase II portion.

SECONDARY OBJECTIVES:

  1. Determine the progression-free survival (PFS) and overall survival (OS) after treatment with BGB-290 and TMZ in recurrent IDH1/2-mutant gliomas in Arms A and B.

II. Determine the duration of response to therapy in recurrent IDH1/2-mutant glioma.

III. Confirm the safety and tolerability of BGB-290 in combination with TMZ.

EXPLORATORY OBJECTIVES:

  1. Assess tumor response rates, PFS, and OS in patients with World Health Organization (WHO) grade IV glioblastoma (GBM) treated with BGB-290 and TMZ.

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

IV. Assess the methylation profiling with Infinium methylation assays. V. Quantify 2-hydroxyglutarate (2HG) in archival formalin-fixed paraffin-embedded (FFPE) specimens via liquid chromatography mass spectrometry (LC-MS) detection and correlate with treatment response.

VI. Correlate response with 2HG levels, somatic alterations, gene expression/methylation patterns in FFPE tumor tissue.

VII. Assess tumor tissue BGB-290 levels, 2HG, and PolyADP-ribosylation (PARylation) in a patient subset treated with drug prior to re-resection.

VIII. Evaluate changes in tumor growth rate in subjects with non-enhancing glioma based on fluid attenuated inverse recovery (FLAIR) tumor volume measurements of serial MRI exams.

IX. Assess if change in tumor growth rate (based on FLAIR tumor volume) in subjects with non-enhancing glioma before and after treatment is associated with progression by Response Assessment in Neuro-Oncology for Low Grade Gliomas (RANO LGG; phase II patients only) or survival.

OUTLINE: This is a phase I, dose de-escalation study of temozolomide followed by a phase II study.

PHASE I: Patients receive PARP inhibitor BGB-290 orally (PO) twice daily (BID) on days 1-28 and temozolomide PO once daily (QD) on days 1-28, 1-21, 1-14, or 1-7. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

SURGICAL PORTION: 10 patients eligible for re-resection at the time of recurrence receive PARP inhibitor BGB-290 PO BID on days 1-6 and QD on day 7 (the morning of surgery). Within 45 days after surgery, patients receive PARP inhibitor BGB-290 PO BID on days 1-28 and temozolomide on the schedule established in Phase I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II: Patients receive PARP inhibitor BGB-290 PO BID on days 1-28 and temozolomide PO QD on the schedule established in Phase I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, every 2 months for 2 years, then every 6 months thereafter.

Being tested
PARP Inhibitor BGB-290, Temozolomide, Therapeutic Conventional Surgery
Medical subject headings
Glioblastoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT03914742
Study groupRoleWhat they receive
Phase 1: Dose FindingExperimentalRecurrent 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
Receives: Drug: PARP Inhibitor BGB-290; Drug: Temozolomide
Phase 2: Arm A Alkylator-resistantExperimentalGrade 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
Receives: Drug: PARP Inhibitor BGB-290; Drug: Temozolomide
Phase 2: Arm B NOT Alkylator-resistantExperimentalGrade 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
Receives: Drug: PARP Inhibitor BGB-290; Drug: Temozolomide
GBM ArmExperimentalExploratory grade IV patients only BGB290 at Ph II dose for 7 days pre-surgery Progressed following RT + Chemo
Receives: Drug: PARP Inhibitor BGB-290; Drug: Temozolomide
Surgical ArmExperimentalRecurrent 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)
Receives: Drug: PARP Inhibitor BGB-290; Drug: Temozolomide; Procedure: Therapeutic Conventional Surgery

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: up to 28 days

  2. 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

    Measured: up to 28 days

  3. 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.

    Measured: up to 2 years

Secondary outcomes (3)

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

    Time from date of treatment start to date of initial scan indicating progression

    Measured: up to 2 years

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

    Median time from start date of treatment to date of death

    Measured: up to 2 years

  3. Duration of Response Phase 2

    Time from date of initial scan indicating complete or partial response to a date of the initial scan deemed tumor progression. Response is defined by RANO criteria as follows: 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; Progressive Disease (PD)= ≥25% increase size of T1-Gd+ disease, or increased T2/FLAIR signal, or presence of new lesion, or worsening clinical status.

    Measured: up to 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Apr 2019
  2. Study start16 Feb 2020
  3. Primary completion31 Oct 2023
  4. Study completion31 Oct 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Model description
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
Masking
None (open label)
Enrolment
67 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03914742
Sponsor's protocol ID
ABTC-1801
Other IDs
UM1CA137443
Status last verified
Jan 2025
First submitted
11 Apr 2019
Last updated
14 Jan 2025
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing PARP Inhibitor BGB-290, Temozolomide and Therapeutic Conventional Surgery in people with IDH1 Mutation and IDH2 Mutation, run by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins at 12 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 32 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 14 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 12 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 16 Dec 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Participants With Dose Limiting Toxicity (DLT) Rate Less Than or Equal to 33% (Dose Level 1) (time frame: up to 28 days). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03914742.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jan 2025.

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