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

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ClinicalTrials.gov Identifier: NCT03914742
Recruitment Status : Not yet recruiting
First Posted : April 15, 2019
Last Update Posted : September 13, 2019
Sponsor:
Collaborators:
National Cancer Institute (NCI)
BeiGene
Information provided by (Responsible Party):
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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.

Condition or disease Intervention/treatment Phase
IDH1 Mutation IDH2 Mutation Recurrent Glioblastoma Recurrent WHO Grade II Glioma Recurrent WHO Grade III Glioma Drug: PARP Inhibitor BGB-290 Drug: Temozolomide Procedure: Therapeutic Conventional Surgery Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention 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)
Primary Purpose: Treatment
Official Title: Phase I/II Study of BGB-290 With Temozolomide in Recurrent Gliomas With IDH1/2 Mutations
Estimated Study Start Date : November 2019
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : July 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase 1: Dose Finding

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
Given PO
Other Name: BGB-290, PARP, Inhibitor BGB-290

Drug: Temozolomide
Given PO
Other Name: Temodar, Methazolastone

Experimental: Phase 2: Arm A Alkylator-resistant

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
Given PO
Other Name: BGB-290, PARP, Inhibitor BGB-290

Drug: Temozolomide
Given PO
Other Name: Temodar, Methazolastone

Experimental: Phase 2: Arm B NOT Alkylator-resistant

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
Given PO
Other Name: BGB-290, PARP, Inhibitor BGB-290

Drug: Temozolomide
Given PO
Other Name: Temodar, Methazolastone

Experimental: GBM Arm
Exploratory grade IV patients only BGB290 at Ph II dose for 7 days pre-surgery Progressed following RT + Chemo
Drug: PARP Inhibitor BGB-290
Given PO
Other Name: BGB-290, PARP, Inhibitor BGB-290

Drug: Temozolomide
Given PO
Other Name: Temodar, Methazolastone

Experimental: Surgical Arm
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
Given PO
Other Name: BGB-290, PARP, Inhibitor BGB-290

Drug: Temozolomide
Given PO
Other Name: Temodar, Methazolastone

Procedure: Therapeutic Conventional Surgery
resection surgery




Primary Outcome Measures :
  1. Phase I: Maximum tolerated dose (MTD) [ Time Frame: up to 28 days ]
    defined as the combination regimen that yields a dose limiting toxicity (DLT) rate less than, or equal to 33%

  2. Phase I: Percentage of participants with adverse events [ Time Frame: up to 90 days post treatment ]
    Percentage of participants who experience grade 3 or higher toxicities as defined by Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

  3. Phase II: Tumor radiographic response [ Time Frame: up to 2 years ]
    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.


Secondary Outcome Measures :
  1. Phase II: Progression-free survival (PFS) [ Time Frame: up to 2 years ]
    Time from date of treatment start to date of initial scan indicating progression

  2. Phase II: Overall survival (OS) [ Time Frame: up to 2 years ]
    Median time from start date of treatment to date of death

  3. Duration of response [ Time Frame: up to 2 years ]
    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.

  4. Percentage of participants with serious or life-threatening adverse events [ Time Frame: up to 2 years ]
    Percentage of participants with serious or life-threatening toxicities as defined by CTCAE version 5.0



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • PHASE I: Patients must have histologically confirmed WHO grade II-III glioma that is progressive or recurrent following at least one prior chemoradiation regimen. 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 status. 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.

Exclusion Criteria:

  • 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.

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): NCT03914742


Contacts
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Contact: ABTC 410-955-8837 msheeh13@jhmi.edu
Contact: ABTC 410-955-3657 jfisher@jhmi.edu

Locations
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United States, Alabama
UAB Comprehensive Cancer Center Not yet recruiting
Birmingham, Alabama, United States, 35294
United States, California
UCLA Comprehensive Cancer Center Not yet recruiting
Los Angeles, California, United States, 90095
UCSF Comprehensive Cancer Center Not yet recruiting
San Francisco, California, United States, 94143
United States, Maryland
Johns Hopkins University Not yet recruiting
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Dana Farber Cancer Institute Not yet recruiting
Boston, Massachusetts, United States, 02114
United States, Michigan
Josephine Ford Cancer Center at Henry Ford Hospital Not yet recruiting
Detroit, Michigan, United States, 48202
United States, New York
Memorial Sloan-Kettering Cancer Center Not yet recruiting
New York, New York, United States, 10065
United States, North Carolina
Wake Forest University Comprehensive Cancer Center Not yet recruiting
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
Cleveland Clinic Taussig Cancer Center Not yet recruiting
Cleveland, Ohio, United States, 44106
United States, Pennsylvania
University of Pennsylvania Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Hillman Cancer Center at University of Pittsburgh Cancer Institute Not yet recruiting
Pittsburgh, Pennsylvania, United States, 15232
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
National Cancer Institute (NCI)
BeiGene
Investigators
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Study Chair: Ranjit Bindra, MD ABTC/Yale University

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Responsible Party: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT03914742     History of Changes
Other Study ID Numbers: ABTC-1801
UM1CA137443 ( U.S. NIH Grant/Contract )
First Posted: April 15, 2019    Key Record Dates
Last Update Posted: September 13, 2019
Last Verified: September 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
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
Alkylating Agents
Antineoplastic Agents, Alkylating
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors