Clinical Trials /

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

NCT03914742

Description:

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.

Related Conditions:
  • Malignant Glioma
  • WHO Grade II Glioma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: BGB-290 and Temozolomide in Treating Patients With Recurrent Gliomas With IDH1/2 Mutations
  • Official Title: Phase I/II Study of BGB-290 With Temozolomide in Recurrent Gliomas With IDH1/2 Mutations

Clinical Trial IDs

  • ORG STUDY ID: ABTC-1801
  • SECONDARY ID: UM1CA137443
  • NCT ID: NCT03914742

Conditions

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

Interventions

DrugSynonymsArms
PARP Inhibitor BGB-290BGB-290, PARP, Inhibitor BGB-290Phase 1: Dose Finding
TemozolomideTemodar, MethazolastonePhase 1: Dose Finding

Purpose

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.

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.

      PRIMARY OBJECTIVES:

      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 I) 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. (Phase II) 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. (Phase II)

      SECONDARY OBJECTIVES:

      I. 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:

      I. 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.
    

Trial Arms

NameTypeDescriptionInterventions
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
  • PARP Inhibitor BGB-290
  • 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
  • PARP Inhibitor BGB-290
  • 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
  • PARP Inhibitor BGB-290
  • Temozolomide
GBM ArmExperimentalExploratory grade IV patients only BGB290 at Ph II dose for 7 days pre-surgery Progressed following RT + Chemo
  • PARP Inhibitor BGB-290
  • 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)
  • PARP Inhibitor BGB-290
  • Temozolomide

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Maximum tolerated dose (MTD)
Time Frame:up to 28 days
Safety Issue:
Description:defined as the combination regimen that yields a dose limiting toxicity (DLT) rate less than, or equal to 33%

Secondary Outcome Measures

Measure:Phase II: Progression-free survival (PFS)
Time Frame:up to 2 years
Safety Issue:
Description:Time from date of treatment start to date of initial scan indicating progression
Measure:Phase II: Overall survival (OS)
Time Frame:up to 2 years
Safety Issue:
Description:Median time from start date of treatment to date of death
Measure:Duration of response
Time Frame:up to 2 years
Safety Issue:
Description: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.
Measure:Percentage of participants with serious or life-threatening adverse events
Time Frame:up to 2 years
Safety Issue:
Description:Percentage of participants with serious or life-threatening toxicities as defined by CTCAE version 5.0

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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