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.
Inclusion Criteria:
- 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:
- 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.
