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

  • STATUS
    Recruiting
  • End date
    Jul 17, 2023
  • participants needed
    100
  • sponsor
    Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Updated on 17 September 2021
cancer
corticosteroids
nitrosoureas
serum pregnancy test
measurable disease
hydroxychloroquine
neutrophil count
tumor cells
carcinoma in situ
aptt
thromboplastin
glioblastoma multiforme
temozolomide
procarbazine
brain tumor
lomustine
therapeutic conventional surgery
alkylating agents
formalin-fixed paraffin-embedded

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.

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.

Details
Condition Recurrent WHO Grade II Glioma, IDH1 Mutation, Recurrent WHO Grade III Glioma, Recurrent Glioblastoma, IDH2 Mutation, recurrent low grade glioma, IDH2 Gene Mutation
Treatment Temozolomide, therapeutic conventional surgery, PARP Inhibitor BGB-290
Clinical Study IdentifierNCT03914742
SponsorSidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Last Modified on17 September 2021

Eligibility

Yes No Not Sure

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
weeks from the completion of radiation
weeks from a nitrosourea chemotherapy
weeks from a non-nitrosourea chemotherapy
weeks from any investigational (not Food and Drug Administration [FDA]-approved) agents
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
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note