- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03872427
Testing Whether Cancers With Specific Mutations Respond Better to Glutaminase Inhibitor, Telaglenastat Hydrochloride, Anti-Cancer Treatment, BeGIN Study
A Phase II Basket Trial of Glutaminase Inhibitor (BEGIN) Telaglenastat (CB-839) HCL in Patients With NF1 Aberrations, NF1 Mutant Malignant Peripheral Nerve Sheath Tumors (MPNST), KEAP1/NRF2 and LKB1 Aberrant Tumors
Study Overview
Status
Conditions
Detailed Description
PRIMARY OBJECTIVE:
I. To assess the best overall response rate (BORR) achieved by 6 months of telaglenastat (CB-839) hydrochloride (HCl) treatment in specific pathway aberrant tumors (MPNST, NF1, KEAP1/NRF2 & STK11/ LKB1).
SECONDARY OBJECTIVES:
I. To determine the safety, progression-free survival (PFS), time to progression (TTP) and overall survival (OS).
II. To determine the overall response rate (ORR) (highest objective response achieved between start of therapy and progression), time to response (TTR) and clinical benefit rate (CBR) of telaglenastat (CB-839)HCl.
III. To assess pharmacodynamic changes and adaptive responses and correlate with response to treatment as well as disease progression (correlative objective).
EXPLORATORY OBJECTIVES:
I. Correlate fludeoxyglucose F-18 (18-F FDG) positron emission tomography (PET)/computed tomography (CT) pre-therapy and 8-weeks post-therapy response to telaglenastat (CB-839) HCl therapy.
II. Evaluate changes in level of circulating tumor deoxyribonucleic acid (DNA) at baseline, one month on-treatment and time of progression (Molecular Characterization Laboratory [MoCHA Labs]) to treatment response.
III. Quantify the peripheral blood concentrations of the metabolites: aspartate, glutamate, glutamine and arginine (@Mayo clinic Oncometabolomics core) and correlate with response.
IV. Evaluate the pharmacodynamic (PD) effect of telaglenastat (CB-839) HCl on systemic levels of the tricarboxylic acid (TCA) cycle metabolites in peripheral blood (baseline and one month) as part of the protocol.
V. Evaluate tumor by reverse phase protein array (@core facility at MD Anderson) and ribonucleic acid (RNA) sequencing (seq) to evaluate changes from pre-treatment, during treatment and post treatment specimens.
VI. Perform patient-derived tumor xenograft (PDX) modelling-co-clinical trials (@Dr. Funda Meric-Bernstam's lab MD Anderson) to understand response/resistance mechanisms and also evaluate combination therapies for future development.
OUTLINE:
Patients receive telaglenastat hydrochloride orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, magnetic resonance imaging (MRI), or PET/CT during screening and on study, and collection of blood samples during screening and on study.
After completion of study treatment, patients are followed up every 3 months thereafter.
Study Type
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Alabama
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Birmingham, Alabama, United States, 35233
- University of Alabama at Birmingham Cancer Center
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Florida
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Aventura, Florida, United States, 33180
- UM Sylvester Comprehensive Cancer Center at Aventura
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Coral Gables, Florida, United States, 33146
- UM Sylvester Comprehensive Cancer Center at Coral Gables
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Deerfield Beach, Florida, United States, 33442
- UM Sylvester Comprehensive Cancer Center at Deerfield Beach
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Miami, Florida, United States, 33136
- University of Miami Miller School of Medicine-Sylvester Cancer Center
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Miami, Florida, United States, 33176
- UM Sylvester Comprehensive Cancer Center at Kendall
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Plantation, Florida, United States, 33324
- UM Sylvester Comprehensive Cancer Center at Plantation
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Tampa, Florida, United States, 33612
- Moffitt Cancer Center
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Tampa, Florida, United States, 33607
- Moffitt Cancer Center-International Plaza
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Tampa, Florida, United States, 33612
- Moffitt Cancer Center - McKinley Campus
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Illinois
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Chicago, Illinois, United States, 60611
- Northwestern University
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Kansas
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Fairway, Kansas, United States, 66205
- University of Kansas Clinical Research Center
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Hays, Kansas, United States, 67601
- HaysMed University of Kansas Health System
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Kansas City, Kansas, United States, 66160
- University of Kansas Cancer Center
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Olathe, Kansas, United States, 66061
- Olathe Health Cancer Center
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Pittsburg, Kansas, United States, 66762
- Ascension Via Christi - Pittsburg
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Salina, Kansas, United States, 67401
- Salina Regional Health Center
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Topeka, Kansas, United States, 66606
- University of Kansas Health System Saint Francis Campus
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Westwood, Kansas, United States, 66205
- University of Kansas Hospital-Westwood Cancer Center
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Kentucky
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Lexington, Kentucky, United States, 40536
- University of Kentucky/Markey Cancer Center
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Maryland
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Bethesda, Maryland, United States, 20892
- National Institutes of Health Clinical Center
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Bethesda, Maryland, United States, 20892
- National Cancer Institute Developmental Therapeutics Clinic
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Massachusetts
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Boston, Massachusetts, United States, 02215
- Dana-Farber Cancer Institute
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Missouri
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Kansas City, Missouri, United States, 64108
- Truman Medical Centers
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New York
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New York, New York, United States, 10032
- NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
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New York, New York, United States, 10016
- Laura and Isaac Perlmutter Cancer Center at NYU Langone
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North Carolina
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Clemmons, North Carolina, United States, 27012
- Wake Forest University at Clemmons
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Winston-Salem, North Carolina, United States, 27157
- Wake Forest University Health Sciences
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Ohio
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Columbus, Ohio, United States, 43210
- Ohio State University Comprehensive Cancer Center
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Pennsylvania
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Pittsburgh, Pennsylvania, United States, 15232
- University of Pittsburgh Cancer Institute (UPCI)
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Texas
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Houston, Texas, United States, 77030
- M D Anderson Cancer Center
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Patients must have histologically confirmed malignancy that is metastatic or unresectable
Patient must have histopathologic confirmation of advanced solid tumor with NF1 mutation, NF1 mutant MPNST, KEAP1/NRF2 mutant and STK11/LKB1 mutant tumors (molecular profiling performed in any Clinical Laboratory Improvement Act [CLIA] certified lab [including tumor and circulating cell-free (cf)DNA], e.g. Caris, FoundationOne, FoundationAct, Oncomine, Guardant etc.)
- NOTE: For all cohorts annotation for actionability will be performed by the PRECISION ONCOLOGY DECISION SUPPORT (PODS) TEAM SHEIKH KHALIFA BIN ZAYED AL NAHYAN INSTITUTE FOR PERSONALIZED CANCER THERAPY (IPCT) THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER 6565 MD ANDERSON BLVD, HOUSTON, TX 77030
- Patient must have no standard therapies available
- Patient must be aged greater than 18 years old for all cohorts
- Patients for NF1 mutant MPNST and NF1 mutant non-MPNST cohorts must be >= 40 kg
- Patient must be at least 4 weeks since any prior surgery or radiotherapy
- Females of childbearing potential must have a negative serum pregnancy test (=< 14 days) prior to start of trial treatment
- Response Evaluation Criteria in Solid Tumors (RECIST) measurable disease and biopsiable targetable lesion
- Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) by chest x-ray or as >= 10 mm (>= 1 cm) with CT scan, magnetic resonance imaging (MRI), or calipers by clinical exam
- Patients with treated brain metastases are eligible if there is no evidence of progression for at least 4 weeks after central nervous system (CNS)-directed treatment, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
- Leukocytes >= 3,000/mcL
- Absolute neutrophil count >= 1,000/mcL
- Platelets >= 100,000/mcL
- Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) and up to 3 ml/dL for patients with Gilbert's disease
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN and =< 5 x institutional ULN for patients with liver metastases
- Creatinine =< institutional ULN, as age appropriate OR
- Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
- The effects of telaglenastat (CB-839) HCl on the developing human fetus are unknown. For this reason and because anti-metabolic agents like telaglenastat (CB-839) HCl are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. 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 4 months after completion of telaglenastat (CB-839) HCl administration
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
- Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1)
- Patients who are receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic composition to telaglenastat (CB-839) HCl
- Patients with glioma will be excluded
- Patients with active or prior history of hepatitis B or C will be excluded
- Telaglenastat (CB-839) HCl is a weak in vitro inhibitor of CYP2C9. Therefore, patients receiving any medications or substances that are substrates of CYP2C9 are eligible, but should use caution with substrates that have a narrow therapeutic index. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant women are excluded from this study because telaglenastat (CB-839) HCl is anti-metabolic agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with telaglenastat (CB-839) HCl, breastfeeding should be discontinued if the mother is treated with telaglenastat (CB-839) HCl
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Treatment (telaglenastat hydrochloride)
Patients receive telaglenastat hydrochloride PO BID on days 1-28.
Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Patients also undergo CT, MRI, or PET/CT during screening and on study, and collection of blood samples during screening and on study.
|
Undergo collection of blood
Other Names:
Undergo MRI
Other Names:
Correlative studies
Other Names:
Undergo PET/CT
Other Names:
Given PO
Other Names:
Undergo CT or PET/CT
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Best overall response rate
Time Frame: Up to 6 months from treatment start date
|
Will be based on Response Evaluation Criteria in Solid Tumors version 1.1.
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Up to 6 months from treatment start date
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Incidence of adverse events
Time Frame: Up to 2 years from treatment start date
|
Will be assessed by Common Terminology Criteria for Adverse Events version 5.0.
Will tabulate toxicity by cohort, type, severity and attribution.
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Up to 2 years from treatment start date
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Progression-free survival
Time Frame: Time to progression or death whichever comes first, assessed up to 2 years from treatment start date
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Will estimate using the Kaplan-Meier method with time zero set to cycle 1, day 1 (C1D1).
Will estimate the medians and select probabilities along with 95% confidence intervals.
If more than a handful of patients die without progression, will use Aalen-Johansen estimates to adjust for the competing risk of death.
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Time to progression or death whichever comes first, assessed up to 2 years from treatment start date
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Time to progression
Time Frame: Time to progression starting at C1D1, assessed up to 2 years from treatment start date
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Will estimate the medians and select probabilities along with 95% confidence intervals.
If more than a handful of patients die without progression, will use Aalen-Johansen estimates to adjust for the competing risk of death.
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Time to progression starting at C1D1, assessed up to 2 years from treatment start date
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Overall survival
Time Frame: Time to death from any cause, assessed up to 2 years from treatment start date
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Will estimate using the Kaplan-Meier method with time zero set to C1D1.
Will estimate the medians and select probabilities along with 95% confidence intervals.
If more than a handful of patients die without progression, will use Aalen-Johansen estimates to adjust for the competing risk of death.
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Time to death from any cause, assessed up to 2 years from treatment start date
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Overall response rate
Time Frame: From start of treatment until disease progression/recurrence, assessed up to 2 years
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From start of treatment until disease progression/recurrence, assessed up to 2 years
|
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Clinical benefit rate
Time Frame: Up to 2 years from treatment start date
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Up to 2 years from treatment start date
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Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Pharmacodynamic (PD) tumor oncometabolite levels of glutamine
Time Frame: Baseline up to between 0-8 hours post-glutaminase inhibitor CB-839 hydrochloride dose
|
Will assess PD changes before and after treatment using the Wilcoxon signed rank test.
Will correlate these changes with response to treatment using Wilcoxon rank sum test.
Will also perform a receiver operating characteristic curve analysis.
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Baseline up to between 0-8 hours post-glutaminase inhibitor CB-839 hydrochloride dose
|
PD tumor oncometabolite levels of glutamate
Time Frame: Baseline up to between 0-8 hours post-glutaminase inhibitor CB-839 hydrochloride dose
|
Will assess PD changes before and after treatment using the Wilcoxon signed rank test.
Will correlate these changes with response to treatment using Wilcoxon rank sum test.
Will also perform a receiver operating characteristic curve analysis.
|
Baseline up to between 0-8 hours post-glutaminase inhibitor CB-839 hydrochloride dose
|
PD tumor oncometabolite levels of aspartate
Time Frame: Baseline up to between 0-8 hours post-glutaminase inhibitor CB-839 hydrochloride dose
|
Will assess PD changes before and after treatment using the Wilcoxon signed rank test.
Will correlate these changes with response to treatment using Wilcoxon rank sum test.
Will also perform a receiver operating characteristic curve analysis.
|
Baseline up to between 0-8 hours post-glutaminase inhibitor CB-839 hydrochloride dose
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center LAO
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Nervous System Diseases
- Neoplasms, Connective and Soft Tissue
- Neoplasms by Histologic Type
- Neuromuscular Diseases
- Neoplasms, Nerve Tissue
- Peripheral Nervous System Diseases
- Nervous System Neoplasms
- Neoplasms, Connective Tissue
- Sarcoma
- Peripheral Nervous System Neoplasms
- Neoplasms, Fibrous Tissue
- Fibrosarcoma
- Neurofibroma
- Neoplasms
- Nerve Sheath Neoplasms
- Neurofibrosarcoma
Other Study ID Numbers
- NCI-2019-01365 (Registry Identifier: CTRP (Clinical Trial Reporting Program))
- UM1CA186688 (U.S. NIH Grant/Contract)
- NCI10220
- 10220 (Other Identifier: CTEP)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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