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Testing Whether Cancers With Specific Mutations Respond Better to Glutaminase Inhibitor, CB-839 HCl, Anti-Cancer Treatment, BeGIN Study

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ClinicalTrials.gov Identifier: NCT03872427
Recruitment Status : Not yet recruiting
First Posted : March 13, 2019
Last Update Posted : June 25, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This phase II trial studies how well glutaminase inhibitor CB-839 hydrochloride (CB-839 HCl) works in treating patients with specific genetic mutations and solid tumors or malignant peripheral nerve sheath tumors that have spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable). Glutaminase converts an amino acid (building block of proteins) called glutamine to glutamate, which can support several cellular pathways. CB-839 works by blocking glutamine activity needed for the growth of cells. When this activity is blocked, the growth of cancer cells may stop and the cancer cells may then die. Cancer is caused by changes (mutations) to genes that control the way cells function and uncontrolled cell growth may result in tumor formation. Specific genetic mutations studied in this clinical trial are NF1 mutation for malignant peripheral nerve sheath tumors, and NF1, KEAP1/NRF2, or STK11/LKB1 mutation for other solid tumors. CB-839 HCl may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition or disease Intervention/treatment Phase
Advanced Malignant Solid Neoplasm KEAP1 Gene Mutation Metastatic Malignant Solid Neoplasm NF1 Gene Mutation NF1 Mutation Positive Malignant Peripheral Nerve Sheath Tumor NFE2L2 Gene Mutation STK11 Gene Mutation Unresectable Malignant Solid Neoplasm Drug: Glutaminase Inhibitor CB-839 Hydrochloride Other: Pharmacodynamic Study Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess the best overall response rate (BORR) achieved by 6 months of CB-839 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), time to response (TTR) and clinical benefit rate (CBR) of 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 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 to treatment response.

III. Quantify the peripheral blood concentrations of the metabolites: aspartate, glutamate, glutamine and arginine and correlate with response.

IV. Evaluate the pharmacodynamic (PD) effect of 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 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 to understand response / resistance mechanisms and also evaluate combination therapies for future development.

OUTLINE:

Patients receive glutaminase inhibitor CB-839 hydrochloride orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks, then every 3 months thereafter.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 108 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Basket Trial of Glutaminase Inhibitor (BeGIN) CB-839 HCl in Patients With NF1 Aberrations, NF1 Mutant Malignant Peripheral Nerve Sheath Tumors (MPNST), KEAP1/NRF2 and LKB1 Aberrant Tumors
Estimated Study Start Date : October 10, 2019
Estimated Primary Completion Date : June 1, 2021
Estimated Study Completion Date : June 1, 2021


Arm Intervention/treatment
Experimental: Treatment (glutaminase inhibitor CB-839 hydrochloride)
Patients receive glutaminase inhibitor CB-839 hydrochloride PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: Glutaminase Inhibitor CB-839 Hydrochloride
Given PO
Other Name: CB-839 HCl

Other: Pharmacodynamic Study
Correlative studies
Other Name: PHARMACODYNAMIC




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. Progression-free survival [ Time Frame: Time to progression or death whichever comes first, assessed up to 2 years from treatment start date ]
    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.

  3. Time to progression [ Time Frame: Time to progression starting at C1D1, assessed up to 2 years from treatment start date ]
    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.

  4. Overall survival [ Time Frame: Time to death from any cause, assessed up to 2 years from treatment start date ]
    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.

  5. Overall response rate [ Time Frame: From start of treatment until disease progression/recurrence, assessed up to 2 years ]
  6. Clinical benefit rate [ Time Frame: Up to 2 years from treatment start date ]

Other Outcome Measures:
  1. 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.

  2. 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.

  3. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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], eg. 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 be aged greater than 18 years old for all cohorts except as specified below.
  • Patients 12 and above years of age for NF1 mutation and NF1 mutant MPNST cohort must be >= 40 kg

    • Adolescent and young adult (AYA) patients for this trial would potentially be eligible for pediatric Molecular Analysis for Therapy Choice (MATCH) once progressed and similarly, screened AYA patients for pediatric MATCH once progressed would be eligible for this trial
  • 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 OR
  • Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • The effects of CB-839 HCl on the developing human fetus are unknown. For this reason and because anti-metabolic agents like 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 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 CB-839 HCl
  • Patients with glioma will be excluded
  • Patients with active or prior history of hepatitis B or C will be excluded
  • 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 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 CB-839 HCl, breastfeeding should be discontinued if the mother is treated with CB-839 HCl

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): NCT03872427


Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Vivek Subbiah University of Texas MD Anderson Cancer Center LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03872427     History of Changes
Other Study ID Numbers: NCI-2019-01365
NCI-2019-01365 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NCI10220
10220 ( Other Identifier: University of Texas MD Anderson Cancer Center LAO )
10220 ( Other Identifier: CTEP )
UM1CA186688 ( U.S. NIH Grant/Contract )
First Posted: March 13, 2019    Key Record Dates
Last Update Posted: June 25, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm

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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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Nerve Sheath Neoplasms
Neurofibrosarcoma
Neoplasms
Neoplasms, Nerve Tissue
Neoplasms by Histologic Type
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Fibrosarcoma
Neoplasms, Fibrous Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Sarcoma
Neurofibroma