Clinical Trials /

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

NCT03872427

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-01365
  • SECONDARY ID: NCI-2019-01365
  • SECONDARY ID: NCI10220
  • SECONDARY ID: 10220
  • SECONDARY ID: 10220
  • SECONDARY ID: UM1CA186688
  • NCT ID: NCT03872427

Conditions

  • Advanced Malignant Solid Neoplasm
  • Metastatic Malignant Solid Neoplasm
  • NF1 Mutation Positive Malignant Peripheral Nerve Sheath Tumor
  • Unresectable Malignant Solid Neoplasm

Interventions

DrugSynonymsArms
Glutaminase Inhibitor CB-839 HydrochlorideCB-839 HClTreatment (glutaminase inhibitor CB-839 hydrochloride)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (glutaminase inhibitor CB-839 hydrochloride)ExperimentalPatients 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.
  • Glutaminase Inhibitor CB-839 Hydrochloride

Eligibility 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], 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

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

Primary Outcome Measures

Measure:Best overall response rate
Time Frame:Up to 6 months from treatment start date
Safety Issue:
Description:Will be based on Response Evaluation Criteria in Solid Tumors version 1.1.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 2 years from treatment start date
Safety Issue:
Description:Will be assessed by Common Terminology Criteria for Adverse Events version 5.0. Will tabulate toxicity by cohort, type, severity and attribution.
Measure:Progression-free survival
Time Frame:Time to progression or death whichever comes first, assessed up to 2 years from treatment start date
Safety Issue:
Description: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.
Measure:Time to progression
Time Frame:Time to progression starting at C1D1, assessed up to 2 years from treatment start date
Safety Issue:
Description: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.
Measure:Overall survival
Time Frame:Time to death from any cause, assessed up to 2 years from treatment start date
Safety Issue:
Description: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.
Measure:Overall response rate
Time Frame:From start of treatment until disease progression/recurrence, assessed up to 2 years
Safety Issue:
Description:
Measure:Clinical benefit rate
Time Frame:Up to 2 years from treatment start date
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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