Patient case: 11-year-old male with Peutz-Jeghers syndrome; genetic feature: STK11

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

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.

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.

Eligibility: 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

Relevance to patient case: not relevant