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Testing Whether Cancers with Specific Mutations Respond Better to Glutaminase Inhibitor, Telaglenastat Hydrochloride, Anti-Cancer Treatment, BeGIN Study

Trial Status: Active

This phase II trial studies how well glutaminase inhibitor telaglenastat 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. Telaglenastat hydrochloride 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. Telaglenastat hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

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
  • 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 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

Alabama

Birmingham
University of Alabama at Birmingham Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 205-934-0220

Florida

Aventura
UM Sylvester Comprehensive Cancer Center at Aventura
Status: ACTIVE
Contact: Site Public Contact
Phone: 954-461-2180
Coral Gables
UM Sylvester Comprehensive Cancer Center at Coral Gables
Status: ACTIVE
Contact: Site Public Contact
Phone: 305-243-2647
Deerfield Beach
UM Sylvester Comprehensive Cancer Center at Deerfield Beach
Status: ACTIVE
Contact: Site Public Contact
Phone: 305-243-2647
Miami
UM Sylvester Comprehensive Cancer Center at Kendall
Status: ACTIVE
Contact: Site Public Contact
Phone: 305-243-2647
University of Miami Miller School of Medicine-Sylvester Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 305-243-2647
Plantation
UM Sylvester Comprehensive Cancer Center at Plantation
Status: ACTIVE
Contact: Site Public Contact
Phone: 305-243-2647
Tampa
Moffitt Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-679-0775
Moffitt Cancer Center - McKinley Campus
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-679-0775
Moffitt Cancer Center-International Plaza
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-679-0775

Illinois

Chicago
Northwestern University
Status: ACTIVE
Contact: Site Public Contact
Phone: 312-695-1301

Kansas

Fairway
University of Kansas Clinical Research Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 913-588-3671
Hays
HaysMed University of Kansas Health System
Status: ACTIVE
Contact: Site Public Contact
Phone: 785-623-5774
Kansas City
University of Kansas Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 913-588-3671
Olathe
Olathe Health Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 913-355-8000
Pittsburg
Ascension Via Christi - Pittsburg
Status: ACTIVE
Contact: Site Public Contact
Phone: 620-235-7900
Salina
Salina Regional Health Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 785-452-7038
Topeka
University of Kansas Health System Saint Francis Campus
Status: ACTIVE
Contact: Site Public Contact
Phone: 785-295-8000
Westwood
University of Kansas Hospital-Westwood Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 913-588-3671

Kentucky

Lexington
University of Kentucky / Markey Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 859-257-3379

Maryland

Bethesda
National Cancer Institute Developmental Therapeutics Clinic
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-411-1222
National Institutes of Health Clinical Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-411-1222

Massachusetts

Boston
Dana-Farber Cancer Institute
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-442-3324

Missouri

Kansas City
Truman Medical Centers
Status: ACTIVE
Contact: Site Public Contact
Phone: 816-404-4375

New York

New York
Laura and Isaac Perlmutter Cancer Center at NYU Langone
Status: ACTIVE
Contact: Site Public Contact
NYP / Columbia University Medical Center / Herbert Irving Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 212-305-6361

North Carolina

Clemmons
Wake Forest University at Clemmons
Status: ACTIVE
Contact: Site Public Contact
Phone: 888-716-9259
Winston-Salem
Wake Forest University Health Sciences
Status: ACTIVE
Contact: Site Public Contact
Phone: 336-713-6771

Ohio

Columbus
Ohio State University Comprehensive Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 800-293-5066

Pennsylvania

Pittsburgh
University of Pittsburgh Cancer Institute (UPCI)
Status: ACTIVE
Contact: Site Public Contact
Phone: 412-647-8073

Texas

Houston
M D Anderson Cancer Center
Status: ACTIVE
Contact: Site Public Contact
Phone: 877-632-6789

PRIMARY OBJECTIVE:

I. To assess the best overall response rate (BORR) achieved by 6 months of telaglenastat hydrochloride (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) (highest objective response achieved between start of therapy and progression), 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 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.

After completion of study treatment, patients are followed up every 3 months thereafter.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
University of Texas MD Anderson Cancer Center LAO

Principal Investigator
Vivek Subbiah

  • Primary ID 10220
  • Secondary IDs NCI-2019-01365, NCI10220
  • Clinicaltrials.gov ID NCT03872427