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.
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
