A Phase II Basket Trial of Glutaminase Inhibitor (BEGIN) Telaglenastat (CB-839) HCL in Patients With NF1 Aberrations, NF1 Mutant Malignant Peripheral Nerve Sheath Tumors (MPNST), KEAP1/NRF2 and LKB1 Aberrant Tumors
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 54
- 试验地点
- 56
- 主要终点
- Best Overall Response Rate by 6 Months
研究概览
简要总结
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.
详细描述
PRIMARY OBJECTIVE:
I. To assess the best overall response rate (BORR) achieved by 6 months of telaglenastat (CB-839) hydrochloride (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 telaglenastat (CB-839)HCl.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •Patient must be aged greater than 18 years old for all cohorts
- •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 telaglenastat (CB-839) HCl on the developing human fetus are unknown. For this reason and because anti-metabolic agents like telaglenastat (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 telaglenastat (CB-839) HCl administration
- •Ability to understand and the willingness to sign a written informed consent document
排除标准
- •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 telaglenastat (CB-839) HCl
- •Patients with glioma will be excluded
- •Patients with active or prior history of hepatitis B or C will be excluded
- •Telaglenastat (CB-839) HCl is a weak in vitro inhibitor of CYP2C
- •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 telaglenastat (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 telaglenastat (CB-839) HCl, breastfeeding should be discontinued if the mother is treated with telaglenastat (CB-839) HCl
研究组 & 干预措施
Treatment (telaglenastat hydrochloride)
Patients receive telaglenastat hydrochloride PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or PET/CT during screening and on study, and collection of blood samples during screening and on study.
干预措施: Positron Emission Tomography (Procedure)
Treatment (telaglenastat hydrochloride)
Patients receive telaglenastat hydrochloride PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or PET/CT during screening and on study, and collection of blood samples during screening and on study.
干预措施: Computed Tomography (Procedure)
Treatment (telaglenastat hydrochloride)
Patients receive telaglenastat hydrochloride PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or PET/CT during screening and on study, and collection of blood samples during screening and on study.
干预措施: Magnetic Resonance Imaging (Procedure)
Treatment (telaglenastat hydrochloride)
Patients receive telaglenastat hydrochloride PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or PET/CT during screening and on study, and collection of blood samples during screening and on study.
干预措施: Pharmacodynamic Study (Other)
Treatment (telaglenastat hydrochloride)
Patients receive telaglenastat hydrochloride PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or PET/CT during screening and on study, and collection of blood samples during screening and on study.
干预措施: Telaglenastat Hydrochloride (Drug)
Treatment (telaglenastat hydrochloride)
Patients receive telaglenastat hydrochloride PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo CT, MRI, or PET/CT during screening and on study, and collection of blood samples during screening and on study.
干预措施: Biospecimen Collection (Procedure)
结局指标
主要结局
Best Overall Response Rate by 6 Months
时间窗: Up to 6 months from treatment start date
Best overall response rate (BORR) based on RECIST V1.1 achieved by 6 months of CB-839 HCl treatment
次要结局
- Overall Survival(Time to death from any cause, assessed up to 2 years from treatment start date)
- Overall Response Rate(From start of treatment until disease progression/recurrence, assessed up to 2 years)
- Incidence of Adverse Events(Up to 2 years from treatment start date)
- Progression-free Survival(Time to progression or death whichever comes first, assessed up to 2 years from treatment start date)
- Time to Progression(Time to progression starting at C1D1, assessed up to 2 years from treatment start date)
- Clinical Benefit Rate(Up to 2 years from treatment start date)
- Overall Response Rate(From start of treatment until disease progression/recurrence, assessed up to 2 years)
- Clinical Benefit Rate(Up to 2 years from treatment start date)
- Incidence of Adverse Events(Up to 2 years from treatment start date)
- Progression-free Survival(Time to progression or death whichever comes first, assessed up to 2 years from treatment start date)
- Time to Progression(Time to progression starting at C1D1, assessed up to 2 years from treatment start date)
- Overall Survival(Time to death from any cause, assessed up to 2 years from treatment start date)