Phase I Trial of ZEN003694 (ZEN-3694) in Combination With Capecitabine in Patients With Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 30
- 试验地点
- 39
- 主要终点
- Incidence of adverse events
研究概览
简要总结
This phase I trial tests the safety, side effects, and best dose of ZEN003694 in combination with the usual treatment with capecitabine in treating patients with cancer that has spread from where it first started (primary site) to other places in the body (metastatic) or cannot be removed by surgery (unresectable) and that it has progressed on previous standard treatment. ZEN003694 is an inhibitor of a family of proteins called the bromodomain and extra-terminal (BET). It may prevent the growth of tumor cells that over produce BET protein. Capecitabine is in a class of medications called antimetabolites. It is taken up by cancer cells and breaks down into fluorouracil, a substance that kills cancer cells. Giving ZEN003694 in combination with capecitabine may be safe in treating patients with metastatic or unresectable solid tumors.
详细描述
PRIMARY OBJECTIVE:
I. To determine the safety and tolerability, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of BET bromodomain inhibitor ZEN-3694 (ZEN003694 [ZEN-3694]) in combination with capecitabine in patients with solid tumors.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity of ZEN003694 (ZEN-3694) in combination with capecitabine.
II. To determine the pharmacokinetics (PK) of ZEN003694 (ZEN-3694) in combination with capecitabine.
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
- •Dose Escalation additional criteria: Patients must have histologically confirmed cancer that is metastatic or unresectable and must have progressed on standard therapies which would have included fluorouracil (5-FU) or capecitabine
- •Dose Escalation additional criteria specifically for colorectal cancer (CRC) patients: Willingness and ability to undergo a pre-treatment biopsy
- •Dose Expansion additional criteria: Patients must have histologically confirmed CRC that is metastatic or unresectable and must have progressed on standard therapies which would have included 5-FU or capecitabine
- •Dose Expansion additional criteria: Willingness and ability to undergo pre- and on- treatment biopsies
- •Patients must have measurable disease
- •Age >= 18 years. Because no dosing or adverse event data are currently available on the use of ZEN003694 (ZEN-3694) in combination with capecitabine in patients < 18 years of age, children are excluded from this study
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Karnofsky >= 60%)
- •Availability of archival tumor tissue at the time of patient enrollment for molecular profiling studies
- •Prior to study dosing, previous systemic therapy must have been completed for at least five half-lives or 2 weeks, whichever is shorter
- •Absolute neutrophil count >= 1,000/mcL
- •Platelets >= 100,000/mcL
- •Total bilirubin =< 1.5 institutional upper limit of normal (ULN)
- •Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
- •Glomerular filtration rate (GFR) >= 50 mL/min/1.73 m^2
- •Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
- •For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
- •Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
- •Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
- •Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
- •Patients should be New York Heart Association Functional Classification of class 2B or better
- •The effects of ZEN003694 (ZEN-3694) and capecitabine on the developing human fetus are unknown. For this reason and because BET inhibitors as well as other therapeutic agents used in this trial 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. Women of child-bearing potential and 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 6 months after completion of ZEN003694 (ZEN-3694) and capecitabine administration
- •Ability to understand and the willingness to sign a written informed consent document. Legally authorized representatives may sign and give informed consent on behalf of study participants
排除标准
- •Previous treatment with BET inhibitors
- •History of inability to tolerate capecitabine at the projected treatment dose on this trial
- •Use of oral Factor Xa inhibitors (i.e., rivaroxaban, apixaban, betrixaban, edoxaban otamixaban, letaxaban, eribaxaban) and Factor IIa inhibitors (i.e., dabigatran). Low molecular weight heparin is allowed
- •Treatment for HIV, hepatitis B or hepatitis C only if this interferes with the current treatment (e.g. through drug-drug interactions)
- •Gastrointestinal pathology or history that adversely impacts the ability to take or absorb oral medication
- •Hepatic tumor burden > 30% or peritoneal carcinomatosis
- •Untreated/uncontrolled central nervous system (CNS) disease
- •Known dihydropyrimidine dehydrogenase (DPD) deficiency
- •Severe intercurrent illness or comorbidity
- •Inability to comply with the protocol and/or not willing or who will not be available for follow-up assessments
- •Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1) with the exception of alopecia and neuropathy up to and including grade 2
- •Patients who are receiving any other investigational agents
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to ZEN003694 (ZEN-3694) or other agents used in study
- •Patients receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 are ineligible. Strong inhibitors of CYP3A4 must be discontinued at least 7 days, and inducers 14 days prior to the first dose of ZEN003694 and capecitabine. Substrates of CYP1A2 with narrow therapeutic window must be avoided while taking ZEN003694
- •Pregnant women are excluded from this study because ZEN003694 (ZEN-3694) is an 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 ZEN003694 (ZEN-3694), breastfeeding should be discontinued if the mother is treated with ZEN003694 (ZEN-3694). These potential risks may also apply to other agents used in this study
研究组 & 干预措施
Treatment (ZEN003694, capecitabine)
Patients receive ZEN003694 PO QD and capecitabine PO BID 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI, PET/CT, and collection of blood samples throughout the trial. Patients may also undergo biopsies during screening and while on the study.
干预措施: Positron Emission Tomography (Procedure)
Treatment (ZEN003694, capecitabine)
Patients receive ZEN003694 PO QD and capecitabine PO BID 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI, PET/CT, and collection of blood samples throughout the trial. Patients may also undergo biopsies during screening and while on the study.
干预措施: Biopsy Procedure (Procedure)
Treatment (ZEN003694, capecitabine)
Patients receive ZEN003694 PO QD and capecitabine PO BID 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI, PET/CT, and collection of blood samples throughout the trial. Patients may also undergo biopsies during screening and while on the study.
干预措施: Capecitabine (Drug)
Treatment (ZEN003694, capecitabine)
Patients receive ZEN003694 PO QD and capecitabine PO BID 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI, PET/CT, and collection of blood samples throughout the trial. Patients may also undergo biopsies during screening and while on the study.
干预措施: BET Bromodomain Inhibitor ZEN-3694 (Drug)
Treatment (ZEN003694, capecitabine)
Patients receive ZEN003694 PO QD and capecitabine PO BID 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI, PET/CT, and collection of blood samples throughout the trial. Patients may also undergo biopsies during screening and while on the study.
干预措施: Computed Tomography (Procedure)
Treatment (ZEN003694, capecitabine)
Patients receive ZEN003694 PO QD and capecitabine PO BID 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI, PET/CT, and collection of blood samples throughout the trial. Patients may also undergo biopsies during screening and while on the study.
干预措施: Biospecimen Collection (Procedure)
Treatment (ZEN003694, capecitabine)
Patients receive ZEN003694 PO QD and capecitabine PO BID 2 weeks on, 1 week off during each treatment cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo CT or MRI, PET/CT, and collection of blood samples throughout the trial. Patients may also undergo biopsies during screening and while on the study.
干预措施: Magnetic Resonance Imaging (Procedure)
结局指标
主要结局
Incidence of adverse events
时间窗: Up to 30 days after last dose
Adverse events and serious adverse events will be tabulated for each dose levels. As per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, the term toxicity is defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Recommended phase 2 dose (RP2D)
时间窗: Up to 30 days after last dose
Will be determined based on the MTD and later cycle adverse event (AE) rates.
Incidence of adverse events
时间窗: Up to 30 days after last dose
Adverse events and serious adverse events will be tabulated for each dose levels. As per National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0, the term toxicity is defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Maximum tolerated dose (MTD)
时间窗: During the first cycle of therapy (Cycles = 21 days)
Defined as the highest dose level with no more than 1/6 dose-limiting toxicity.
Recommended phase 2 dose (RP2D)
时间窗: Up to 30 days after last dose
Will be determined based on the MTD and later cycle adverse event (AE) rates.
次要结局
- Anti-tumor activity of ZEN003694 (ZEN-3694) in combination with capecitabine(Up to 12 months)
- Progression free survival (PFS)(Up to 12 months)
- Objective response rate (ORR)(Up to 12 months)
- Pharmacokinetics (PK) of ZEN003694 (ZEN-3694) in combination with capecitabine(Up to 12 months)
- Pharmacodynamics (PD) of ZEN003694 (ZEN-3694) in combination with capecitabine(Up to 12 months)
- Molecular subpopulations particularly sensitized to BETi and capecitabine(Up to 12 months)