A Phase 1, Open-label, Multicenter, Randomized, 2-Period, Crossover Study to Evaluate the Bioequivalence and Food Effect Bioavailability of CC-486 (Oral Azacitidine) Tablets in Adult Cancer Subjects
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Celgene
- 入组人数
- 89
- 试验地点
- 10
- 主要终点
- Pharmacokinetics AUC-t - Stage I (Bioequivalence)
研究概览
简要总结
This is a Phase 1, open-label, multicenter, randomized, 2-stage crossover study consisting of 2 phases:
Stage I - Pharmacokinetics (Bioequivalence), with an Extension Stage II - Pharmacokinetics (Food Effect) with an Extension
This study will enroll approximately 60 subjects in stage I and 60 subjects in stage II with hematologic or solid tumor malignancies, excluding gastrointestinal tumors and tumors that have originated or metastasized to the liver for which no standard treatment exists or have progressed or recurred following prior therapy. Subjects must not be eligible for therapy of higher curative potential where an alternative treatment has been shown to prolong survival in an analogous population. Approximately 23 sites in the US and 2 in Canada will participate in this study.
详细描述
Stage I - Pharmacokinetics (Bioequivalence)
Subjects will be randomized to receive CC-486 300 mg orally on each of the two pharmacokinetic (PK) study days based on the dosing sequences they are randomized to:
Dosing Sequence 1: 2x150 mg tablets followed by 1x30 mg tablet. Dosing Sequence 2: 1x300 mg tablet followed by 2x150 mg tablets. Each dose will be administered in the clinic at least 48 hours apart between PK dosing day 1 and PK dosing day 2 over a period no longer than 10 days under fasted conditions.
Stage II - Pharmacokinetics (Food Effect)
Subjects will be randomized to receive CC-486 300 mg orally on each of the two PK study days based on the dosing sequences they are randomized to:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 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
- •Subjects must satisfy the following criteria to be enrolled in the study:
- •Age ≥ 18 years of age at the time of signing the informed consent document.
- •Understand and voluntarily sign an informed consent document prior to any study related assessments/procedures are conducted.
- •Documented diagnosis of any of the following:
- •Myelodysplastic Syndrome (MDS) according to the World Health Organization (WHO) 2008 classification
- •Acute myeloid leukemia (AML)
- •Multiple myeloma (MM), limited to those patients for whom standard curative or palliative treatments do not exist or are no longer effective
- •Non-Hodgkin's lymphoma (NHL), limited to those patients for whom standard curative or palliative treatment do not exist or are no longer effective,
- •Hodgkin's lymphoma (HL), limited to those patients for whom standard curative or palliative treatment do not exist or are no longer effective
- •Metastatic or inoperable solid tumors* (except gastrointestinal tumors or tumors that originated or metastasized to the liver) for which no standard treatment exists, or have progressed or recurred following prior therapy.
- •Subjects must not be eligible for therapy of higher curative potential where an alternative treatment has been shown to prolong survival in an analogous population.
- •Patients with a history of treated brain metastases should be clinically stable for ≥ 4 weeks prior to signing the informed consent. Glucocorticoid therapy for central nervous system (CNS) edema is permitted if ≤ 20 mg of prednisolone (or equivalent).
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-
- •Have a life expectancy of ≥ 3 months.
- •Have stable renal function without dialysis for at least 2 months prior to Investigational Product (IP) administration defined by:
- •Serum creatinine < 2.5 x the upper limit of normal (ULN)
- •An average calculated creatinine clearance > 30 mL/min/1.73 m^2
- •Have organ and marrow function at the screening and pre-dose visits as defined by:
- •Hemoglobin ≥ 8 g/dL
- •Absolute neutrophil count (ANC) ≥ 0.75 x 10^3/uL without treatment with a myeloid growth factor within 3 days prior to first dose of IP
- •Platelets ≥ 30 x 10^3/uL
- •Total bilirubin ≤ 1.5 x Upper Limits of Normal (ULN)
- •Aspartate aminotransferase (AST) ≤ 2 x ULN
- •Alanine aminotransferase (ALT) ≤ 2 x ULN
- •Have a 12-lead Electrocardiogram (ECG) that is not clinically significant at screening, as determined by the investigator
- •Females of childbearing potential (FCBP) may participate, providing the subject meets the following conditions:
- •Agree to use at least two effective contraceptive methods (oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) or agree to practice true abstinence throughout the study, and for 3 months following the last dose of IP; and
- •Negative serum pregnancy test at screening (sensitivity of at least 25 mIU/mL); (Note that the screening serum pregnancy test can be used as the test prior to starting IP in the pharmacokinetics phase if it is performed within the 72-hour timeframe), and
- •Negative serum or urine pregnancy test (investigator's discretion; sensitivity of at least 25 mIU/mL) within 72 hours prior to starting IP in the extension phase. (Note: subjects must have negative serum or urine pregnancy test prior to dosing on Day 1 of each treatment cycle in the extension phase.)
- •Male subjects must:
- •a. Practice true abstinence* or agree to the use of at least two physician-approved contraceptive methods throughout the course of the study and should avoid fathering a child during the course of the study for at least 3 months following the last dose of IP.
- •* True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the patient. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception].
- •Able to adhere to the study visit schedule and other protocol requirements.
排除标准
- •Women who are pregnant or nursing (lactating).
- •Gastrointestinal tumors, tumors that have originated or metastasized to the liver, or other tumors known to interfere with the absorption, distribution, metabolism, or excretion of drugs.
- •Had chemotherapy or radiotherapy within 4 weeks prior to the first day of Investigational Product (IP) administration.
- •Have been treated with an investigational agent within 4 weeks prior to the first day of IP administration.
- •Have ongoing clinically significant adverse event(s) due to prior treatments administered as determined by the investigator.
- •Significant active cardiac disease within the previous 6 months, including:
- •New York Heart Association (NYHA) class IV congestive heart failure
- •Significant cardiac arrhythmia or unstable angina or angina requiring surgical or medical intervention; and/or
- •Myocardial infarction
- •Have known or suspected hypersensitivity to azacitidine or any other ingredient used in the manufacturing of Azacitidine.
- •Uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment)
- •History of inflammatory bowel disease (e.g. Crohn's disease, ulcerative colitis), celiac disease, prior gastrectomy, gastric bypass, upper bowel removal, or any other gastrointestinal disorder or defect that would interfere with the absorption of the study drug and/or predispose the subject to an increased risk of gastrointestinal toxicity.
- •Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
- •Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study
- •Any condition that confounds the ability to interpret data from the study
- •Impaired ability to swallow oral medication
- •Any condition that confounds the ability to interpret data from the study
研究组 & 干预措施
CC-486 Arm 1 (Oral Azacitidine) Dosing Sequence 1
Two 150-mg tablets of CC-486 under fasting condition on PK dosing Day 1, followed by one 300-mg tablet of CC-486 on PK dosing Day 2; If PI chooses to treat the patient in the extension phase with Azacitidine, Vidaza (Azacitidine for Injection) 75 mg/m2 intravenously (IV) or subcutaneously (SC) daily x 7 days every 4 weeks for less than or equal to 6 (28-day) cycles will be administered.
干预措施: CC-486 (Drug)
CC-486 Arm 1 (Oral Azacitidine) Dosing Sequence 1
Two 150-mg tablets of CC-486 under fasting condition on PK dosing Day 1, followed by one 300-mg tablet of CC-486 on PK dosing Day 2; If PI chooses to treat the patient in the extension phase with Azacitidine, Vidaza (Azacitidine for Injection) 75 mg/m2 intravenously (IV) or subcutaneously (SC) daily x 7 days every 4 weeks for less than or equal to 6 (28-day) cycles will be administered.
干预措施: Vidaza (Drug)
CC-486 Arm 2 (Oral Azacitidine) Dosing Sequence 1
One 300-mg tablet of oral CC-486 under fasting condition on PK dosing Day 1, followed by one 300-mg tablet of oral CC-486 under fed condition on PK dosing Day 2; If PI chooses to treat the patient in the extension phase with Azacitidine, Vidaza (Azacitidine for Injection) 75 mg/m2 intravenously (IV) or subcutaneously (SC) daily x 7 days every 4 weeks for less than or equal to 6 (28-day) cycles will be administered.
干预措施: CC-486 (Drug)
CC-486 Arm 2 (Oral Azacitidine) Dosing Sequence 1
One 300-mg tablet of oral CC-486 under fasting condition on PK dosing Day 1, followed by one 300-mg tablet of oral CC-486 under fed condition on PK dosing Day 2; If PI chooses to treat the patient in the extension phase with Azacitidine, Vidaza (Azacitidine for Injection) 75 mg/m2 intravenously (IV) or subcutaneously (SC) daily x 7 days every 4 weeks for less than or equal to 6 (28-day) cycles will be administered.
干预措施: Vidaza (Drug)
CC-486 Arm 1 (Oral Azacitidine) Dosing Sequence 2
One 300-mg tablets of CC-486 under fasting condition on PK dosing Day 1, followed by two 150-mg tablets on PK dosing Day 2; If PI chooses to treat the patient in the extension phase with Azacitidine, Vidaza (Azacitidine for Injection) 75 mg/m2 intravenously (IV) or subcutaneously (SC) daily x 7 days every 4 weeks for less than or equal to 6 (28-day) cycles will be administered.
干预措施: CC-486 (Drug)
CC-486 Arm 1 (Oral Azacitidine) Dosing Sequence 2
One 300-mg tablets of CC-486 under fasting condition on PK dosing Day 1, followed by two 150-mg tablets on PK dosing Day 2; If PI chooses to treat the patient in the extension phase with Azacitidine, Vidaza (Azacitidine for Injection) 75 mg/m2 intravenously (IV) or subcutaneously (SC) daily x 7 days every 4 weeks for less than or equal to 6 (28-day) cycles will be administered.
干预措施: Vidaza (Drug)
CC-486 Arm 2 (Oral Azacitidine) Dosing Sequence 2
One 300-mg tablet of oral CC-486 under fed condition on PK dosing Day 1, followed by one tablet of 300-mg oral CC-486 under fasted conditions on PK dosing Day 2; if PI chooses to treat the patient in the extension phase with Azacitidine, Vidaza (Azacitidine of Injection) 75 mg/m2 intravenously (IV) or subcutaneously (SC) daily x 7 days every 4 weeks for less than or equal to 6 (28-day) cycles will be administered.
干预措施: CC-486 (Drug)
CC-486 Arm 2 (Oral Azacitidine) Dosing Sequence 2
One 300-mg tablet of oral CC-486 under fed condition on PK dosing Day 1, followed by one tablet of 300-mg oral CC-486 under fasted conditions on PK dosing Day 2; if PI chooses to treat the patient in the extension phase with Azacitidine, Vidaza (Azacitidine of Injection) 75 mg/m2 intravenously (IV) or subcutaneously (SC) daily x 7 days every 4 weeks for less than or equal to 6 (28-day) cycles will be administered.
干预措施: Vidaza (Drug)
结局指标
主要结局
Pharmacokinetics AUC-t - Stage I (Bioequivalence)
时间窗: Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose
Area under the concentration-time curve from time zero to the last quantifiable time point calculated by the linear trapezoidal rule
Pharmacokinetics Tmax - Stage I (Bioequivalence)
时间窗: Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose
The observed time to first maximum concentration
Pharmacokinetics λz (Terminal Rate) - Stage I (Bioequivalence)
时间窗: Dosing Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.3.5, 4, 6, and 8 hours post-dose
Terminal phase rate constant, determined by linear regression of the terminal points of the log-linear concentration-time curve
Pharmacokinetics Apparent total clearance (CL/F) - Stage I (Bioequivalence)
时间窗: Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose
Apparent total clearance, calculated as Dose/AUC∞
Pharmacokinetics Tmax - Stage II (Food Effect Bioavailability)
时间窗: PK Dosing Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose.
The observed time to first maximum concentration
Pharmacokinetics Cmax - Stage I (Bioequivalence)
时间窗: Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose
The observed maximum concentration
Pharmacokinetics Apparent volume of distribution (Vd/F) - Stage I (Bioequivalence)
时间窗: Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose
Apparent volume of distribution, calculated according to the equation: Vd/F = (CL/F) / λz
Pharmacokinetics Terminal Half-Life (t½) - Stage I (Bioequivalence)
时间窗: Dosing Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose
Terminal phase half-life, calculated according to the following equation: t½ = 0.693/λz
Pharmacokinetics Cmax - Stage II (Food Effect Bioavailability)
时间窗: PK Dosing Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose.
The observed maximum concentration
Pharmacokinetics AUC-infinity - Stage I (Bioequivalence)
时间窗: Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose
Area under the concentration time-curve from time zero to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity. It will be calculated as AUC∞ = \[AUCt + Ct/λz\]. Ct is the last quantifiable concentration
Pharmacokinetics AUC-infinity - Stage II (Food Effect Bioavailability)
时间窗: PK Dosing Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose.
Area under the concentration time-curve from time zero to infinity, calculated by the linear trapezoidal rule and extrapolated to infinity. It will be calculated as AUC∞ = \[AUCt + Ct/λz\]. Ct is the last quantifiable concentration.
Pharmacokinetics λz (Terminal Rate) - Stage II (Food Effect Bioavailability)
时间窗: PK Dosing Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose.
Terminal phase rate constant, determined by linear regression of the terminal points of the log-linear concentration-time curve
Pharmacokinetics Terminal Half-Life (t½) - Stage II (Food Effect Bioavailability)
时间窗: PK Dosing Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose.
Terminal phase half-life, calculated according to the following equation: t½ = 0.693/λz
Pharmacokinetics Apparent total clearance (CL/F) - Stage II (Food Effect Bioavailability)
时间窗: PK Dosing Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose.
Apparent total clearance, calculated as Dose/AUC∞
Pharmacokinetics AUC-t - Stage II (Food Effect Bioavailability)
时间窗: PK Dosing Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose.
Area under the concentration-time curve from time zero to the last quantifiable time point calculated by the linear trapezoidal rule.
Pharmacokinetics Apparent volume of distribution (Vd/F) - Stage II (Food Effect Bioavailability)
时间窗: PK Dosing Day 1 and PK Dosing Day 2 prior to each dose administration of IP (CC-486), known as pre-dose, and over the 8-hour period following each dose administration of IP (CC-486) at 0.25, 0.5, 1, 1.5, 2, 2.5,3, 3.5, 4, 6, and 8 hours post-dose.
Apparent volume of distribution, calculated according to the equation: Vd/F = (CL/F) / λz
次要结局
- Adverse Events (AEs)(Up to 18 months)