AN OPEN-LABEL PHASE IB STUDY OF PALBOCICLIB (ORAL CDK 4/6 INHIBITOR) PLUS ABRAXANE (REGISTERED) (NAB-PACLITAXEL) IN PATIENTS WITH METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Pfizer
- 入组人数
- 76
- 试验地点
- 26
- 主要终点
- Number of Participants With Dose Limiting Toxicities
研究概览
简要总结
This is a Phase 1, open label, multi center, multiple dose, dose escalation, safety, pharmacokinetic and pharmacodynamic study of palbociclib in combination with nab-P, in sequential cohorts of adult patients with mPDAC, with MTD expansion cohort(s). Approximately 30-60 patients are expected to be enrolled in the overall study.
详细描述
The study has 2 parts:
• Part A (Dose-Escalation Cohorts): Consecutive cohorts of patients will receive escalating doses of oral palbociclib in combination with intravenous nab-P in 28-day cycles, in order to estimate the MTD(s) of the combination. The starting doses will be 75 mg palbociclib, and 100 mg/m2 nab-P. The observation period for dose-limiting toxicities (DLTs) will be from Day 1 to Day 28. Pharmacokinetic (PK) and pharmacodynamic (PD) properties of palbociclib and nab-P will also be assessed. Up to approximately 30 patients will be enrolled. The criteria for dose escalation will be based on a modified toxicity probability interval (mTPI) method.
• Part B [MTD Expansion Cohort(s)]: When the MTD(s) of palbociclib plus nab-P has been estimated with confidence, enrollment will proceed into 1 or 2 MTD expansion cohort(s) of up to 20 patients each at the MTD(s). The objective of the MTD expansion cohort(s) will be to provide additional information on safety, tolerability, biomarkers, PD activity, and PK/PD relationship for the combination regimen in order to determine the RP2D. The MTD expansion cohort(s) will only enroll patients who have not received previous treatment for their metastatic disease in order to evaluate preliminary activity of the combination in the target patient population.
All patients (in Part A and B) will receive nab-P intravenously once weekly for 3 weeks out of each 28-day cycle. Palbociclib oral dosing will be once daily on Days 1-21 of each 28-day cycle. To allow for PK evaluation of nab-P administered alone, nab-P will be administered on Day -2 for Cycle 1 only. Subsequent cycles will administer both nab-P and palbociclib on Day 1. Alternate dosing schedules for palbociclib may be explored based on emerging PK, PD, and safety data.
Patients will be treated as long as they are clinically benefiting from investigational product without unacceptable toxicity, objective disease progression, or withdrawal of consent. A modified visit schedule will be implemented for patients who are on investigational product for more than 2 years.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 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
- •Histologically or cytologically-confirmed metastatic pancreatic ductal adenocarcinoma.
- •Availability of a tumor tissue specimen. If no archived tumor tissue is available, then a de novo biopsy is required for patient participation.
- •Karnofsky Performance Status 70 or greater.
- •Adequate Bone Marrow, Renal, and Liver Function.
排除标准
- •Prior treatment with a CDK 4/6 inhibitor.
- •Prior treatment with nab-P for the treatment of metastatic disease.
- •Patients with known CNS metastases, carcinomatous meningitis, or leptomeningeal disease as indicated by clinical symptoms, cerebral edema, and/or progressive growth.
- •Diagnosis of any other malignancy within 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
- •QTc >480 msec, or family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes.
- •Uncontrolled electrolyte disorders.
- •Cardiac or pulmonary disorders within 6 months of enrollment.
- •Known human immunodeficiency virus infection.
- •History of interstitial lung disease or pneumonitis.
- •Other severe acute or chronic medical or psychiatric condition that may increase the risk associated with study participation.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to nab-P.
- •Difficulty swallowing capsules or requirement for a feeding tube.
- •Previous high-dose chemotherapy requiring stem cell rescue.
- •Pregnant female patients; breastfeeding female patients; male patients with partners currently pregnant.
- •Active inflammatory or other gastrointestinal disease,
- •Active bleeding disorder in the past 6 months.
- •Patients treated within the last 7 days prior to the start of IP with strong/moderate CYP3A4 inhibitors, strong/moderate CYP3A4 inducers, CYP2C8 inhibitors, strong/moderate CYP2C8 inducers, or drugs that are known to prolong the QT interval.
研究组 & 干预措施
Palbociclib + Nab-Paclitaxel
Palbociclib oral dosing on Days 1 to 21 of each 28-day cycle. Nab-paclitaxel IV dosing on Days -2, 6, and 13 of Cycle 1, and on Days 1, 8, and 15 of subsequent cycles.
干预措施: Palbociclib (Drug)
Palbociclib + Nab-Paclitaxel
Palbociclib oral dosing on Days 1 to 21 of each 28-day cycle. Nab-paclitaxel IV dosing on Days -2, 6, and 13 of Cycle 1, and on Days 1, 8, and 15 of subsequent cycles.
干预措施: Nab-Paclitaxel (Drug)
结局指标
主要结局
Number of Participants With Dose Limiting Toxicities
时间窗: From Day 1 until pre-dose Cycle 2 Day 1
Adverse events (AEs) considered as dose limiting toxicities (DLTs) included: hematologic: Grade 4 neutropenia lasting \>4 days; Febrile neutropenia (defined as neutropenia Grade\>=3 \[absolute neutrophil count {ANC}\<1000 cells/cubic millimeter {mm\^3}\] and a body temperature \>=38.5 \[degrees centigrade\]℃) requiring antibiotic or antifungal treatment; any Grade 4 thrombocytopenia (\<25000/mm\^3 or 25.0\*10\^9/\[liter\]L). Non-hematologic: Grade \>=3 toxicities, except those that had not been maximally treated (eg, nausea, vomiting, diarrhea). Any AE that caused a palbociclib treatment interruption of greater than 7 consecutive days or caused any combination of interruption/reduction for \>=14 days. Any AE that caused omission or reduction of at least 2 of the 3 weekly doses of nab-P.
次要结局
- Six-month Progression-free Survival Rate (6m-PFSR)(From screening to 6 months after first dose of investigational product)
- Progression Free Survival(From screening to 365 days from the last dose of investigational product)
- Number of Participants With Laboratory Abnormalities(From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product).)
- Number of Participants With 20% Maximum Reduction From Baseline in Ca19-9(From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product).)
- Palbociclib Multiple Dose Trough Plasma Concentration(Ctrough)(Cycle 1 Day 13 at 0 (pre-dose), 2, 4, 6, 8 and 24 hours post palbociclib dose, and pre-dose on Cycle 2, Days 1 and 15.)
- Palbociclib Multiple Dose Apparent Clearance (CL/F)(Cycle 1 Day 13 at 0 (pre-dose), 2, 4, 6, 8 and 24 hours post palbociclib dose, and pre-dose on Cycle 2, Days 1 and 15.)
- Nab-P Cmax(Prior to nab-P infusion and at 30 min (end of infusion), 1, 2, 4, 6, 8, 24, and 48 hours post the start of paclitaxel infusion on Day -2 and 13 of Cycle 1.)
- Nab-P Tmax(Prior to nab-P infusion and at 30 min (end of infusion), 1, 2, 4, 6, 8, 24, and 48 hours post the start of paclitaxel infusion on Day -2 and 13 of Cycle 1.)
- Number of Participants With Adverse Events(From the signing of informed consent up to 56 days after the last administration of the investigational product, or 365 days from the first dose of investigational product, whichever is later)
- Number of Participants With 70% Maximum Reduction From Baseline in Ca19-9(From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product).)
- Overall Survival (OS)(From screening to 365 days from the last dose of investigational product)
- Palbociclib Multiple Dose Maximum Plasma Concentration (Cmax)(Cycle 1 Day 13 at 0 (pre-dose), 2, 4, 6, 8 and 24 hours post palbociclib dose, and pre-dose on Cycle 2, Days 1 and 15.)
- Palbociclib Area Under the Plasma Concentration-time Curve for Dosing Interval τ (AUCτ)(Cycle 1 Day 13 at 0 (pre-dose), 2, 4, 6, 8 and 24 hours post palbociclib dose, and pre-dose on Cycle 2, Days 1 and 15.)
- Number of Participants With Vital Signs Data Meeting Pre-specified Criteria(From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product).)
- Objective Response Rate(From screening to 365 days from the last dose of investigational product)
- Duration of Response(From screening to 365 days from the last dose of investigational product)
- Palbociclib Multiple Dose Time for Cmax (Tmax)(Cycle 1 Day 13 at 0 (pre-dose), 2, 4, 6, 8 and 24 hours post palbociclib dose, and pre-dose on Cycle 2, Days 1 and 15.)
- Number of Participants With 50% Maximum Reduction From Baseline in Ca19-9(From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product).)
- Number of Participants With 90% Maximum Reduction From Baseline in Ca19-9(From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product).)
- Retinoblastoma Protein (Rb) Percent Positive Cell (Nuclear Staining)(From Day-2 to up to 63 days from last dose of investigational product)
- Rb H-score Nuclear Staining(From Day-2 to up to 63 days from last dose of investigational product)
- Nab-P Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinite Time (AUCinf)(Prior to nab-P infusion and at 30 min (end of infusion), 1, 2, 4, 6, 8, 24, and 48 hours post the start of paclitaxel infusion on Day -2 and 13 of Cycle 1.)
- Number of Participants With Positive p16(From Day-2 to up to 63 days from last dose of investigational product)
- Nab-P Area Under the Plasma Concentration-time Curve From Time 0 to Last Quantifiable Concentration (AUClast)(Prior to nab-P infusion and at 30 min (end of infusion), 1, 2, 4, 6, 8, 24, and 48 hours post the start of paclitaxel infusion on Day -2 and 13 of Cycle 1.)
- Nab-P Terminal Plasma Elimination Half-life (t1/2)(Prior to nab-P infusion and at 30 min (end of infusion), 1, 2, 4, 6, 8, 24, and 48 hours post the start of paclitaxel infusion on Day -2 and 13 of Cycle 1.)
- Nab-P Clearance (CL)(Prior to nab-P infusion and at 30 min (end of infusion), 1, 2, 4, 6, 8, 24, and 48 hours post the start of paclitaxel infusion on Day -2 and 13 of Cycle 1.)
- Nab-P Volume of Distribution (Vz)(Prior to nab-P infusion and at 30 min (end of infusion), 1, 2, 4, 6, 8, 24, and 48 hours post the start of paclitaxel infusion on Day -2 and 13 of Cycle 1.)