Dose-Escalation Study Of Palbociclib + Nab-Paclitaxel In mPDAC

• Number of participants with Dose-limiting toxicities (DLT) [ Time Frame: Baseline up to 28 days ]
  DLT defined as any of the following events occurring during the first 28 days of palbociclib and considered at least possibly-related to study medication: Grade 4 neutropenia lasting > 4 days; Febrile neutropenia (defined as neutropenia Grade ≥3 [ANC <1000 cells/mm3] and a body temperature ≥38.5°C) requiring antibiotic or antifungal treatment; Any Grade 4 thrombocytopenia (<25,000/mm3 or <25.0 x 109/L); Grade 3 toxicities, except those that have not been maximally treated (eg, nausea, vomiting, diarrhea); Any palbociclib treatment delay of greater than 7 days; Omission of at least 2 of the 3 weekly doses of nab-P.
  
  

• Palbociclib Area Under the Curve (AUC) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 2, 4, 6, 8, and 24 hours post dose. Cycle 2 Days 1 and 15: Pre-dose. ]
  AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.
  
  
• Nab-Paclitaxel Area Under the Curve (AUC) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, and 48 hours post dose. Cycle 2 Days 1 and 15: Pre-dose. ]
  AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.
  
  
• Palbociclib Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 2, 4, 6, 8, and 24 hours post dose; Cycle 2, Days 1 and 15: Pre-dose. ]
  
• Nab-Paclitaxel Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, and 48 hours post dose. Cycle 2 Days 1 and 15: Pre-dose. ]
  
• Palbociclib Plasma Decay Half-Life (t1/2) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 2, 4, 6, 8, and 24 hours post dose; Cycle 2 Days 1 and 15: Pre-dose. ]
  Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
  
  
• Nab-Paclitaxel Plasma Decay Half-Life (t1/2) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, and 48 hours post dose. Cycle 2 Days 1 and 15: Pre-dose. ]
  Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
  
  
• Palbociclib Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 2, 4, 6, 8, and 24 hours post dose; Cycle 2 Days 1 and 15: Pre-dose. ]
  
• Nab-Paclitaxel Time to Reach Maximum Observed Plasma Concentration (Tmax) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, and 48 hours post dose. Cycle 2 Days 1 and 15: Pre-dose. ]
  
• Palbociclib Apparent Oral Clearance (CL/F) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 2, 4, 6, 8, and 24 hours post dose; Cycle 2 Days 1 and 15: Pre-dose. ]
  Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
  
  
• Nab-Paclitaxel Apparent Oral Clearance (CL/F) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, and 48 hours post dose. Cycle 2 Days 1 and 15: Pre-dose. ]
  Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population pharmacokinetic (PK) modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
  
  
• Palbociclib Volume of Distribution at Steady State (Vss) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 2, 4, 6, 8, and 24 hours post dose; Cycle 2 Days 1 and 15: Pre-dose. ]
  Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.
  
  
• Nab-Paclitaxel Volume of Distribution at Steady State (Vss) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, and 48 hours post dose. Cycle 2 Days 1 and 15: Pre-dose. ]
  Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) is the apparent volume of distribution at steady-state.
  
  
• Palbociclib Systemic Clearance (CL) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 2, 4, 6, 8, and 24 hours post dose; Cycle 2 Days 1 and 15: Pre-dose. ]
  CL is a quantitative measure of the rate at which a drug substance is removed from the body.
  
  
• Nab-Paclitaxel Systemic Clearance (CL) [ Time Frame: Cycle 1 Day -2 and 13: Pre-dose, 30 minutes, 1, 2, 4, 6, 8, 24, and 48 hours post dose. Cycle 2 Days 1 and 15: Pre-dose. ]
  CL is a quantitative measure of the rate at which a drug substance is removed from the body.
  
  
• Blood CA 19-9 Levels [ Time Frame: Day 1 of each cycle for approximately 12 months ]
  CA 19-9 measures the level of tumor-associated antigens found in the blood. CA 19-9 antigens are foreign substances released by pancreatic tumor cells.
  
  
• Objective Response Rate - Percentage of Participants With Complete or Partial Response [ Time Frame: Baseline until approximately 12 months. ]
  Percentage of participants with objective response based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Measured from baseline until disease progression or death due to any cause.
  
  
• Duration of Response (DR) [ Time Frame: Baseline until approximately 12 months. ]
  Time in weeks/months from the first documentation of objective tumor response to objective tumor progression or death due to any cancer. Duration of tumor response is calculated as (the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR [which ever occurred first] that was subsequently confirmed plus 1) divided by 7 (or 30.44 if in months). DR was calculated for the subgroup of participants with a confirmed objective tumor response. DR is usually categorized by the median with its 95% Confidence Interval (CI), range and 25% and 75% percentiles.
  
  
• Progression-Free Survival (PFS) [ Time Frame: Baseline until approximately 12 months. ]
  The period from study entry until disease progression, death or date of last contact.
  
  
• Six-Month PFS Rate [ Time Frame: When last patient has been enrolled for 6 months. ]
  Percentage of patients who do not have progressive disease after 6 months on study.
  
  
• Overall Survival (OS) [ Time Frame: Baseline until approximately 13 months. ]
  Time in weeks or months from the start of study treatment to date of death due to any cause. OS is calculated as (the death date or last known alive date (if death date unavailable) minus the date of first dose of study medication plus 1 divided by 7 or 30.44 if in months.
  
  
• Tumor Tissue Biomarkers (p16 and Rb1 expression) [ Time Frame: Baseline and end of study treatment (approximately 9 months). ]
  Tumor tissue biomarkers (p16 and Rb1 expression by immunohistochemistry)
  
  

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.