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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Metastatic Pancreatic Ductal Adenocarcinoma	Drug: Palbociclib; Drug: Nab-Paclitaxel	Phase 1

Detailed Description:

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	100 participants
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	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
Actual Study Start Date :	November 23, 2015
Estimated Primary Completion Date :	June 19, 2018
Estimated Study Completion Date :	November 20, 2018

Arms and Interventions

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Arm	Intervention/treatment
Experimental: 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.	Drug: Palbociclib; Palbociclib oral dosing on Days 1 to 21 of each 28-day cycle.; Other Name: Ibrance Drug: Nab-Paclitaxel; Nab-paclitaxel IV dosing on Days -2, 6, and 13 of Cycle 1, and on Days 1, 8, and 15 of subsequent cycles.; Other Name: Abraxane

Outcome Measures

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Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. 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.
3. 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. ]
4. 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. ]
5. 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.
6. 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.
7. 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. ]
8. 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. ]
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. 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)

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Contacts and Locations

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Contacts

Contact: Pfizer CT.gov Call Center	1-800-718-1021	ClinicalTrials.gov_Inquiries@pfizer.com

Locations

United States, Arizona
Scottsdale Healthcare Hospitals DBA HonorHealth	Recruiting
Scottsdale, Arizona, United States, 85258
Virginia G. Piper Cancer Pharmacy	Recruiting
Scottsdale, Arizona, United States, 85258
United States, California
UC San Diego Medical Center - La Jolla (Thornton Hospital)	Active, not recruiting
La Jolla, California, United States, 92037-0845
UC San Diego Moores Cancer Center - Investigational Drug Services	Active, not recruiting
La Jolla, California, United States, 92037-0845
UC San Diego Moores Cancer Center	Active, not recruiting
La Jolla, California, United States, 92093
UC San Diego Medical Center - Hillcrest	Active, not recruiting
San Diego, California, United States, 92103
United States, Colorado
Drug Shipment Address: Anschutz Cancer Pavilion	Recruiting
Aurora, Colorado, United States, 80045
University of Colorado Cancer Center	Recruiting
Aurora, Colorado, United States, 80045
University of Colorado Denver, CTO (CTRC)	Recruiting
Aurora, Colorado, United States, 80045
University of Colorado Hospital - Anschutz Inpatient Pavilion (AIP)	Recruiting
Aurora, Colorado, United States, 80045
University of Colorado Hospital - Anschutz Outpatient Pavilion (AOP)	Recruiting
Aurora, Colorado, United States, 80045
United States, Maryland
Oncology Investigational Drug Services (Drug Shipment Only)	Active, not recruiting
Baltimore, Maryland, United States, 21231-2410
The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Active, not recruiting
Baltimore, Maryland, United States, 21231
Johns Hopkins Hospital	Active, not recruiting
Baltimore, Maryland, United States, 21287
United States, Massachusetts
Beth Israel Deaconess Medical Center	Recruiting
Boston, Massachusetts, United States, 02215
United States, Missouri
Siteman Cancer Center - West County	Recruiting
Creve Coeur, Missouri, United States, 63141
Barnes-Jewish Hospital	Recruiting
Saint Louis, Missouri, United States, 63110
Washington University Infusion Center Pharmacy	Recruiting
Saint Louis, Missouri, United States, 63110
Washington University School of Medicine	Recruiting
Saint Louis, Missouri, United States, 63110
Siteman Cancer Center - South County	Recruiting
Saint Louis, Missouri, United States, 63129
Siteman Cancer Center	Recruiting
Saint Peters, Missouri, United States, 63376
United States, Utah
University of Utah, Huntsman Cancer Hospital	Recruiting
Salt Lake City, Utah, United States, 84112
University of Utah, Huntsman Cancer Institute	Recruiting
Salt Lake City, Utah, United States, 84112
Spain
Hospital Universitario de Fuenlabrada. Unidad de Farmacia (Only Drug Shipment)	Recruiting
Fuenlabrada, Madrid, Spain, 28942
Hospital Universitario Fuenlabrada	Recruiting
Fuenlabrada, Madrid, Spain, 28942
Hospital Universitari Vall D'Hebron	Recruiting
Barcelona, Spain, 08035
Hospital Universitario 12 de Octubre Servicio de Farmacia	Recruiting
Madrid, Spain, 28041
Hospital Universitario 12 de Octubre	Recruiting
Madrid, Spain, 28041

Sponsors and Collaborators

Pfizer

Celgene

Investigators

Study Director:	Pfizer CT.gov Call Center	Pfizer

More Information

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Additional Information:

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Responsible Party:	Pfizer
ClinicalTrials.gov Identifier:	NCT02501902 History of Changes
Other Study ID Numbers:	A5481059; 2015-001307-31 ( EudraCT Number )
First Posted:	July 17, 2015
Last Update Posted:	April 17, 2018
Last Verified:	April 2018

Keywords provided by Pfizer:

Ibrance, palbociclib, Abraxane, nab-paclitaxel, pancreas,

Additional relevant MeSH terms:

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Paclitaxel; Palbociclib; Albumin-Bound Paclitaxel	Antineoplastic Agents, Phytogenic; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Molecular Mechanisms of Pharmacological Action; Protein Kinase Inhibitors; Enzyme Inhibitors