Clinical trial NCT02501902: Dose-Escalation Study Of Palbociclib + Nab-Paclitaxel In mPDAC
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Metastatic Pancreatic Ductal Adenocarcinoma
Keywords: Ibrance, palbociclib, Abraxane, nab-paclitaxel, pancreas,
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
Collaborators: name: Celgene
First posted: 2015-07-17
Enrollment: 76
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities
timeFrame: From Day 1 until pre-dose Cycle 2 Day 1
Secondary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: 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
measure: Number of Participants With Laboratory Abnormalities
timeFrame: From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product).
measure: Number of Participants With Vital Signs Data Meeting Pre-specified Criteria
timeFrame: From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product).
measure: Number of Participants With 20% Maximum Reduction From Baseline in Ca19-9
timeFrame: From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product).
measure: Number of Participants With 50% Maximum Reduction From Baseline in Ca19-9
timeFrame: From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product).
measure: Number of Participants With 70% Maximum Reduction From Baseline in Ca19-9
timeFrame: From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product).
measure: Number of Participants With 90% Maximum Reduction From Baseline in Ca19-9
timeFrame: From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product).
measure: Objective Response Rate
timeFrame: From screening to 365 days from the last dose of investigational product
measure: Duration of Response
timeFrame: From screening to 365 days from the last dose of investigational product
measure: Progression Free Survival
timeFrame: From screening to 365 days from the last dose of investigational product
measure: Six-month Progression-free Survival Rate (6m-PFSR)
timeFrame: From screening to 6 months after first dose of investigational product
measure: Overall Survival (OS)
timeFrame: From screening to 365 days from the last dose of investigational product
measure: Number of Participants With Positive p16
timeFrame: From Day-2 to up to 63 days from last dose of investigational product
measure: Retinoblastoma Protein (Rb) Percent Positive Cell (Nuclear Staining)
timeFrame: From Day-2 to up to 63 days from last dose of investigational product
measure: Rb H-score Nuclear Staining
timeFrame: From Day-2 to up to 63 days from last dose of investigational product
measure: Palbociclib Multiple Dose Maximum Plasma Concentration (Cmax)
timeFrame: 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.
measure: Palbociclib Multiple Dose Time for Cmax (Tmax)
timeFrame: 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.
measure: Palbociclib Area Under the Plasma Concentration-time Curve for Dosing Interval τ (AUCτ)
timeFrame: 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.
measure: Palbociclib Multiple Dose Trough Plasma Concentration(Ctrough)
timeFrame: 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.
measure: Palbociclib Multiple Dose Apparent Clearance (CL/F)
timeFrame: 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.
measure: Nab-P Cmax
timeFrame: 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.
measure: Nab-P Tmax
timeFrame: 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.
measure: Nab-P Area Under the Plasma Concentration-time Curve From Time 0 to Last Quantifiable Concentration (AUClast)
timeFrame: 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.
measure: Nab-P Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinite Time (AUCinf)
timeFrame: 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.
measure: Nab-P Terminal Plasma Elimination Half-life (t1/2)
timeFrame: 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.
measure: Nab-P Clearance (CL)
timeFrame: 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.
measure: Nab-P Volume of Distribution (Vz)
timeFrame: 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.
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Scottsdale Healthcare Hospitals DBA HonorHealth
state: Arizona
city: Scottsdale
country: United States
facility: Virginia G. Piper Cancer Pharmacy
state: Arizona
city: La Jolla
country: United States
facility: UC San Diego Medical Center - La Jolla (Thornton Hospital)
state: California
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center - Investigational Drug Services
state: California
city: La Jolla
country: United States
facility: UC San Diego Moores Cancer Center
state: California
city: San Diego
country: United States
facility: UC San Diego Medical Center - Hillcrest
state: California
city: Aurora
country: United States
facility: Anschutz Cancer Pavilion
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Denver, CTO (CTRC)
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital - Anschutz Inpatient Pavilion (AIP)
state: Colorado
city: Aurora
country: United States
facility: University of Colorado Hospital - Anschutz Outpatient Pavilion (AOP)
state: Colorado
city: Baltimore
country: United States
facility: The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Medical Center
state: Massachusetts
city: Creve Coeur
country: United States
facility: Siteman Cancer Center - West County
state: Missouri
city: Saint Louis
country: United States
facility: Barnes-Jewish Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University Infusion Center Pharmacy
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center - South County
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center
state: Missouri
city: Salt Lake City
country: United States
facility: University of Utah, Huntsman Cancer Hospital
state: Utah
city: Salt Lake City
country: United States
facility: University of Utah, Huntsman Cancer Institute
state: Utah
city: Fuenlabrada
country: Spain
facility: Hospital Universitario de Fuenlabrada. Unidad de Farmacia
state: Madrid
city: Fuenlabrada
country: Spain
facility: Hospital Universitario Fuenlabrada
state: Madrid
city: Barcelona
country: Spain
facility: Hospital Universitari Vall D'Hebron, Servicio de Oncología Médica
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre Servicio de Farmacia
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References: