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