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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Metastatic Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: Palbociclib
* Drug: Nab-Paclitaxel


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palbociclib + Nab-Paclitaxel<br>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<br>* Palbociclib oral dosing on Days 1 to 21 of each 28-day cycle.<br>* Other names: Ibrance;Drug: Nab-Paclitaxel<br>* Nab-paclitaxel IV dosing on Days -2, 6, and 13 of Cycle 1, and on Days 1, 8, and 15 of subsequent cycles.<br>* Other names: Abraxane;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities | 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. | From Day 1 until pre-dose Cycle 2 Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | An AE was any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An serious AE (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening; initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. Treatment-emergent AEs were those with initial onset or increasing in severity after the first dose of investigational product. Disease progression was not considered a treatment emergent AE unless the participant died of disease prior to 28 days after discontinuation of treatment. Treatment emergent AEs with cause possibly, probably or definitely related to treatment, as judged by the investigator, were defined as treatment-related AEs. AEs were graded by investigator according to CTCAE v4.03. | 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 Laboratory Abnormalities | The number of participants with following laboratory abnormalities meeting any of the Grades 1 to 4 classified according to NCI CTCAE v4.0 were summarized: hematology (anemia, hemoglobin increased, lymphocyte count increased, lymphopenia, neutrophils, platelets and white blood cells) and chemistry laboratory tests (alanine aminotransferase, alkaline phosphatase, amylase, aspartate aminotransferase, bilirubin, creatinine, hypercalcemia, hyperglocemia, hyperkalemia, hypermagnesemia, hypernatremia, hypoalbuminemia, hypocalcemia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, lipase). | From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product). | 
| Number of Participants With Vital Signs Data Meeting Pre-specified Criteria | Vital signs evaluation included sitting diastolic blood pressure (DBP), systolic blood pressure (SBP), and pulse rate. Suggest text: Vital signs categorical summary included: 1)SBP>150mmHg or DBP>100mmHg; 2)SBP>200mmHg or DBP>110mmHg; 3)SBP increase >=20 and <40mmHg; 4)SBP increase >=40 and <60mmHg; 5)SBP increase>=60mmHg; 6)DBP increase >=10 and <20mmHg; 7)DBP increase >=20 and <30mmHg; 8)DBP increase >=30mmHg; 9)pulse rate>120bpm; 10)pulse rate<50bpm. | 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 | Carbohydrate antigen 19-9 (Ca19-9) is a clinical pharmacodynamic (PD) marker associated with metastatic pancreatic ductal adenocarcinoma (mPDAC). | From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product). | 
| Number of Participants With 50% Maximum Reduction From Baseline in Ca19-9 | Ca19-9 is a clinical PD marker associated with metastatic mPDAC. | From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product). | 
| Number of Participants With 70% Maximum Reduction From Baseline in Ca19-9 | Ca19-9 is a clinical PD marker associated with metastatic mPDAC. | 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 | Ca19-9 is a clinical PD marker associated with metastatic mPDAC. | From screening to the end of treatment/withdrawal visit (up to 63 days from last dose of investigational product). | 
| Objective Response Rate | Percentage of participants who achieved objective response (OR) based on investigator assessment is presented. OR is defined as a complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Objective response rate (ORR) was defined as the percentage of participants with a best overall response of CR or PR relative to all anti-tumor evaluable participants. | From screening to 365 days from the last dose of investigational product | 
| Duration of Response | The duration of response was defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurred first. Disease progression was defined as 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed, with a minimum absolute increase of 5 mm. | From screening to 365 days from the last dose of investigational product | 
| Progression Free Survival | The progression free survival (PFS) was defined as the time from the date of first dose to the date of the first documentation of objective tumor progression as per RECIST v1.1 or death due to any cause in the absence of documented progression disease, whichever occurred first. | From screening to 365 days from the last dose of investigational product | 
| Six-month Progression-free Survival Rate (6m-PFSR) | 6m-PFS was defined as PFS status (progression free and alive, or not) at Month 6. It was summarized as a product limit estimator based on the Kaplan-Meier method to account for censored events. | From screening to 6 months after first dose of investigational product | 
| Overall Survival (OS) | OS was defined as the time from the date of first dose to the date of death due to any cause. Following the end of treatment visit, survival status was collected in all participants every month until 12 months (365 days) had elapsed from the last dose of investigational product. | From screening to 365 days from the last dose of investigational product | 
| Number of Participants With Positive p16 | p16 is a tumor suppressor protein which plays an important role in cell cycle regulation. The analysis of biomarker p16 expression might aid in the identification of patient subpopulations most likely to benefit from treatment. The results from p16 expression testing by immunohistochemistry (IHC) was used for sensitivity analyses. (a) and (b) :p16 cutoff utilizing the optimal cut point identified by the ORC analysis for the OS (a) or PFS (b) and the p16 positive tumor cells. | From Day-2 to up to 63 days from last dose of investigational product | 
| Retinoblastoma Protein (Rb) Percent Positive Cell (Nuclear Staining) | Rb is a tumor suppressor protein that is dysfunctional in several major cancers. The results from Rb expression testing by IHC was used for sensitivity analyses. | From Day-2 to up to 63 days from last dose of investigational product | 
| Rb H-score Nuclear Staining | Rb is a tumor suppressor protein that is dysfunctional in several major cancers. The results from Rb expression testing by IHC was used for sensitivity analyses. The H-score is a method of assessing the extent of nuclear immunoreactivity, applicable to steroid receptors. The score is obtained by the formula: 3*percentage of strongly staining nuclei + 2*percentage of moderately staining nuclei + percentage of weakly staining nuclei, giving the range of 0 to 300 | From Day-2 to up to 63 days from last dose of investigational product | 
| Palbociclib Multiple Dose Maximum Plasma Concentration (Cmax) | The palbociclib multiple dose maximum plasma concentration(Cmax) was observed directly from data. | 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 Time for Cmax (Tmax) | The palbociclib multiple dose time for Cmax (Tmax) was observed directly from data. | 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) | The palbociclib area under the plasma concentration-time curve for dosing interval τ (AUCτ) was observed directly from data. | 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 Trough Plasma Concentration(Ctrough) | The palbociclib multiple dose trough plasma concentration (Ctrough) was observed directly from data. | 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) | The palbociclib multiple dose apparent clearance (CL/F) was observed directly from data. | 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 | The nab-P Cmax on Cycle 1 Day -1 and Day 13 were observed directly from data. | 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 | The nab-P Tmax on Day -1 and Day 13 were observed directly from data. | 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 Area Under the Plasma Concentration-time Curve From Time 0 to Last Quantifiable Concentration (AUClast) | The nab-P area under the plasma concentration-time curve from time 0 to last quantifiable concentration (AUClast) on Day -1 and Day 13 were observed directly from data. | 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 Area Under the Plasma Concentration-time Curve From Time 0 Extrapolated to Infinite Time (AUCinf) | The nab-P area under the plasma concentration-time curve from time 0 extrapolated to infinite time (AUCinf) on Day -1 and Day 13 observed directly from data. | 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) | The nab-P t1/2 on Day -1 and Day 13 were observed directly from data. | 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) | The nab-P clearance on Day -1 and Day 13 were observed directly from data. | 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) | The nab-P on Day -1 and Day 13 were observed directly from data. | 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ibrance, palbociclib, Abraxane, nab-paclitaxel, pancreas,