Study Of PF-03084014 In Combination With Gemcitabine And Nab-Paclitaxel In Patients With Metastatic Pancreatic Adenocarcinoma Not Previously Treated With Anticancer Therapies

Study Overview
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Brief Summary
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This study consists of a Phase 1b portion aimed to determine the maximum tolerated dose and the safety profile of PF-03084014 in combination with gemcitabine and nab-paclitaxel followed by a Phase 2 portion to evaluate the efficacy of the triple combination in terms of overall survival in patients with metastatic pancreatic ductal adenocarcinoma not previously treated with anticancer therapies.

Official Title
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PHASE 1/2 STUDY OF PF-03084014 IN COMBINATION WITH GEMCITABINE AND NAB-PACLITAXEL IN PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA

Conditions
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Metastatic Cancer Pancreas

Intervention / Treatment
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* Drug: PF-03084014
* Drug: Gemcitabine
* Drug: Nab-paclitaxel
* Drug: PF-03084014
* Drug: Gemcitabine
* Drug: Nab-paclitaxel
* Drug: Gemcitabine
* Drug: Nab-paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically diagnosis of metastatic ductal adenocarcinoma of the pancreas. No prior radiotherapy, surgery chemotherapy or investigational therapy for metastatic disease. Prior adjuvant therapy with 5-FU or gemcitabine (± gemcitabine post radiation) administered as radiosensitizer allowed, provided at least 6 months have elapsed between the last dose and study registration Tumor tissue available (Archival 6 months old or de novo biopsy) Measurable disease as per RECIST 1.1 Performance Status (ECOG) 0 or 1 Exclusion Criteria: Symptomatic brain metastases requiring steroids Prior therapy with gamma secretase inhibitors or other Notch pathway inhibitor Major surgery within 4 weeks of registration in the current study Known hypersensitivity to gemcitabine or nab-paclitaxel or any of the excipients Current or anticipated need for food or drugs that are strong/moderate CYP3A4 inhibitors or inducers Diagnosis of any second malignancy within 3 years prior to registration

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
Allocation: Randomized
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1<br>PF-03084014 in combination with gemcitabine and nab-paclitaxel | Drug: PF-03084014<br>* Tablets, orally administered twice daily on a continuous dosing schedule in 28 days cycles. Doses: 100 -150 mg BID<br>Drug: Gemcitabine<br>* Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 1000 mg/m2.<br>Drug: Nab-paclitaxel<br>* Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 125 mg/m2.<br>* Other names: Abraxane;|
| Experimental: Phase 2 Arm A<br>PF-03084014 in combination with gemcitabine and nab-paclitaxel | Drug: PF-03084014<br>* Tablets, orally administered twice daily on a continuous dosing schedule in 28 days cycles. Phase 2 dose will be the recommended phase 2 dose defined in phase 1.<br>Drug: Gemcitabine<br>* Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 1000 mg/m2.<br>Drug: Nab-paclitaxel<br>* Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 125 mg/m2.<br>* Other names: Abraxane;|
| Active Comparator: Phase 2 Arm B<br>Gemcitabine plus nab-Paclitaxel | Drug: Gemcitabine<br>* Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 1000 mg/m2.<br>Drug: Nab-paclitaxel<br>* Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 125 mg/m2.<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 (DLTs) in Cycle 1 | DLT was defined as any of the following events occurring during the first cycle of treatment and considered at least possibly-related to study medication: any Grade 3 or 4 clinically-relevant non-hematologic and/or hematologic toxicity, delay of more than 2 weeks in receiving the next scheduled cycle due to persisting treatment-related toxicities. | Cycle 1 (28 days) | 
| Overall Survival (OS) in Phase 2 | Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact. | From start of study treatment, collected every 3 months until death (up to 5 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 1 | Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to study drug was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category. Severity was graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Grade 1=mild, Grade 2=moderate, Grade 3=Severe or medically significant but not immediately life-threatening, Grade 4=life-threatening. | Baseline up to 28-35 days post last administration of study drug | 
| Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 2 | Counts of participants who had treatment-emergent adverse events (TEAEs), defined as newly occurring or worsening after first dose. Relatedness to study drug was assessed by the investigator (Yes/No). Participants with multiple occurrences of an AE within a category were counted once within the category. Severity was graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE). Grade 1=mild, Grade 2=moderate, Grade 3=Severe or medically significant but not immediately life-threatening, Grade 4=life-threatening. | Baseline up to 28-35 days post last administration of study drug | 
| Number of Participants With Laboratory Abnormalities in Phase 1 | Following parameters were analyzed for laboratory examination: hematology (hemoglobin, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (urea, creatinine, glucose, calcium, sodium, potassium, chloride, magnesium, phosphate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid); urinalysis (protein, blood, microscopy[if urine tested positive for blood or protein]). | Screening; Cycle 1 Days 1, 8, 15, 22; up to 28-35 days post last administration of study drug | 
| Number of Participants With Laboratory Abnormalities in Phase 2 | Following parameters were analyzed for laboratory examination: hematology (hemoglobin, platelet count, white blood cell count, total neutrophils, eosinophils, monocytes, basophils, lymphocytes); blood chemistry (urea, creatinine, glucose, calcium, sodium, potassium, chloride, magnesium, phosphate, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, uric acid); urinalysis (protein, blood, microscopy[if urine tested positive for blood or protein]). | Screening; Days 1, 8, 15 of each cycle; up to 28-35 days post last administration of study drug | 
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs at Phases 1 and 2 | Following parameters were analyzed for examination of vital signs: systolic and diastolic blood pressure, heart rate, weight and body surface area. | Baseline up to 28-35 days after treatment discontinuation | 
| Number of Participants With Worsening QTc Results in Phase 1 | Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) were corrected for heart rate (QTc) using Fridericia (QTcF) and Bazett (QTcB) formulas. Any change from baseline in QTc was considered as worsening in ECG and was classified accordingly to the Common Terminology Criteria (CTC) grade. Grading was as follows: prolonged QTc of 450 to 480 milliseconds (msec)=Grade 1, 481 to 500 msec=Grade 2, more than or equal to (>=) 501 msec on at least 2 seperate ECGs=Grade 3, >=501 or more than (>) 60 msec change from baseline and Torsade de pointes or polymorphic ventricular tachycardia or signs of serious arrhythmia=Grade 4. | Screening, Cycle 1 Days 3 and 22, Cycles 2 and 3 Day 1, end of treatment | 
| Number of Participants With Worsening QTc Results in Phase 2 | Triplicate 12-lead electrocardiogram (ECG) measurements (each recording separated by approximately 2 minutes) were performed and average was calculated. The time corresponding to beginning of depolarization to repolarization of the ventricles (QT interval) were corrected for heart rate (QTc) using Fridericia (QTcF) and Bazett (QTcB) formulas. Any change from baseline in QTc was considered as worsening in ECG and was classified accordingly to the Common Terminology Criteria (CTC) grade. Grading was as follows: prolonged QTc of 450 to 480 milliseconds (msec)=Grade 1, 481 to 500 msec=Grade 2, more than or equal to (>=) 501 msec on at least 2 seperate ECGs=Grade 3, >=501 or more than (>) 60 msec change from baseline and Torsade de pointes or polymorphic ventricular tachycardia or signs of serious arrhythmia=Grade 4. | Screening, Cycle 1 Days 1 and 22, Cycles 2 and 3 Day 1, end of treatment | 
| Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 | AUC included AUC from time 0 extrapolated to infinite time (AUCinf), AUC from time 0 to end of dosing interval (AUCtau, tau=12 hours), and AUC from time 0 to last measured concentration (AUClast). | PF-03084014: Cycle 1 Days 3, 15, 22; Day 1 of subsequent cycles; and end of treatment. nab-P: Cycle 1 Days 1-3 and 15-17. Gemcitabine: Cycle 1 Days 1 and 15. | 
| Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 2 | AUC included AUC from time 0 extrapolated to infinite time (AUCinf), AUC from time 0 to end of dosing interval (AUCtau), and AUC from time 0 to last measured concentration (AUClast). | Cycle 1 Day 1 till end of last cycle | 
| Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 1 |  | PF-03084014: Cycle 1 Days 3, 15, 22; Day 1 of subsequent cycles; and end of treatment. nab-P: Cycle 1 Days 1-3 and 15-17. Gemcitabine: Cycle 1 Days 1 and 15. | 
| Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 2 |  | Cycle 1 Day 1 till end of last cycle | 
| Systemic Clearance (CL) of Nab-paclitaxel in Phase 1 |  | Cycle 1 Days 1-3, and 15-17 | 
| Systemic Clearance (CL) of Gemcitabine in Phase 1 |  | Cycle 1 Days 1 and 15 | 
| Systemic Clearance (CL) of PF-03084014, Nab-P and GEM in Phase 2 |  | Cycle 1 Day 1 till end of last cycle | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 1 |  | PF-03084014: Cycle 1 Days 3, 15, 22; Day 1 of subsequent cycles; and end of treatment. nab-P: Cycle 1 Days 1-3 and 15-17. Gemcitabine: Cycle 1 Days 1 and 15. | 
| Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 2 |  | Cycle 1 Day 1 till end of last cycle | 
| Volume of Distribution at Steady State (Vss) for Nab-P and GEM in Phase 1 |  | Cycle 1 (Days 1 and 15 for gemcitabine; Days 1-3 and 15-17 for nab-paclitaxel) | 
| Volume of Distribution at Steady State (Vss) for PF-03084014, Nab-P and GEM in Phase 2 |  | Cycle 1 Day 1 till end of last cycle | 
| Plasma Decay Half-life (t1/2) for Nab-P and GEM in Phase 1 |  | Cycle 1 (Days 1 and 15 for gemcitabine; Days 1-3 and 15-17 for nab-paclitaxel) | 
| Plasma Decay Half-life (t1/2) for PF-03084014, Nab-P and GEM in Phase 2 |  | Cycle 1 Day 1 till end of last cycle | 
| Number of Participants With Objective Response (OR) in Phase 1 | Number of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than (<) 10 mm). No new lesions. PR was defined as more than or equal to (>=) 30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. | Screening till 28-35 days post last administration of study drug | 
| Number of Participants With Objective Response (OR) in Phase 2 | Number of participants with objective response based on assessment of complete response (CR) or partial response (PR) according to Response Evaluation Criteria In Solid Tumors (RECIST). CR was defined as complete disappearance of all target lesions and non-target disease, with the exception of nodal disease. All nodes, both target and non-target, must decrease to normal (short axis less than (<) 10 mm). No new lesions. PR was defined as more than or equal to (>=) 30% decrease under baseline of the sum of diameters of all target lesions. The short axis was used in the sum for target nodes, while the longest diameter was used in the sum for all other target lesions. No unequivocal progression of non-target disease. No new lesions. | Screening till 28-35 days post last administration of study drug | 
| Duration of Response (DR) for Phases 1 and 2 | Duration of response (DR) defined as the difference in days between the first date criteria for progression occurred or the participant died due to any cause and the first date that criteria for a PR or CR were met. DR calculated as (months) = (progression/death date - first date of OR + 1) divided by 30.4. CR: disappearance of all target lesions. PR: at least 30% decrease in the sum of diameters of target lesions. | Baseline, every 8 weeks until disease progression or unacceptable toxicity (up to 5 years) | 
| 1-year and 2-year OS in Phase 2 | Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact. | From start of study treatment, collected every 3 months until death (up to 5 years) | 
| Progression-free Survival (PFS) in Phase 2 | PFS was defined as the time from the date of first dose to the date of the first documentation of objective tumor progression or death on study due to any cause, whichever occurred first. PFS (in months) was calculated as (first event date - date of randomization +1) divided by 30.4. | From start of study treatment, collected every 3 months until death (up to 5 years) | 
| Brief Pain Inventory-Short Form (BPI-sf) Score - Phase 2 | BPI-sf is an 11-item self-report questionnaire that is designed to assess the severity and impact of pain on daily functions. BPI-sf are 4 questions that assess pain intensity (worst, least, average, right now) and 7 questions that assess impact of pain on daily functions (general activity, mood, walking ability, normal work, relations with other people, sleep, enjoyment of life). Each question is answered on a scale ranging from 0 to 10; '0=No pain and 10=Pain as bad as you can imagine'. Measure can be scored by item, with lower scores being indicative of less pain or pain interference. | Day 1 of Cycle 1 and subsequent cycles; end of treatment | 
| Change From Baseline in European Quality of Life Questionnaire (EQ-5D) - Phase 2 | EQ-5D: 6-item participant rated questionnaire to assess health-related quality of life in terms of a single utility score. There were 2 components: a Health State Profile and a Visual Analog Scale. Published weights are available that allow for the creation of a single summary score. Overall scores range from 0-1, with low scores representing a higher level of dysfunction. | Baseline till end of treatment | 
| European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire (EORTC QLQ-C30) - Phase 2 | EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). Most questions used 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale (1 'very poor' to 7 'Excellent'). Scores averaged, transformed to 0-100 scale; higher score=better level of functioning or greater degree of symptoms. | Baseline till end of treatment |