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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02109445
Recruitment Status : Terminated (The study was terminated on 24JUN15 due to change in strategy of PF-03084014 development.No safety/efficacy concerns were behind the reason of trial termination)
First Posted : April 9, 2014
Results First Posted : June 12, 2017
Last Update Posted : January 10, 2019
Sponsor:
Collaborator:
Academic GI Cancer Consortium (AGICC)
Information provided by (Responsible Party):
Pfizer

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Metastatic Cancer Pancreas Drug: PF-03084014 Drug: Gemcitabine Drug: Nab-paclitaxel Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 3 participants
Allocation: Randomized
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: PHASE 1/2 STUDY OF PF-03084014 IN COMBINATION WITH GEMCITABINE AND NAB-PACLITAXEL IN PATIENTS WITH PREVIOUSLY UNTREATED METASTATIC PANCREATIC DUCTAL ADENOCARCINOMA
Actual Study Start Date : September 3, 2014
Actual Primary Completion Date : November 6, 2014
Actual Study Completion Date : November 6, 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase 1
PF-03084014 in combination with gemcitabine and nab-paclitaxel
Drug: PF-03084014
Tablets, orally administered twice daily on a continuous dosing schedule in 28 days cycles. Doses: 100 -150 mg BID

Drug: Gemcitabine
Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 1000 mg/m2.

Drug: Nab-paclitaxel
Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 125 mg/m2.
Other Name: Abraxane

Experimental: Phase 2 Arm A
PF-03084014 in combination with gemcitabine and nab-paclitaxel
Drug: PF-03084014
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.

Drug: Gemcitabine
Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 1000 mg/m2.

Drug: Nab-paclitaxel
Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 125 mg/m2.
Other Name: Abraxane

Active Comparator: Phase 2 Arm B
Gemcitabine plus nab-Paclitaxel
Drug: Gemcitabine
Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 1000 mg/m2.

Drug: Nab-paclitaxel
Intravenously administered on Days 1, 8, 15 in 28 days cycles at the dose of 125 mg/m2.
Other Name: Abraxane




Primary Outcome Measures :
  1. Number of Participants With Dose-limiting Toxicities (DLTs) in Cycle 1 [ Time Frame: Cycle 1 (28 days) ]
    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.

  2. Overall Survival (OS) in Phase 2 [ Time Frame: From start of study treatment, collected every 3 months until death (up to 5 years) ]
    Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact.


Secondary Outcome Measures :
  1. Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 1 [ Time Frame: Baseline up to 28-35 days post last administration of study drug ]
    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.

  2. Number of Participants With Adverse Events (AEs) by Seriousness and Relationship to Treatment in Phase 2 [ Time Frame: Baseline up to 28-35 days post last administration of study drug ]
    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.

  3. Number of Participants With Laboratory Abnormalities in Phase 1 [ Time Frame: Screening; Cycle 1 Days 1, 8, 15, 22; up to 28-35 days post last administration of study drug ]
    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]).

  4. Number of Participants With Laboratory Abnormalities in Phase 2 [ Time Frame: Screening; Days 1, 8, 15 of each cycle; up to 28-35 days post last administration of study drug ]
    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]).

  5. Number of Participants With Clinically Significant Change From Baseline in Vital Signs at Phases 1 and 2 [ Time Frame: Baseline up to 28-35 days after treatment discontinuation ]
    Following parameters were analyzed for examination of vital signs: systolic and diastolic blood pressure, heart rate, weight and body surface area.

  6. Number of Participants With Worsening QTc Results in Phase 1 [ Time Frame: Screening, Cycle 1 Days 3 and 22, Cycles 2 and 3 Day 1, end of treatment ]
    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.

  7. Number of Participants With Worsening QTc Results in Phase 2 [ Time Frame: Screening, Cycle 1 Days 1 and 22, Cycles 2 and 3 Day 1, end of treatment ]
    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.

  8. Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 1 [ Time Frame: 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. ]
    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).

  9. Area Under the Concentration-time Curve (AUC) for PF-03084014, Nab-P and Gemcitabine in Phase 2 [ Time Frame: Cycle 1 Day 1 till end of last cycle ]
    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).

  10. Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 1 [ Time Frame: 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. ]
  11. Maximum Observed Plasma Concentration (Cmax) for PF-03084014, Nab-P and GEM in Phase 2 [ Time Frame: Cycle 1 Day 1 till end of last cycle ]
  12. Systemic Clearance (CL) of Nab-paclitaxel in Phase 1 [ Time Frame: Cycle 1 Days 1-3, and 15-17 ]
  13. Systemic Clearance (CL) of Gemcitabine in Phase 1 [ Time Frame: Cycle 1 Days 1 and 15 ]
  14. Systemic Clearance (CL) of PF-03084014, Nab-P and GEM in Phase 2 [ Time Frame: Cycle 1 Day 1 till end of last cycle ]
  15. Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 1 [ Time Frame: 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. ]
  16. Time to Reach Maximum Observed Plasma Concentration (Tmax) for PF-03084014, Nab-P and GEM in Phase 2 [ Time Frame: Cycle 1 Day 1 till end of last cycle ]
  17. Volume of Distribution at Steady State (Vss) for Nab-P and GEM in Phase 1 [ Time Frame: Cycle 1 (Days 1 and 15 for gemcitabine; Days 1-3 and 15-17 for nab-paclitaxel) ]
  18. Volume of Distribution at Steady State (Vss) for PF-03084014, Nab-P and GEM in Phase 2 [ Time Frame: Cycle 1 Day 1 till end of last cycle ]
  19. Plasma Decay Half-life (t1/2) for Nab-P and GEM in Phase 1 [ Time Frame: Cycle 1 (Days 1 and 15 for gemcitabine; Days 1-3 and 15-17 for nab-paclitaxel) ]
  20. Plasma Decay Half-life (t1/2) for PF-03084014, Nab-P and GEM in Phase 2 [ Time Frame: Cycle 1 Day 1 till end of last cycle ]
  21. Number of Participants With Objective Response (OR) in Phase 1 [ Time Frame: Screening till 28-35 days post last administration of study drug ]

    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.


  22. Number of Participants With Objective Response (OR) in Phase 2 [ Time Frame: Screening till 28-35 days post last administration of study drug ]

    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.


  23. Duration of Response (DR) for Phases 1 and 2 [ Time Frame: Baseline, every 8 weeks until disease progression or unacceptable toxicity (up to 5 years) ]
    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.

  24. 1-year and 2-year OS in Phase 2 [ Time Frame: From start of study treatment, collected every 3 months until death (up to 5 years) ]
    Overall survival was the duration from randomization to death. For participants who are alive, overall survival was censored at the last contact.

  25. Progression-free Survival (PFS) in Phase 2 [ Time Frame: From start of study treatment, collected every 3 months until death (up to 5 years) ]
    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.

  26. Brief Pain Inventory-Short Form (BPI-sf) Score - Phase 2 [ Time Frame: Day 1 of Cycle 1 and subsequent cycles; end of treatment ]
    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.

  27. Change From Baseline in European Quality of Life Questionnaire (EQ-5D) - Phase 2 [ Time Frame: Baseline till end of treatment ]
    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.

  28. European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire (EORTC QLQ-C30) - Phase 2 [ Time Frame: Baseline till end of treatment ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02109445


Locations
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United States, Colorado
Anschutz Inpatient Pavilion
Aurora, Colorado, United States, 80045
University of Colorado Cancer Center
Aurora, Colorado, United States, 80045
University of Colorado Denver, CTO (CTRC)
Aurora, Colorado, United States, 80045
United States, New York
University of Rochester Investigational Drug Pharmacy
Rochester, New York, United States, 14642
University of Rochester
Rochester, New York, United States, 14642
Sponsors and Collaborators
Pfizer
Academic GI Cancer Consortium (AGICC)
Investigators
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Study Director: Pfizer CT.gov Call Center Pfizer

Additional Information:
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Responsible Party: Pfizer
ClinicalTrials.gov Identifier: NCT02109445    
Other Study ID Numbers: A8641019
2013-005574-21 ( EudraCT Number )
First Posted: April 9, 2014    Key Record Dates
Results First Posted: June 12, 2017
Last Update Posted: January 10, 2019
Last Verified: December 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests
Additional relevant MeSH terms:
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Adenocarcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Gemcitabine
Paclitaxel
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs