AG-013736 In Combination With Gemcitabine Versus Gemcitabine Alone For Patients With Metastatic Pancreatic Cancer

• ClinicalTrials.gov Identifier: NCT00219557
• Recruitment Status: Completed
• First Posted: September 22, 2005
• Results First Posted: August 24, 2012
• Last Update Posted: May 14, 2019
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: September 13, 2005
• First Posted Date: September 22, 2005
• Results First Submitted Date: February 25, 2012
• Results First Posted Date: August 24, 2012
• Last Update Posted Date: May 14, 2019
• Actual Study Start Date: July 5, 2005
• Actual Primary Completion Date: March 14, 2008 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 22, 2019)

Overall Survival (OS) [ Time Frame: Baseline of Phase 2 to death or until at least 1 year after the randomization of the last participant ]

Time in days from randomization to date of death due to any cause. OS was calculated as the death date minus the date of randomization plus 1. Death was determined from adverse event data (where outcome was death) or from follow-up contact data (where the participant current status was death).

• Original Primary Outcome Measures (submitted: September 13, 2005): determine whether the overall survival of the combination of AG 013736 and gemcitabine is superior to that of gemcitabine alone in patients who have advanced pancreatic cancer that has not been previously treated with systemic therapy.

Current Secondary Outcome Measures (submitted: April 22, 2019)

• Dose Confirmation of Axitinib (AG-013736) on Basis of Number of Participants With Dose Limiting Toxicity (DLT) [ Time Frame: Phase 1 baseline up to Week 4 ]
  Dose of axitinib (AG-013736) was confirmed if not more than 1 out of 6 participants experienced a DLT during first cycle. DLT included grade (Gr) 4 neutropenia or thrombocytopenia, greater than or equal to (>=) Gr 3 anemia or non hematological toxicities for >= 7 days (except alopecia) or >= Gr 1 hemoptysis or >=2 gram /24 hours proteinuria or inability to resume background chemotherapy or axitinib (AG-013736) dosing within 14 days of stopping due to treatment related toxicity.
• Dose Confirmation of Gemcitabine on Basis of Number of Participants With Dose Limiting Toxicity (DLT) [ Time Frame: Phase 1 Baseline up to Week 4 ]
  Dose of gemcitabine was confirmed if not more than 1 out of 6 participants experienced a DLT during first cycle. DLT included grade (Gr) 4 neutropenia or thrombocytopenia, greater than or equal to (>=) Gr 3 anemia or non hematological toxicities for >= 7 days (except alopecia) or >= Gr 1 hemoptysis or >=2 gram /24 hours proteinuria or inability to resume background chemotherapy or axitinib (AG-013736) dosing within 14 days of stopping due to treatment related toxicity.
• Maximum Observed Plasma Concentration (Cmax) for Axitinib (AG-013736) [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3.5, 4.5, 9.5, and 12.5 hours (hr) post-dose on Day 15 of Phase 1 Cycle 1 ]
• Area Under the Curve From Time Zero to 24 Hours [AUC (0-24)] of Axitinib (AG-013736) [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3.5, 4.5, 9.5, and 12.5 hr post-dose on Day 15 of Phase 1 Cycle 1 ]
  AUC (0-24) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to 24 hours (0-24).
• Time to Reach Maximum Observed Plasma Concentration (Tmax) of Axitinib (AG-013736) [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3.5, 4.5, 9.5, and 12.5 hr post-dose on Day 15 of Phase 1 Cycle 1 ]
  Tmax was based on the actual time points when the samples were collected.
• Plasma Decay Half-life (t1/2) of Axitinib (AG-013736) [ Time Frame: 0 (pre-dose), 0.5, 1, 1.5, 2, 3.5, 4.5, 9.5, and 12.5 hr post-dose on Day 15 of Phase 1 Cycle 1 ]
  Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
• Maximum Observed Plasma Concentration (Cmax) of Gemcitabine [ Time Frame: 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 9 and 12 hr after start of infusion on Day 15 of Phase 1 Cycle 1 ]
• Area Under the Curve From Time Zero to Extrapolated Infinite Time [AUC (0 - ∞)] of Gemcitabine [ Time Frame: 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 9 and 12 hr after start of infusion on Day 15 of Phase 1 Cycle 1 ]
  AUC (0 - ∞) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞). It is obtained from AUC (0 - t) plus AUC (t - ∞).
• Plasma Decay Half-life (t1/2) of Gemcitabine [ Time Frame: 0 (pre-dose), 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 9 and 12 hr after start of infusion on Day 15 of Phase 1 Cycle 1 ]
  Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
• Population Pharmacokinetics of Axitinib (AG-013736) in Phase 2 [ Time Frame: Phase 2 Day 1 (Pre-dose), Day 29, Day 57 and then every 8 weeks until disease progression or discontinuation from study or up to 80 weeks ]
  Data for this outcome measure are not reported here because the analysis population includes participants who were not enrolled in this study. ClinicalTrials.gov is designed for reporting results from only those participants who were enrolled in the study and described in the Participant Flow and Baseline Characteristics modules.
• Percentage of Participants With Overall Response (OR) [ Time Frame: Phase 2 baseline to disease progression or discontinuation from study, assessed every 8 weeks up to 80 weeks ]
  Percentage of participants with OR based assessment of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumors (RECIST). Confirmed responses are those that persist on repeat imaging study at least 4 weeks after initial documentation of response. CR are defined as the disappearance of all lesions (target and/or non-target). PR are those with at least 30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum of longest dimensions.
• Duration of Response (DR) [ Time Frame: Phase 2 baseline to disease progression or discontinuation from study due to any cause, assessed every 8 weeks up to 80 weeks ]
  Time in days from the first documentation of objective tumor response to objective tumor progression or death due to any cancer. Duration of tumor response was calculated as the date of the first documentation of objective tumor progression or death due to cancer minus the date of the first CR or PR that was subsequently confirmed plus 1. DR was calculated for the subgroup of participants with a confirmed objective tumor response.
• Progression-free Survival (PFS) [ Time Frame: Phase 2 baseline until the date of first documented progression or death due to any cause, assessed every 8 weeks up to 80 weeks ]
  Time in days from randomization to first documentation of objective tumor progression or death due to any cause. PFS was calculated as first event date minus the date of randomization plus 1. Tumor progression was determined from oncologic assessment data (where data meet the criteria for progressive disease [PD]), or from adverse event (AE) data (where the outcome was "Death").
• One Year Survival Probability [ Time Frame: Phase 2 baseline to disease progression or death due to any cause or at least 1 year after the first dose for the last participant ]
  One year survival probability was defined as the probability of survival at one year after the date of randomization based on the Kaplan Meier estimate.
• Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) Score at Day 1 of Every Cycle and End of Study [ Time Frame: Phase 2 baseline [Day (D)1 of Cycle (C)1], Day 1 of all subsequent cycles up to Cycle 14 and end of study (EoS). ]
  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. Change from baseline=Cycle/Day score minus baseline score.
• Change From Baseline in 26-item Pancreatic Cancer-specific Quality of Life Questionnaire (QLQ-PAN26) Score at Day 1 of Every Cycle and End of Study [ Time Frame: Phase 2 baseline [Day (D) 1 of Cycle (C)1], Day 1 of all subsequent cycles up to Cycle 14 and end of study (EoS). ]
  QLQ-PAN26 consists of 26 questions (Qs) relating to disease symptoms, treatment (Tx) side effects and emotional issues specific to pancreatic cancer (PC). Questions include on altered bowel habits, pain, dietary changes, disease and Tx-related symptoms and issues related to the emotional and social well-being of participants with PC. All 26 Qs are answered on 4-point Likert scale ranging from '1=not at all' to 4='very much' and subsequently transformed into scales that range from 0-100. Higher scores on functioning scales=better functioning; higher scores on the symptom scales=more symptoms.

• Original Secondary Outcome Measures (submitted: September 13, 2005): determine the adverse event profile and dose limiting toxicities for the combination; evaluate population pharmacokinetics of AG 013736; determine the response rate and duration of response in patients who have measurable disease at baseline
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: AG-013736 In Combination With Gemcitabine Versus Gemcitabine Alone For Patients With Metastatic Pancreatic Cancer
• Official Title: A RANDOMIZED PHASE 2 STUDY OF THE ANTI-ANGIOGENESIS AGENT AG-013736 IN COMBINATION WITH GEMCITABINE IN PATIENTS WITH CHEMOTHERAPY-NAIVE ADVANCED PANCREATIC CANCER PRECEDED BY A PHASE 1 PORTION
• Brief Summary: This is a Phase 2 study being conducted at multiple centers in the United States, Europe and Canada. Patients having pancreatic cancer that is locally advanced or that has spread to other parts of the body (i.e., metastatic) are eligible to participate. Patients must have not had any prior systemic treatment for advanced disease. The purpose of the study is to test whether the angiogenesis inhibitor Axitinib [AG-013736] in combination with gemcitabine is an effective treatment for advanced pancreatic cancer vs. gemcitabine alone by overall survival.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Pancreatic Neoplasms

Intervention

• Drug: Gemcitabine
  Gemcitabine 1000 mg/m^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks
• Drug: AG-013736
  Axitinib (AG-013736) 5 mg tablet orally BID starting from Day 1 of Cycle 1, in cycles of 4 weeks.
• Drug: Gemcitabine
  Gemcitabine 1000 mg/m^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.

Study Arms

• Active Comparator: Gemcitabine
  Intervention: Drug: Gemcitabine
• Experimental: Axitinib [AG-013736] plus gemcitabine
  Interventions:

  • Drug: AG-013736
  • Drug: Gemcitabine

• Publications *: Spano JP, Chodkiewicz C, Maurel J, Wong R, Wasan H, Barone C, Letourneau R, Bajetta E, Pithavala Y, Bycott P, Trask P, Liau K, Ricart AD, Kim S, Rixe O. Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study. Lancet. 2008 Jun 21;371(9630):2101-8. doi: 10.1016/S0140-6736(08)60661-3. Epub 2008 May 29.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 16, 2012): 111
• Original Enrollment (submitted: September 13, 2005): 102
• Actual Study Completion Date: March 14, 2008
• Actual Primary Completion Date: March 14, 2008 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• patients with advanced (localized but surgically unresectable or metastatic) histologically/cytologically proven epithelial cancer of the exocrine pancreas
• no prior therapy for metastatic disease

Exclusion Criteria:

• patients with locally advanced disease who are candidates for radiation therapy.
• uncontrolled brain metastases (a controlled brain metastasis must be previously treated, asymptomatic, and without growth for 4 months)

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Canada, France, Germany, Italy, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT00219557
• Other Study ID Numbers: A4061016; 2005-000053-30 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

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

• Current Responsible Party: Pfizer
• Original Responsible Party: Not Provided
• Current Study Sponsor: Pfizer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Pfizer CT.gov Call Center; Pfizer

• PRS Account: Pfizer
• Verification Date: April 2019