Study Of Gemcitabine Plus AG-013736 Versus Gemcitabine For Advanced Pancreatic Cancer.

• ClinicalTrials.gov Identifier: NCT00471146
• Recruitment Status: Completed
• First Posted: May 9, 2007
• Results First Posted: July 16, 2012
• Last Update Posted: July 16, 2012
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: May 7, 2007
• First Posted Date: May 9, 2007
• Results First Submitted Date: February 25, 2012
• Results First Posted Date: July 16, 2012
• Last Update Posted Date: July 16, 2012
• Study Start Date: July 2007
• Actual Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 14, 2012)

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

Time in weeks from randomization to date of death due to any cause. OS was calculated as (the death date minus the date of randomization plus 1) divided by 7. 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: May 7, 2007): Overall survival is the primary endpoint. A total of 596 patients and 460 events are required for a log rank test to have an overall 1 sided significance level of 0.025 and power of 0.90.

Current Secondary Outcome Measures (submitted: June 14, 2012)

• Progression Free Survival (PFS) [ Time Frame: Baseline until disease progression or at least 1 year after the randomization of last participant ]
  Time in weeks from randomization to the first documentation of objective tumor progression or death due to any cause. PFS was calculated as = (first event date minus randomization date plus 1) divided by 7. 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").
• Percentage of Participants With Objective Response (OR) [ Time Frame: Baseline, every 8 weeks until tumor progression or death ]
  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 response were those that persisted on repeat imaging study at least 4 weeks after initial documentation of response. CR was defined as disappearance of all lesions (target and/or non target). PR were those with at least 30 percent decrease in sum of the longest dimensions of target lesions taking as a reference the baseline sum longest dimensions, with non target lesions not increased or absent.
• Duration of Response (DR) [ Time Frame: Baseline until death or at least 1 year after the randomization of last participant ]
  Time in weeks from the first documentation of objective tumor response to objective tumor progression or death due to any cause. 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) divided by 7.
• Change From Baseline in European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire Core-30 (EORTC QLQ- C30) Score [ Time Frame: Baseline, Day 1 (D1) of each cycle (C2-C13) up to 28 days after the last dose (follow-up) or early withdrawal ]
  EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status (GHS), 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 European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Pancreatic 26 (EORTC QLQ- PAN26) Score [ Time Frame: Baseline, Day 1 (D1) of each cycle (C2-C13) up to 28 days after the last dose (follow-up) or early withdrawal ]
  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= greater degree of symptoms or treatment side effects and emotional issues.
• Change From Baseline Brief Pain Inventory-short Form (BPI-sf) Score [ Time Frame: Baseline, Day 1 (D1) of each cycle (C2-C13) up to 28 days after the last dose (follow-up) or early withdrawal ]
  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.
• Change From Baseline in Euro QoL Questionnaire- 5 Dimension (EQ-5D) Health State Profile [ Time Frame: Baseline, Day 1 (D1) of each cycle (C2-C13) up to 28 days after the last dose (follow-up) or early withdrawal ]
  EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, anxiety and depression; 1 indicates better health state (no problems); 3 indicates worst health state (eg, "confined to bed"). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; higher score indicates a better health state.
• Change From Baseline in Euro QoL Questionnaire- 5 Dimension (EQ-5D) VAS Score [ Time Frame: Baseline, Day 1 (D1) of each cycle (C2-C13) up to 28 days after the last dose (follow-up) or early withdrawal ]
  EQ-5D: participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state.
• Population Pharmacokinetic (PK) Analysis for Axitinib (AG-013736) [ Time Frame: Day 1 (pre-dose), Day 29, Day 57 and then every 8 weeks up to 23 months ]
  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.

Original Secondary Outcome Measures (submitted: May 7, 2007)

• Progression free survival (the time from randomization to first documentation of objective tumor progression or to death due to any cause, whichever occurs first).
• Objective response rate (the proportion of patients with confirmed response according to RECIST, relative to all randomized patients who have baseline measurable disease).
• Duration of response (the time from the first documentation of objective tumor response to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first).
• Safety and tolerability of AG-013736 plus gemcitabine. All patients who receive any study treatment will be included in the final summaries and listings of safety data.
• Health-related quality of life, pain ratings, and health status of patients in each arm as measured by the Eur Org for the Res and Trtmnt of Cancer, Qual of Life Quest Core 30 and Pancreatic 26, BPI sf, and EQ 5D. [ Time Frame: Questionnaires will be completed prior to dosing and ideally before any clinical assessments. ]
• Population pharmacokinetic analysis using AG-013736 plasma concentrations.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study Of Gemcitabine Plus AG-013736 Versus Gemcitabine For Advanced Pancreatic Cancer.
• Official Title: A Randomized, Double-Blind Phase 3 Study Of Gemcitabine Plus AG-013736 Versus Gemcitabine Plus Placebo For The First-Line Treatment Of Patients With Locally Advanced, Unresectable Or Metastatic Pancreatic Cancer.
• Brief Summary: The purpose of this study is to determine whether investigational study drug, AG-013736, and gemcitabine are effective in the first-line treatment of advanced pancreatic cancer.
• Detailed Description: This study was prematurely discontinued for futility on 23 January 2009, based on a planned interim analysis by an independent Data Safety Monitoring Board (DSMB) that found no evidence of improvement in the primary endpoint (survival) in patients treated with axitinib and gemcitabine compared to gemcitabine alone. Enrollment on this study has been discontinued.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Carcinoma, Pancreatic Ductal

Intervention

• Drug: AG-013736
  oral administration, starting dose 5 mg twice daily [BID] every day until unacceptable toxicity or tumor progression.
• Drug: Gemcitabine
  intravenous administration at 1,000 mg/m^2 day 1, day 8 and day 15 every 4 weeks (conventional dose) until unacceptable toxicity or tumor progression.
• Drug: placebo
  placebo

Study Arms

• Experimental: A
  Interventions:

  • Drug: AG-013736
  • Drug: Gemcitabine
• Active Comparator: B
  Interventions:

  • Drug: Gemcitabine
  • Drug: placebo

• Publications *: Kindler HL, Ioka T, Richel DJ, Bennouna J, Letourneau R, Okusaka T, Funakoshi A, Furuse J, Park YS, Ohkawa S, Springett GM, Wasan HS, Trask PC, Bycott P, Ricart AD, Kim S, Van Cutsem E. Axitinib plus gemcitabine versus placebo plus gemcitabine in patients with advanced pancreatic adenocarcinoma: a double-blind randomised phase 3 study. Lancet Oncol. 2011 Mar;12(3):256-62. doi: 10.1016/S1470-2045(11)70004-3.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 1, 2011): 630
• Original Enrollment (submitted: May 7, 2007): 596
• Actual Study Completion Date: November 2010
• Actual Primary Completion Date: January 2009 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Histologically or cytologically confirmed, metastatic or locally-, advanced pancreatic adenocarcinoma not amenable to curative resection.
• Adequate renal, hepatic and bone marrow function.
• Performance status 0 or 1.

Exclusion Criteria:

• Prior treatment with any systemic chemotherapy for metastatic disease.
• Prior treatment with gemcitabine, AG-013736, or other vascular endothelial growth factor inhibitors.
• Current or recent bleeding, thromboembolic event and or use of a thrombolytic agent.
• Inability to take oral medication.

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: Argentina, Australia, Austria, Belgium, Canada, France, Germany, Hong Kong, Hungary, India, Ireland, Italy, Japan, Korea, Republic of, Netherlands, Russian Federation, Singapore, South Africa, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States
• Removed Location Countries: Portugal

Administrative Information

• NCT Number: NCT00471146
• Other Study ID Numbers: A4061028
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• 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: June 2012