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

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

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.

Study Overview

• Status: Completed
• Conditions: Pancreatic Neoplasms
• Intervention / Treatment: Drug: Gemcitabine; Drug: Gemcitabine; Drug: AG-013736

• Study Type: Interventional
• Enrollment (Actual): 111
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Gent, Belgium, 9000
    • Universitair Ziekenhuis Gent/Dienst Gastroenterologie
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
    • Winnipeg, Manitoba, Canada, R2H 2A6
      • Cancer Care Manitoba
  • Ontario
    • Sault Ste Marie, Ontario, Canada, P6A 2C4
      • Sault Area Hospital
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2X 3J4
      • CHUM, Hopital Saint-Luc
• France
  • Marseille, France, 13005
    • Hôpital La Timone
  • Paris Cedex 13, France, 75651
    • Hopital de La Pitie Salpetriere
  • Toulouse, France, 31052
    • Institut Claudius Regaud
  • Saint Herblain Cedex
    • Saint-Herblain, Saint Herblain Cedex, France, 44805
      • Service Oncologie Medicale
• Germany
  • Berlin, Germany, 13353
    • Medizinische Klinik mit Schwerpunkt Haematologie und Onkologie, Charité-Universitaetsmedizin Berlin
• Italy
  • Milano, Italy, 20133
    • Fondazione IRCCS, Istituto Nazionale Tumori, Oncologia Medica B
  • Roma, Italy, 00168
    • Unita Operativa, Oncologia Medica, Istituto di Medicina Interna e Geriatria
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clinic i Provincial de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d´Hebron
  • Sevilla, Spain, 41013
    • Hospital Universitario Virgen Del Rocio
• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XU
    • Western General Hospitals Nhs Trust
  • London, United Kingdom, W12 OHS
    • Hammersmith Hospital
  • Hampshire
    • Southampton, Hampshire, United Kingdom, SO16 6YD
      • Cancer Research UK Clinical Centre
  • Leicestershire
    • Leicester, Leicestershire, United Kingdom, LE1 5WW
      • Department of Cancer Studies & Molecular Medicine
• United States
  • California
    • Antioch, California, United States, 94509
      • East Bay Medical Oncology/Hematology Medical Associates Inc.
    • Berkeley, California, United States, 94704
      • Alta Bates Comprehensive Cancer Center
    • Concord, California, United States, 94520
      • Bay Area Cancer Research Group
    • Concord, California, United States, 94520
      • East Bay Medical Oncology/Hematology Medical Associates, Inc.
  • Connecticut
    • Stamford, Connecticut, United States, 06902-3628
      • Hematology Oncology, P.C.
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami Hospital & Clinics
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital & Clinics
    • Tampa, Florida, United States, 33612-9497
      • H Lee Moffitt Cancer Center & Research Institute
  • Maine
    • Biddeford, Maine, United States, 04005
      • Maine Center for Cancer Medicine and Blood Disorders
    • Brunswick, Maine, United States, 04011
      • Maine Center for Cancer Medicine and Blood Disorders
    • Scarborough, Maine, United States, 04074
      • Maine Center for Cancer Medicine and Blood Disorders
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Arch Medical Services, Inc. d/b/a The Center for Cancer Care and Research
    • Washington, Missouri, United States, 63090
      • Arch Medical Services, Inc. d/b/a The Center for Cancer Care and Research
  • Nebraska
    • Lincoln, Nebraska, United States, 68510
      • Southeast Nebraska Cancer Center, Southeast Nebraska Hematology and Oncology Consultants, P.C.
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
      • Piedmont Hematology Oncology Association
    • Winston-Salem, North Carolina, United States, 27292
      • Piedmont Hematology Oncology Associates
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Hospital and Clinics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Gemcitabine	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: Gemcitabine; Gemcitabine 1000 mg/m^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.
Experimental: Axitinib [AG-013736] plus gemcitabine	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: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	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).	Baseline of Phase 2 to death or until at least 1 year after the randomization of the last participant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Confirmation of Axitinib (AG-013736) on Basis of Number of Participants With Dose Limiting Toxicity (DLT)	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.	Phase 1 baseline up to Week 4
Dose Confirmation of Gemcitabine on Basis of Number of Participants With Dose Limiting Toxicity (DLT)	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.	Phase 1 Baseline up to Week 4
Maximum Observed Plasma Concentration (Cmax) for Axitinib (AG-013736)		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)	AUC (0-24) = Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to 24 hours (0-24).	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
Time to Reach Maximum Observed Plasma Concentration (Tmax) of Axitinib (AG-013736)	Tmax was based on the actual time points when the samples were collected.	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 (t1/2) of Axitinib (AG-013736)	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	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
Maximum Observed Plasma Concentration (Cmax) of Gemcitabine		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	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 - ∞).	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 (t1/2) of Gemcitabine	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.	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
Population Pharmacokinetics of Axitinib (AG-013736) in Phase 2	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.	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
Percentage of Participants With Overall Response (OR)	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.	Phase 2 baseline to disease progression or discontinuation from study, assessed every 8 weeks up to 80 weeks
Duration of Response (DR)	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.	Phase 2 baseline to disease progression or discontinuation from study due to any cause, assessed every 8 weeks up to 80 weeks
Progression-free Survival (PFS)	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").	Phase 2 baseline until the date of first documented progression or death due to any cause, assessed every 8 weeks up to 80 weeks
One Year Survival Probability	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.	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
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	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.	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).
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	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.	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).

Collaborators and Investigators

• Sponsor: Pfizer

Publications and helpful links

General 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.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2005
• Primary Completion (Actual): March 14, 2008
• Study Completion (Actual): March 14, 2008

Study Registration Dates

• First Submitted: September 13, 2005
• First Submitted That Met QC Criteria: September 13, 2005
• First Posted (Estimate): September 22, 2005

Study Record Updates

• Last Update Posted (Actual): May 14, 2019
• Last Update Submitted That Met QC Criteria: April 22, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: Randomized Phase 2 Study of AG-013736 in Combination with Gemcitabine versus Gemcitabine Alone in Advanced Pancreatic Cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Endocrine System Diseases; Digestive System Neoplasms; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Gemcitabine; Axitinib
• Other Study ID Numbers: A4061016; 2005-000053-30 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.