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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Pfizer
ClinicalTrials.gov Identifier:
NCT00219557
First received: September 13, 2005
Last updated: July 23, 2012
Last verified: July 2012
Results First Received: February 25, 2012  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Pancreatic Neoplasms
Interventions: Drug: Gemcitabine
Drug: AG-013736

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
No text entered.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Axitinib + Gemcitabine (Phase 1 Lead-In) Axitinib (AG-013736) 5 milligram (mg) tablet orally twice daily (BID) starting from Day 3 of Cycle 1, in cycles of 4 weeks. Gemcitabine 1000 milligram/square meter (mg/m^2) 30 minutes intravenous (IV) infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.
Axitinib + Gemcitabine Axitinib (AG-013736) 5 mg tablet orally BID starting from Day 1 of Cycle 1, in cycles of 4 weeks. Gemcitabine 1000 mg/m^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.
Gemcitabine Gemcitabine 1000 mg/m^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.

Participant Flow for 2 periods

Period 1:   Phase 1
    Axitinib + Gemcitabine (Phase 1 Lead-In)     Axitinib + Gemcitabine     Gemcitabine  
STARTED     8     0     0  
COMPLETED     1     0     0  
NOT COMPLETED     7     0     0  
Lack of Efficacy                 3                 0                 0  
Adverse Event                 2                 0                 0  
Withdrawal by Subject                 1                 0                 0  
Started chemotherapy at other institute                 1                 0                 0  

Period 2:   Phase 2
    Axitinib + Gemcitabine (Phase 1 Lead-In)     Axitinib + Gemcitabine     Gemcitabine  
STARTED     0     69     34  
Treated     0     68     31  
COMPLETED     0     0     1  
NOT COMPLETED     0     69     33  
Lack of Efficacy                 0                 21                 15  
Adverse Event                 0                 22                 2  
Death                 0                 8                 2  
Unspecified                 0                 8                 6  
Withdrawal by Subject                 0                 9                 5  
Treatment not received                 0                 1                 3  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Axitinib + Gemcitabine (Phase 1 Lead-In) Axitinib (AG-013736) 5 milligram (mg) tablet orally twice daily (BID) starting from Day 3 of Cycle 1, in cycles of 4 weeks. Gemcitabine 1000 milligram/square meter (mg/m^2) 30 minutes intravenous (IV) infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.
Axitinib + Gemcitabine Axitinib (AG-013736) 5 mg tablet orally BID starting from Day 1 of Cycle 1, in cycles of 4 weeks. Gemcitabine 1000 mg/m^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.
Gemcitabine Gemcitabine 1000 mg/m^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.
Total Total of all reporting groups

Baseline Measures
    Axitinib + Gemcitabine (Phase 1 Lead-In)     Axitinib + Gemcitabine     Gemcitabine     Total  
Number of Participants  
[units: participants]
  8     69     34     111  
Age, Customized  
[units: Participants]
       
18 years to 44 years     0     2     4     6  
45 years to 64 years     5     31     20     56  
Greater than or equal to 65 years     3     36     10     49  
Gender  
[units: Participants]
       
Female     1     34     18     53  
Male     7     35     16     58  



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

2.  Secondary:   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 ]

3.  Secondary:   Dose Confirmation of Gemcitabine on Basis of Number of Participants With Dose Limiting Toxicity (DLT)   [ Time Frame: Phase 1 Baseline up to Week 4 ]

4.  Secondary:   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 ]

5.  Secondary:   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 Pase 1 Cycle 1 ]

6.  Secondary:   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 ]

7.  Secondary:   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 ]

8.  Secondary:   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 ]

9.  Secondary:   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 ]

10.  Secondary:   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 ]

11.  Secondary:   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 ]

12.  Secondary:   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 ]

13.  Secondary:   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 ]

14.  Secondary:   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 ]

15.  Secondary:   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). ]

16.  Secondary:   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). ]

17.  Secondary:   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 ]
Results not yet posted.   Anticipated Posting Date:   No text entered.   Safety Issue:   No


  Serious Adverse Events
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Time Frame No text entered.
Additional Description The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.

Reporting Groups
  Description
Axitinib + Gemcitabine (Phase 1 Lead-In) Axitinib (AG-013736) 5 milligram (mg) tablet orally twice daily (BID) starting from Day 3 of Cycle 1, in cycles of 4 weeks. Gemcitabine 1000 milligram/square meter (mg/m^2) 30 minutes intravenous (IV) infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.
Axitinib + Gemcitabine Axitinib (AG-013736) 5 mg tablet orally twice daily (BID) from Day 1 of Cycle 1 (28 days) and all subsequent cycles (28 days). Gemcitabine 1000 mg/m^2 30-minute infusion on Day 1, 8 and 15 of each cycle.
Gemcitabine Gemcitabine 1000 mg/m^2 30 minutes IV infusion on Day 1, 8 and 15 of each cycle, in cycles of 4 weeks.

Serious Adverse Events
    Axitinib + Gemcitabine (Phase 1 Lead-In)     Axitinib + Gemcitabine     Gemcitabine  
Total, serious adverse events        
# participants affected / at risk     3/8 (37.50%)     35/68 (51.47%)     10/31 (32.26%)  
Blood and lymphatic system disorders        
Anaemia * 1      
# participants affected / at risk     1/8 (12.50%)     4/68 (5.88%)     1/31 (3.23%)  
Disseminated intravascular coagulation * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Thrombocytopenia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Cardiac disorders        
Atrial fibrillation * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     1/31 (3.23%)  
Atrial flutter * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Myocardial infarction * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Pericardial effusion * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Tachycardia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Ear and labyrinth disorders        
Tinnitus * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Gastrointestinal disorders        
Abdominal distension * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Abdominal pain * 1      
# participants affected / at risk     0/8 (0.00%)     5/68 (7.35%)     0/31 (0.00%)  
Abdominal pain upper * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Abdominal strangulated hernia * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Colitis ischaemic * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Constipation * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Diarrhoea * 1      
# participants affected / at risk     0/8 (0.00%)     3/68 (4.41%)     0/31 (0.00%)  
Duodenal obstruction * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Gastric haemorrhage * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Gastrointestinal haemorrhage * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Haematemesis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Intestinal ischaemia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Intestinal obstruction * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     1/31 (3.23%)  
Melaena * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Nausea * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     2/31 (6.45%)  
Oral pain * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Peritonitis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Pneumatosis intestinalis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Rectal haemorrhage * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Small intestinal haemorrhage * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Small intestinal obstruction * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Vomiting * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
General disorders        
Asthenia * 1      
# participants affected / at risk     0/8 (0.00%)     4/68 (5.88%)     0/31 (0.00%)  
Chest pain * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Device occlusion * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Disease progression * 1      
# participants affected / at risk     0/8 (0.00%)     6/68 (8.82%)     0/31 (0.00%)  
Fatigue * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
General physical health deterioration * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Pain * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Pyrexia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     3/31 (9.68%)  
Multi-organ failure * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Hepatobiliary disorders        
Cholangitis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Cholestasis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Gallbladder obstruction * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Jaundice cholestatic * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Infections and infestations        
Empyema * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Enterobacter bacteraemia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Liver abscess * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Lower respiratory tract infection * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Lung abscess * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Lung infection * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Oral candidiasis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Pneumonia * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Sepsis * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Septic shock * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Infection * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Investigations        
Blood pressure increased * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Platelet count decreased * 1      
# participants affected / at risk     1/8 (12.50%)     0/68 (0.00%)     0/31 (0.00%)  
Metabolism and nutrition disorders        
Cachexia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Dehydration * 1      
# participants affected / at risk     0/8 (0.00%)     3/68 (4.41%)     2/31 (6.45%)  
Failure to thrive * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Hypocalcaemia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Hypokalaemia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Hyponatraemia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Hypophagia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Lactic acidosis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Nervous system disorders        
Convulsion * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Headache * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Neuromyopathy * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Syncope * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Transient ischaemic attack * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Psychiatric disorders        
Confusional state * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Mental status changes * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     1/31 (3.23%)  
Renal and urinary disorders        
Renal impairment * 1      
# participants affected / at risk     0/8 (0.00%)     0/68 (0.00%)     1/31 (3.23%)  
Respiratory, thoracic and mediastinal disorders        
Dyspnoea * 1      
# participants affected / at risk     0/8 (0.00%)     6/68 (8.82%)     0/31 (0.00%)  
Epistaxis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Hypoxia * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Pneumothorax * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Pulmonary embolism * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Vascular disorders        
Deep vein thrombosis * 1      
# participants affected / at risk     0/8 (0.00%)     2/68 (2.94%)     0/31 (0.00%)  
Post thrombotic syndrome * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
Thrombosis * 1      
# participants affected / at risk     0/8 (0.00%)     1/68 (1.47%)     0/31 (0.00%)  
* Events were collected by non-systematic assessment
1 Term from vocabulary, MedDRA v13.1




  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
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