Irinotecan and Docetaxel With or Without Cetuximab in Treating Patients With Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Monoclonal antibodies such as cetuximab can locate tumor cells and either kill them or deliver tumor-killing substances to them without harming normal cells. Combining chemotherapy with cetuximab may kill more tumor cells. PURPOSE: This randomized phase II trial is studying giving irinotecan and docetaxel together with cetuximab to see how well it works compared to irinotecan and docetaxel alone in treating patients with metastatic pancreatic cancer .

Detailed Description
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OBJECTIVES: Determine the efficacy of irinotecan and docetaxel with or without cetuximab, in terms of objective response rate, in patients with metastatic adenocarcinoma of the pancreas. Determine the time to progression and overall survival of patients treated with these regimens. Determine the proportion of patients with tumors that overexpress epidermal growth factor receptor. OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms. Arm A: Patients receive docetaxel IV over 1 hour and irinotecan IV over 30 minutes weekly on days 1, 8, 15, and 22. Arm B: Patients receive docetaxel and irinotecan as in arm A. Patients also receive cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, and 36. Courses repeat in both arms every 6 weeks in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months for 2 years, every 6 months for 1 year, and then periodically thereafter. PROJECTED ACCRUAL: A total of 92 patients (46 per treatment arm)

Official Title
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Phase II Trial of Irinotecan/Docetaxel for Advanced Pancreatic Cancer, With Randomization Between Irinotecan/Docetaxel and Irinotecan/Docetaxel Plus C225 a Monoclonal Antibody to the Epidermal Growth Factor Receptor (EGF-r)

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Biological: cetuximab
* Drug: docetaxel
* Drug: irinotecan hydrochloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed metastatic adenocarcinoma of the pancreas Sufficient tumor tissue from fine needle aspiration, core biopsy, or open biopsy available for epidermal growth factor receptor testing At least 1 unidimensionally measurable primary or metastatic lesionge Age of 18 and over ECOG performance status 0-1 Negative pregnancy test Fertile patients must use effective contraception Creatinine clearance > 60 mL/min LVEF normal Absolute neutrophil count > 1,500/mm^3 Platelet count > 100,000/mm^3 Bilirubin ≤ upper limit of normal (ULN)* SGOT or SGPT and alkaline phosphatase must meet the criteria for 1 of the following*: SGOT or SGPT ≤ 2.5 times ULN AND alkaline phosphatase ≤ ULN SGOT or SGPT ≤ 1.5 times ULN AND alkaline phosphatase > ULN but ≤ 2.5 times ULN SGOT or SGPT ≤ ULN AND alkaline phosphatase > 2.5 but ≤ 4 times ULN NOTE: *Percutaneous stenting or endoscopic retrograde cholangiopancreatography may be used to normalize liver function tests Exclusion Criteria: History of uncontrolled arrhythmias History of congestive heart failure History of uncontrolled angina pectoris Prior chemotherapy Pre-existing neuropathy ≥ grade 2 Prior hypersensitivity to polysorbate 80 Pregnant or nursing

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Irinotecan/Docetaxel<br>Docetaxel was administered intravenously over 60 minutes at a dose of 35 mg/m². Docetaxel was diluted in 100-150 ml of infusion solution. After the completion of the docetaxel infusion, irinotecan was administered intravenously over 30 minutes at a dose of 50 mg/m². Chemotherapy was administered once a week (days 1, 8, 15, 22) for 4 consecutive weeks followed by 2 weeks rest. This constituted a cycle of treatment. Patients were evaluated after 2 cycles. | Drug: docetaxel<br>* Docetaxel was administered intravenously over 60 minutes at a dose of 35 mg/m² once a week (days 1, 8, 15, 22) for 4 consecutive weeks followed by 2 weeks rest. Docetaxel was diluted in 100-150 ml of infusion solution.<br>* Other names: Taxotere;Drug: irinotecan hydrochloride<br>* After the completion of the docetaxel infusion, irinotecan was administered intravenously over 30 minutes at a dose of 50 mg/m² once a week (days 1, 8, 15, 22) for 4 consecutive weeks followed by 2 weeks rest.<br>* Other names: Camptosar;|
| Experimental: Irinotecan/Docetaxel/Cetuximab<br>Patients received Cetuximab intravenously once a week for 6 weeks. On day 1 of cycle 1 only, an initial dose of 400 mg/m² (over 120 minutes) was administered. Thereafter, a once-a-week maintenance dose of 250 mg/m² (infused over 60 minutes), was given. The infusion rate never exceeded 5 ml/minute. On the day of the initial dose, the administration of Cetuximab was followed by the administration of docetaxel, after a 60-minute observation period. (The observation period was 30 minutes following maintenance doses.) Docetaxel was administered intravenously over 60 minutes at a dose of 35 mg/m². Docetaxel was diluted in 100-150 ml of infusion solution. After the completion of the docetaxel infusion, irinotecan was administered intravenously over 30 minutes at a dose of 50 mg/m². Chemotherapy was administered once a week (days 1, 8, 15, 22) for 4 consecutive weeks followed by 2 weeks rest. Cetuximab was administered once a week for 6 consecutive weeks. A cycle of treatment was 6 weeks. | Biological: cetuximab<br>* Patients received cetuximab intravenous infusions, via infusion pump or syringe pump, once a week for 6 weeks.<br>* Other names: C225;Drug: docetaxel<br>* Docetaxel was administered intravenously over 60 minutes at a dose of 35 mg/m² once a week (days 1, 8, 15, 22) for 4 consecutive weeks followed by 2 weeks rest. Docetaxel was diluted in 100-150 ml of infusion solution.<br>* Other names: Taxotere;Drug: irinotecan hydrochloride<br>* After the completion of the docetaxel infusion, irinotecan was administered intravenously over 30 minutes at a dose of 50 mg/m² once a week (days 1, 8, 15, 22) for 4 consecutive weeks followed by 2 weeks rest.<br>* Other names: Camptosar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Objective Response Evaluated by RECIST (Solid Tumor Response Criteria) | Per RECIST criteria, Complete response (CR)= disappearance of all target and nontarget lesions Partial response (PR)= >=30% decrease in the sum of the longest diameters of target lesions from baseline, and persistence of one or more non-target lesion(s) and/or the maintenance of tumor marker level above the normal limits. Objective response = CR + PR | Assessed every 12 weeks until progression | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival was defined as the shorter of: The time from registration to progression. or The time from registration to death without documentation of progression given that the death occured within 4 months of the last disease assessment without progression (or registration, whichever is more recent). Progression is defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, or the appearance of one or more new lesion(s) or unequivocal progression of existing nontarget lesions. | Assessed every 3 months for 2 years and then every 6 months for 1 year | 
| Overall Survival | Overall survival was defined as time from registration to death from any cause. | Assessed every 3 months for 2 years and then every 6 months for 1 year | 
| Epidermal Growth Factor Receptor (EGFR) Status | EGFR expression was be evaluated by staining 5-micron paraffin sections of tumor biopsies with anti-EGFR clone 2-18C9 (DAKO Corporation, Carpinteria, CA) using an indirect immunoperoxidase technique according to the instructions provided by DAKO. In brief, this includes an antigen retrieval pretreatment, the blocking of endogenous peroxidase activity, incubation with anti-EGFR antibody or a negative reagent control, staining with a detection system, visualization, and coverslipping. | Original tumor tissue samples submitted within one month of patient randomization | 
| Proportion of Patients With Thromboembolic Events | To determine the rate of thromboembolic events in this population when prophylactic enoxaparin sodium is administered. | Assessed every 6 weeks while on treatment and for 30 days after the end of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pancreatic cancer, metastatic pancreatic cancer, EGF-r, irinotecan, docetaxel, cetuximab