Pancreatic Cancer
Conditions
Keywords
pancreatic cancer, metastatic pancreatic cancer, EGF-r, irinotecan, docetaxel, cetuximab
Brief summary
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
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)
Interventions
BIOLOGICALcetuximab
Patients received cetuximab intravenous infusions, via infusion pump or syringe pump, once a week for 6 weeks.
DRUGdocetaxel
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.
DRUGirinotecan hydrochloride
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.
Sponsors
National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Objective Response Evaluated by RECIST (Solid Tumor Response Criteria) | Assessed every 12 weeks until progression | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | Assessed every 3 months for 2 years and then every 6 months for 1 year | Progression-free survival was defined as the shorter of: 1. The time from registration to progression. or 2. 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. |
| Overall Survival | Assessed every 3 months for 2 years and then every 6 months for 1 year | Overall survival was defined as time from registration to death from any cause. |
| Epidermal Growth Factor Receptor (EGFR) Status | Original tumor tissue samples submitted within one month of patient randomization | 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. |
| Proportion of Patients With Thromboembolic Events | Assessed every 6 weeks while on treatment and for 30 days after the end of treatment | To determine the rate of thromboembolic events in this population when prophylactic enoxaparin sodium is administered. |
Participant flow
Recruitment details
E8200 opened to accrual on 7/31/2003, accrued its first patient on 12/9/2003, and was suspended on 12/2/2004 for evaluation of response and toxicity. Arm B was reactivated on 7/12/2005 after meeting the response criteria; Arm A was reactivated on 11/23/2005. Arm B and Arm A closed to accrual on 4/17/2006 and 8/23/2006, respectively, after meeting the accrual goal.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Irinotecan/Docetaxel 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. | 44 |
| Arm B: Irinotecan/Docetaxel/Cetuximab 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. | 43 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 6 | 7 |
| Overall Study | Death | 3 | 2 |
| Overall Study | Deterioration of health | 3 | 4 |
| Overall Study | Did not start treatment | 2 | 1 |
| Overall Study | Ineligible | 2 | 2 |
| Overall Study | Other disease | 1 | 0 |
| Overall Study | Patient non-compliance | 1 | 0 |
| Overall Study | QOL diminished | 1 | 0 |
| Overall Study | Rising ca 19-9 | 1 | 0 |
| Overall Study | Still on treatment | 1 | 0 |
| Overall Study | Treatment break > 4 weeks | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Arm A: Irinotecan/Docetaxel | Arm B: Irinotecan/Docetaxel/Cetuximab | Total |
|---|---|---|---|
| Age, Continuous | 60.2 years | 60.6 years | 60.4 years |
| Sex: Female, Male Female | 20 Participants | 6 Participants | 26 Participants |
| Sex: Female, Male Male | 24 Participants | 37 Participants | 61 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 46 / 46 | 45 / 45 |
| serious Total, serious adverse events | 35 / 46 | 36 / 45 |
Outcome results
Primary
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
Time frame: Assessed every 12 weeks until progression
Population: Eligible patients who began treatment were included in the analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Irinotecan/Docetaxel | Proportion of Patients With Objective Response Evaluated by RECIST (Solid Tumor Response Criteria) | 0.045 Proportion of participants |
| Arm B: Irinotecan/Docetaxel/Cetuximab | Proportion of Patients With Objective Response Evaluated by RECIST (Solid Tumor Response Criteria) | 0.07 Proportion of participants |
Secondary
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.
Time frame: Original tumor tissue samples submitted within one month of patient randomization
Population: Eligible and treated patients with EGFR stain results available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: Irinotecan/Docetaxel | Epidermal Growth Factor Receptor (EGFR) Status | Positive | 29 participants |
| Arm A: Irinotecan/Docetaxel | Epidermal Growth Factor Receptor (EGFR) Status | Negative | 1 participants |
| Arm B: Irinotecan/Docetaxel/Cetuximab | Epidermal Growth Factor Receptor (EGFR) Status | Positive | 30 participants |
| Arm B: Irinotecan/Docetaxel/Cetuximab | Epidermal Growth Factor Receptor (EGFR) Status | Negative | 1 participants |
Secondary
Overall Survival
Overall survival was defined as time from registration to death from any cause.
Time frame: Assessed every 3 months for 2 years and then every 6 months for 1 year
Population: Eligible patients who began treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Irinotecan/Docetaxel | Overall Survival | 6.5 months |
| Arm B: Irinotecan/Docetaxel/Cetuximab | Overall Survival | 5.3 months |
Secondary
Progression-free Survival
Progression-free survival was defined as the shorter of: 1. The time from registration to progression. or 2. 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.
Time frame: Assessed every 3 months for 2 years and then every 6 months for 1 year
Population: Eligible patients who began treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Irinotecan/Docetaxel | Progression-free Survival | 3.9 months |
| Arm B: Irinotecan/Docetaxel/Cetuximab | Progression-free Survival | 4.5 months |
Secondary
Proportion of Patients With Thromboembolic Events
To determine the rate of thromboembolic events in this population when prophylactic enoxaparin sodium is administered.
Time frame: Assessed every 6 weeks while on treatment and for 30 days after the end of treatment
Population: Eligible and treated patients
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Irinotecan/Docetaxel | Proportion of Patients With Thromboembolic Events | 0 Proportion of participants |
| Arm B: Irinotecan/Docetaxel/Cetuximab | Proportion of Patients With Thromboembolic Events | 0.023 Proportion of participants |