Pancreatic Cancer
Conditions
Keywords
adenocarcinoma of the pancreas, duct cell adenocarcinoma of the pancreas, stage IV pancreatic cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as gemcitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as panitumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Panitumumab may also stop the growth of pancreatic cancer by blocking blood flow to the tumor. PURPOSE: This randomized phase II trial is studying how well giving panitumumab together with gemcitabine and erlotinib works compared to giving gemcitabine and erlotinib alone in treating patients with metastatic pancreatic cancer.
Detailed description
OBJECTIVES: Primary * To assess whether the addition of panitumumab (a dual-epidermal growth factor receptor inhibitor) to standard chemotherapy comprising gemcitabine hydrochloride and erlotinib hydrochloride results in an improvement in overall survival of patients with previously untreated, metastatic adenocarcinoma of the pancreas. Secondary * To compare objective response rates, progression-free survival, time to treatment failure, quality of life, and adverse event rates in patients treated with these regimens. * To evaluate the downstream marker, KRAS, in stool specimens. OUTLINE: This is a multicenter study. Patients are stratified according to ECOG performance status (0 vs 1) and prior adjuvant chemotherapy (yes vs no). The first 6 patients are assigned to arm II. Subsequent patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15 and oral erlotinib hydrochloride once daily on days 1-28. Treatment repeats every 28 days for 2 courses. Patients achieving a complete response (CR) after 2 courses receive 2 additional courses of treatment; patients achieving a partial response (PR) receive retreatment as above in the absence of disease progression or unacceptable toxicity. Patients achieving a CR after 4 courses of treatment receive maintenance therapy comprising erlotinib hydrochloride daily until the first disease progression. After the first progression, patients are retreated with gemcitabine hydrochloride and erlotinib hydrochloride until second progression (using the first progression tumor measurements as the new baseline reference). * Arm II: Patients receive gemcitabine hydrochloride and erlotinib hydrochloride as in arm I and panitumumab IV over 1 hour on days 1 and 15. Treatment repeats every 28 days for 2 courses. Patients achieving a CR after 2 courses receive 2 additional courses of treatment; patients achieving a PR receive retreatment as above in the absence of disease progression or unacceptable toxicity. Patients achieving a CR after 4 courses of treatment receive maintenance therapy comprising erlotinib hydrochloride daily and panitumumab every 2 weeks until the first disease progression. After the first progression, patients are retreated with gemcitabine hydrochloride, erlotinib hydrochloride, and panitumumab until second progression (using the first progression tumor measurements as the new baseline reference). Stool samples are collected at baseline and analyzed for KRAS mutations via protein analyses. Quality of life will be assessed at baseline, every 2 courses during treatment, and at the end of treatment. After the second progression, patients are followed every 3-6 months for 2 years.
Interventions
BIOLOGICALpanitumumab
Given IV
DRUGerlotinib hydrochloride
Given orally
DRUGgemcitabine hydrochloride
Given IV
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
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
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed adenocarcinoma of the pancreas (ductal or undifferentiated) * Metastatic disease * No islet cell, acinar cell, or cystadenocarcinomas * No locally advanced disease * No history or known presence of CNS metastases PATIENT CHARACTERISTICS: * ECOG performance status 0-1 * Life expectancy ≥ 3 months * ANC ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Total bilirubin ≤ 2 times upper limit of normal (ULN) (patients may be stented) * AST ≤ 2.5 times ULN * Creatinine ≤ 2.0 times ULN * Magnesium ≥ lower limit of normal * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Willing to provide a stool specimen * No malignancy diagnosed within the past 3 years except basal cell or squamous cell skin cancer, prostate cancer (Gleason \< 7), or carcinoma in situ of the cervix * No uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements * No clinically significant cardiovascular disease (i.e., myocardial infarction, unstable angina, symptomatic congestive heart failure, or serious uncontrolled cardiac arrhythmia) within the past year * No known positive test(s) for HIV infection, hepatitis C virus, or acute or chronic active hepatitis B infection * No liver dysfunction from cirrhosis or viral hepatitis * No enteral hyperalimentation * No grapefruit or grapefruit juice during the study PRIOR CONCURRENT THERAPY: * Recovered from prior therapy * More than 4 months since prior radiotherapy, immunotherapy, or biologic therapy * More than 4 weeks since prior and no elective or planned major surgery * More than 2 weeks since prior minor and no elective or planned surgery * No prior cytotoxic chemotherapy for metastatic disease * Adjuvant chemotherapy for completely resected disease or chemoradiotherapy for locally advanced disease is allowed, provided it was administered \> 6 months prior to study entry * Adjuvant chemotherapy must not have contained an EGFR inhibitor * Gemcitabine hydrochloride used as either a radiosensitizer or as maintenance therapy is allowed, provided more than 6 months have elapsed since the last day of treatment * No prior anti-EGFR antibody therapy (e.g., cetuximab) or treatment with small molecule EGFR inhibitors (e.g., gefitinib hydrochloride, erlotinib hydrochloride, or lapatinib) * No concurrent immunotherapy or radiotherapy * No other concurrent chemotherapy * No concurrent colony-stimulating factors during the first course of study therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Up to 2 years | Overall Survival is defined as the time from registration to death due to any cause. The estimate will be done using the Kaplan-Meier method. The primary goal of this trial is to compare the experimental arm (Arm B) to the standard arm (Arm A). The primary analysis will be a comparison of Arm A to Arm B using a one-sided log-rank test between the 2 Kaplan-Meier curves. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Response Rate | Up to 2 years | Evaluated using RECIST version 1.0. Confirmed tumor response rate was defined as achieving partial response (PR) or complete response (CR) in two consecutive assessments at least 6 weeks apart. CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. The confirmed response rate is reported as the number of participants with confirmed responses divided by the number of evaluated participants. |
| Progression-free Survival | Up to 2 years | Progression-free survival is defined as the time from randomization to documentation of disease progression or death, whichever comes first. Progression is defined as at least a 20% increase in the sum of longest dimension (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. The distribution of progression-free survival will be estimated using the method of Kaplan-Meier. The progression-free survival curves will be compared between the 2 arms using a log-rank test. |
| Time to Treatment Failure | Up to 2 years | Time to treatment failure is defined to be the time from the date of randomization to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. If the patient is considered to be a major treatment violation or is taken off study as a nonprotocol failure, the patient will be censored on the date they are removed from treatment. The time to treatment failure will be estimated using the method of Kaplan-Meier. |
| Frequency and Severity of Observed Adverse Effects | Up to 2 years | Patients are assessed for Adverse events each cycle using the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0). The maximum grade for each type of adverse event will be recorded for each patient, and tables will be reviewed to determine adverse event patterns. The number of patients in each arm that reported a grade 3 or higher adverse event and a grade 4 or higher adverse event are reported. A complete listing of all adverse events is reported in the Adverse Events section. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: GE Patients receive 1000 mg/m\^2 gemcitabine hydrochloride IV on days 1, 8, and 15; and 100 mg oral erlotinib hydrochloride on days 1-28. Treatment repeats every 28 days for 2 courses. Patients achieving a complete response (CR) after 2 courses receive 2 additional courses of treatment; patients achieving a partial response (PR) receive retreatment as above. Patients achieving a CR after 4 courses of treatment receive erlotinib hydrochloride until the first disease progression. After the first progression, patients are retreated with gemcitabine hydrochloride and erlotinib hydrochloride until second progression. | 46 |
| Arm B: PGE Patients receive 1000 mg/m\^2 gemcitabine hydrochloride IV on days 1, 8, and 15; 100 mg oral erlotinib hydrochloride on days 1 - 28; and 4.0 mg/kg panitumumab IV on days 1 and 15. Treatment repeats every 28 days for 2 courses. Patients achieving a CR after 2 courses receive 2 additional courses of treatment; patients achieving a PR receive retreatment as above. Patients achieving a CR after 4 courses of treatment receive erlotinib hydrochloride and panitumumab until the first disease progression. After the first progression, patients are retreated with gemcitabine hydrochloride, erlotinib hydrochloride, and panitumumab until second progression. | 46 |
| Total | 92 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 3 | 9 |
Baseline characteristics
| Characteristic | Arm A: GE | Arm B: PGE | Total |
|---|---|---|---|
| Age, Continuous | 60.5 years | 62 years | 61.5 years |
| Region of Enrollment United States | 46 participants | 46 participants | 92 participants |
| Sex: Female, Male Female | 17 Participants | 15 Participants | 32 Participants |
| Sex: Female, Male Male | 29 Participants | 31 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 45 / 46 | 46 / 46 |
| serious Total, serious adverse events | 30 / 46 | 27 / 46 |
Outcome results
Primary
Overall Survival
Overall Survival is defined as the time from registration to death due to any cause. The estimate will be done using the Kaplan-Meier method. The primary goal of this trial is to compare the experimental arm (Arm B) to the standard arm (Arm A). The primary analysis will be a comparison of Arm A to Arm B using a one-sided log-rank test between the 2 Kaplan-Meier curves.
Time frame: Up to 2 years
Population: All treated patients that were eligible were included in the analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: GE | Overall Survival | 4.2 months |
| Arm B: PGE | Overall Survival | 8.3 months |
Comparison: It was calculated that 39 participants randomized in a 1:1 fashion between the 2 arms would have 80% to detect a difference in median survival of 6 vs. 9.7 months for GE vs. PGE respectively with a minimum follow up of 6 months. Sample size was determined using a 1-sided log-rank test at alpha=0.20.p-value: 0.36Log Rank
Secondary
Confirmed Response Rate
Evaluated using RECIST version 1.0. Confirmed tumor response rate was defined as achieving partial response (PR) or complete response (CR) in two consecutive assessments at least 6 weeks apart. CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. The confirmed response rate is reported as the number of participants with confirmed responses divided by the number of evaluated participants.
Time frame: Up to 2 years
Population: All patients that started protocol treatment and were evaluated were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: GE | Confirmed Response Rate | 0.087 rate of confirmed response |
| Arm B: PGE | Confirmed Response Rate | 0.065 rate of confirmed response |
p-value: 1Fisher Exact
Secondary
Frequency and Severity of Observed Adverse Effects
Patients are assessed for Adverse events each cycle using the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0). The maximum grade for each type of adverse event will be recorded for each patient, and tables will be reviewed to determine adverse event patterns. The number of patients in each arm that reported a grade 3 or higher adverse event and a grade 4 or higher adverse event are reported. A complete listing of all adverse events is reported in the Adverse Events section.
Time frame: Up to 2 years
Population: All evaluable patients were included in this analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: GE | Frequency and Severity of Observed Adverse Effects | Grade 3+ Adverse Event | 41 participants |
| Arm A: GE | Frequency and Severity of Observed Adverse Effects | Grade 4+ Adverse Event | 15 participants |
| Arm B: PGE | Frequency and Severity of Observed Adverse Effects | Grade 3+ Adverse Event | 41 participants |
| Arm B: PGE | Frequency and Severity of Observed Adverse Effects | Grade 4+ Adverse Event | 14 participants |
Secondary
Progression-free Survival
Progression-free survival is defined as the time from randomization to documentation of disease progression or death, whichever comes first. Progression is defined as at least a 20% increase in the sum of longest dimension (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. The distribution of progression-free survival will be estimated using the method of Kaplan-Meier. The progression-free survival curves will be compared between the 2 arms using a log-rank test.
Time frame: Up to 2 years
Population: All treated patients were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: GE | Progression-free Survival | 2.0 months |
| Arm B: PGE | Progression-free Survival | 3.6 months |
p-value: 0.419Log Rank
Secondary
Time to Treatment Failure
Time to treatment failure is defined to be the time from the date of randomization to the date at which the patient is removed from treatment due to progression, adverse events, or refusal. If the patient is considered to be a major treatment violation or is taken off study as a nonprotocol failure, the patient will be censored on the date they are removed from treatment. The time to treatment failure will be estimated using the method of Kaplan-Meier.
Time frame: Up to 2 years
Population: All eligible treated patients were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: GE | Time to Treatment Failure | 2.0 months |
| Arm B: PGE | Time to Treatment Failure | 3.8 months |
p-value: 0.36Log Rank