Erlotinib and Gemcitabine With or Without Panitumumab in Treating Patients With Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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Randomized Phase II Trial of Panitumumab, Erlotinib and Gemcitabine vs. Erlotinib and Gemcitabine in Patients With Untreated, Metastatic Pancreatic Adenocarcinoma

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Biological: panitumumab
* Drug: erlotinib hydrochloride
* Drug: gemcitabine hydrochloride


Participation Criteria
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Eligibility Criteria
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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

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: Arm A: GE<br>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. | Drug: erlotinib hydrochloride<br>* Given orally<br>Drug: gemcitabine hydrochloride<br>* Given IV<br>|
| Experimental: Arm B: PGE<br>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. | Biological: panitumumab<br>* Given IV<br>Drug: erlotinib hydrochloride<br>* Given orally<br>Drug: gemcitabine hydrochloride<br>* Given IV<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 2 years | 
| 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. | Up to 2 years | 
| 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. | Up to 2 years | 
| 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. | Up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adenocarcinoma of the pancreas, duct cell adenocarcinoma of the pancreas, stage IV pancreatic cancer