S0727 Gemcitabine Hydrochloride and Erlotinib Hydrochloride With or Without Monoclonal Antibody Therapy in Treating Patients With Metastatic Pancreatic Cancer That Cannot Be Removed By Surgery

Study Overview
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Brief Summary
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This randomized phase I/II trial is studying the side effects and best dose of monoclonal antibody therapy when given together with gemcitabine hydrochloride and erlotinib hydrochloride and to see how well they work compared with giving gemcitabine hydrochloride and erlotinib hydrochloride alone as first-line therapy in treating patients with metastatic pancreatic cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies 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. Giving erlotinib hydrochloride and gemcitabine hydrochloride together with monoclonal antibody therapy may kill more tumor cells.

Detailed Description
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PRIMARY OBJECTIVES: I. To assess the appropriate dose of IMC-A12 (cixutumumab) to use in combination with gemcitabine (gemcitabine hydrochloride) and erlotinib (erlotinib hydrochloride). (Phase I) II. To assess progression-free survival in patients with metastatic pancreatic cancer treated with IMC-A12 plus gemcitabine and erlotinib compared to those treated with gemcitabine plus erlotinib alone. (Phase II) III. To assess overall survival in each of the two treatment arms in this group of patients. (Phase II) IV. To assess the total response probability (confirmed and unconfirmed, complete and partial responses) in each of the two treatment arms in the subset of this group of patients with measurable disease. (Phase II) V. To assess the qualitative and quantitative toxicities in each of the two treatment arms in this group of patients. (Phase II) OUTLINE: This is a multicenter, phase I, dose-escalation study of cixutumumab followed by a randomized, phase II study. Patients are initially enrolled into the phase I portion of the study to determine the recommended phase II dose (RPTD) of cixutumumab. Once the RPTD is determined, patients are enrolled into the phase II portion of the study. PHASE I (LIMITED INSTITUTIONS): Patients receive erlotinib hydrochloride orally (PO) once daily on days 1-28, gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1, 8, and 15, and cixutumumab IV over 60 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II (ALL SWOG MEMBERS): Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive erlotinib hydrochloride, gemcitabine hydrochloride, and cixutumumab at the RPTD as in phase I. ARM II: Patients receive erlotinib hydrochloride and gemcitabine hydrochloride as in arm I. In both arms, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Previously collected tumor tissue is obtained for gene expression analyses by RT-PCR, RNA isolation, and cDNA synthesis. Blood samples are collected periodically for correlative studies. Samples are assessed for the potential relationship between gene expression levels, germline polymorphisms, Ras and P13K mutations and progression-free survival and overall survival. After completion of study treatment, patients are followed every 6 months for up to 3 years.

Official Title
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A Phase I and Randomized Phase II Trial of Gemcitabine + Erlotinib (NSC-718781) + IMC-A12 (NSC-742460) vs. Gemcitabine + Erlotinib as First-Line Treatment in Patients With Metastatic Pancreatic Cancer

Conditions
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Stage IV Pancreatic Cancer

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed pancreatic adenocarcinoma Stage IV disease (any T, any N, M1 [distant metastases]) Unresectable disease Histologic diagnosis based on a metastatic site must be compatible with pancreatic cancer Measurable and/or nonmeasurable disease No endocrine or neuroendocrine tumors, lymphoma of the pancreas, or ampullary cancer No macroscopic residual disease post-resection as the only site of disease No clinically significant ascites No known brain metastases Patients with neurologic signs or symptoms must undergo brain imaging studies AND studies must be negative for disease Zubrod performance status 0-1 ANC ≥ 1,500/mcL Platelet count ≥ 100,000/mcL Hemoglobin ≥ 9 g/dL Leukocytes ≥ 3,000/mcL Total bilirubin normal SGOT or SGPT ≤ 2.5 times upper limit of normal (ULN) Serum creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min Fasting serum glucose < 120 mg/dL or below the ULN Patients with diabetes mellitus who meet this criterion must be on a stable dietary or therapeutic regimen for this condition INR ≤ 1.5 and PTT ≤ 5 seconds above ULN Not pregnant or nursing Fertile patients must use effective contraception Willing to submit previously collected tumor tissue specimens No history of allergic reaction attributed to compounds of similar chemical or biological composition to anti-IGF-1R recombinant monoclonal antibody IMC-A12 No active acute or chronic infections requiring antibiotics No significant ongoing cardiac problems, including any of the following: Myocardial infarction within the past 6 months Uncontrolled hypertension Unstable angina Uncontrolled arrhythmia Congestive heart failure No known HIV infection No other prior malignancy, except for the following: Adequately treated basal cell or squamous cell skin cancer Carcinoma in situ of the cervix Adequately treated stage I or II cancer from which the patient is currently in complete remission Any other cancer from which the patient has been disease-free for 5 years At least 14 days since prior surgery At least 28 days since prior radiotherapy for palliation to metastatic sites Patient must have other untreated metastatic sites that would qualify them for this protocol At least 6 months since prior adjuvant chemotherapy No prior chemotherapy, hormonal therapy, immunotherapy, or chemoradiotherapy for advanced or locally advanced pancreatic cancer, including drugs that target either EGFR or IGFR No plans to receive concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or any other type of therapy for treatment of cancer No prior gemcitabine hydrochloride No prior chimerized or murine monoclonal antibody therapy No concurrent CYP3A4 inducers including, but not limited to, any of the following: Rifampicin Rifabutin Rifapentine Phenytoin Carbamazepine Phenobarbital Hypericum perforatum (St. John's wort) No concurrent CYP3A4 inhibitors including, but not limited to, any of the following: Atazanavir Clarithromycin Indinavir Itraconazole Ketoconazole Nefazodone Nelfinavir Ritonavir Saquinavir Telithromycin Troleandomycin Voriconazole Concurrent prophylactic low-dose coumadin or low molecular weight heparin allowed provided coagulation criteria are met Full-dose anticoagulation allowed provided coagulation criteria are met and are under strict control and monitoring

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 |
| --- | --- |
| Experimental: Arm I (erlotinib, gemcitabine, cixutumumab)<br>Patients receive erlotinib hydrochloride PO once daily on days 1-28, gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15, and cixutumumab IV over 60 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Biological: cixutumumab<br>* Given IV<br>* Other names: IMC-A12;Drug: erlotinib hydrochloride<br>* Given PO<br>* Other names: OSI-774;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;|
| Active Comparator: Arm II (erlotinib, gemcitabine)<br>Patients receive erlotinib hydrochloride and gemcitabine hydrochloride as in arm I. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: erlotinib hydrochloride<br>* Given PO<br>* Other names: OSI-774;Drug: gemcitabine hydrochloride<br>* Given IV<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose Determination | Maximum dose of IMC-A12 (in combination with erlotinib and gemcitabine) at which 3/10 or fewer patients have dose-limiting toxicities (DLT). Toxicities graded according to the NCI Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE 3.0). DLT apply only during cycle 1 and should be drug-related (possible, probable, or definite). | 28 days | 
| Progression-Free Survival | From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact. | Up to 3 years | 
| Response | Confirmed response (CR) is two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. Partial response (PR) is two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration. Unconfirmed CR is one objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR. | Up to 3 years | 
| Toxicity | Number of patients with Grade 3 through 5 adverse events that are related to study drug. Only adverse events that are possibly, probably or definitely related to study drug are reported. | Up to 3 years |