Monoclonal Antibody RAV12 and Gemcitabine in Treating Patients With Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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RATIONALE: Monoclonal antibodies, such as RAV12, 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. 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. Giving RAV12 together with gemcitabine may kill more tumor cells. PURPOSE: This phase II trial is studying the side effects and best dose of monoclonal antibody RAV12 when given together with gemcitabine in treating patients with metastatic pancreatic cancer.

Detailed Description
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OBJECTIVES: To determine the maximum tolerated dose of monoclonal antibody RAV12 when administered with standard gemcitabine hydrochloride in patients with previously untreated metastatic pancreatic cancer. To determine the proportion of these patients surviving at 8 months after initiation of this regimen. To provide point estimates for response rate and duration of response in patients treated with this regimen. To define the toxicity profile of this drug in these patients when administered with standard gemcitabine hydrochloride. To estimate, preliminarily, the progression-free survival and overall survival of these patients after treatment with this regimen. To explore the utility of the tumor marker, carbohydrate antigen 19-9 (CA19-9), in the assessment of these patients. OUTLINE: This is a dose-escalation study of monoclonal antibody RAV12, followed by an efficacy study. The study is conducted in two segments. Segment 1 (dose escalation of RAV12): Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1, 8, 15, and 22 of course 1 and on days 1, 8, and 15 of each subsequent course. Patients also receive RAV12 IV once weekly on days 1, 8, and 15 or twice weekly on days 1, 4 or 5, 8, 11 or 12, 15, and 18 or 19 until the maximum tolerated dose (MTD) is reached. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Segment 2 (efficacy): Once the MTD has been determined, patients receive RAV12 at the MTD and gemcitabine hydrochloride as in segment 1. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. Blood samples are obtained for pharmacokinetic sampling during the dose-escalation segment of the study. Samples are analyzed to determine plasma concentrations of RAV12, gemcitabine hydrochloride, and difluorodeoxyuridine. Blood samples are also examined periodically for expression of serum biomarkers (i.e., CA19-9, RAAG12, and HACA) and for DNA analysis of Fc-gamma receptor polymorphisms. Archival paraffin blocks or slides from biopsy of primary or metastatic deposit or fresh/frozen tissue may be obtained at baseline for additional correlative studies. Samples are analyzed by immunohistochemistry (IHC) for expression of RAAG12 and for development of a companion RAAG12 diagnostic assay. After completion of study therapy, patients are followed every 8 weeks for up to 3 years. PROJECTED ACCRUAL: This study will accrue a total of 18 patients in the dose-escalation segment and 63 patients in the efficacy segment of the trial.

Official Title
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A Phase 2 Evaluation of the Monoclonal Antibody, RAV12, in Combination With Standard Gemcitabine in the Treatment of Patients With Metastatic Pancreatic Cancer Who Have Not Been Previously Treated for Metastatic Disease

Conditions
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Pancreatic Cancer

Intervention / Treatment
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* Biological: RAV12
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically or cytologically confirmed adenocarcinoma of the pancreas Metastatic disease No prior therapy for metastatic disease (except prior adjuvant chemotherapy and/or radiotherapy) At least 1 radiographically measurable site of disease ≥ 2 cm in the largest dimension by traditional CT technique or ≥ 1 cm by spiral CT scan (per RECIST) No known history of current or prior central nervous system (CNS) metastatic disease PATIENT CHARACTERISTICS: Eastern Cooperative Oncology Group performance status 0-2 Absolute neutrophil count ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Hemoglobin ≥ 9.0 g/dL alanine aminotransferase and aspartate aminotransferase ≤ 2.5 times upper limit of normal (ULN) Alkaline phosphatase and γ-glutamyltransferase ≤ 2.5 times ULN Amylase and lipase ≤ 1.5 times ULN Total bilirubin ≤ 1.5 times ULN Creatinine < 1.5 mg/dL Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Must be available for study-related treatments and assessments at the treating institution No known hypersensitivity to any component of gemcitabine hydrochloride No known hypersensitivity to murine or recombinant proteins, polysorbate 80, or any excipient contained in the drug formulation No other primary malignancy that has been in remission for ≤ 3 years except treated nonmelanoma skin cancer, biopsy-confirmed carcinoma in situ of the cervix, squamous intraepithelial lesion on Papanicolaou smear, localized prostate cancer with Gleason score < 6, or resected melanoma in situ No other primary malignancy that has a generally accepted recurrence risk ≥ 10% No active viral, bacterial, or systemic fungal infection requiring parenteral treatment within 4 weeks of enrollment No history of chronic or recurrent infections that require continuous use of antiviral, antifungal, or antibacterial agents No serious underlying medical condition that would impair the patient's ability to receive or tolerate the planned treatment at the investigational site, including significant pulmonary compromise or heart disease of New York Heart Association class III or IV No dementia or altered mental status that would preclude sufficient understanding to provide informed consent PRIOR CONCURRENT THERAPY: See Disease Characteristics More than 4 weeks since prior major surgery More than 4 weeks since prior and no other concurrent investigational agents More than 1 week since prior oral antiviral, antifungal, or antibacterial therapy No concurrent immunosuppressive medications, steroids (except steroid inhaler, ophthalmic solution, nasal spray, or a stable dose of ≤ 10 mg/day of oral prednisone or equivalent), other antineoplastic therapy, or antitumor vaccinations Monoclonal antibody treatment for non-cancer indications must be completed at least 3 half lives from study entry No concurrent prophylactic hematologic growth factors No concurrent megavitamin therapy No concurrent bisphosphonates

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RAV12 plus gemcitabine<br> | Biological: RAV12<br>* RAV12 at 0.375 mg/kg weekly escalated to 0.75 mg/kg weekly, intravenously.<br>Drug: Gemcitabine<br>* 1000 mg/m2 weekly, intravenously<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Alive at 8 Months |  | 8 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Alive at 12 Months |  | 12 months | 
| Partial Response and Complete Response Rates | Based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.0; partial response = 30% decrease in sum of longest diameter. complete response = 100% decrease in sum of longest diameter. Rate of response = proportion of complete or partial responses based on number of patients evaluated. | 8 months | 
| Median Progression-free Survival | Time from the first dose date to the date of first documented progression or death from any cause, whichever occurs first. | up to 11 months | 
| Median Overall Survival | Time from the first dose date to the date of death from any cause | up to 11 months | 
| Participants With Adverse Events | Frequency of adverse events and serious adverse events | Throughout the study, up to 11 months | 
| Cmax | RAV12 and gemcitabine cmax | 29 days | 

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