Corporate decision

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.

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.

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

Throughout the study, up to 11 months