Vaccine Therapy and GM-CSF in Treating Patients With Locally Advanced or Metastatic Pancreatic Cancer That Cannot Be Removed By Surgery

RATIONALE: Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells. Colony-stimulating factors, such as GM-CSF, may increase the number of immune cells found in bone marrow or peripheral blood. Injecting the vaccine directly into the tumor and giving it together with GM-CSF may cause a stronger immune response and kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of vaccine therapy when given together with GM-CSF in treating patients with locally advanced or metastatic pancreatic cancer that cannot be removed by surgery.

OBJECTIVES:

Primary

• To determine the tolerability of delivering two standard doses of intratumoral recombinant fowlpox PANVAC vaccine (PANVAC-F; falimarev) when administered in combination with subcutaneous recombinant vaccinia PANVAC vaccine (PANVAC-V; inalimarev) followed by subcutaneous PANVAC-F vaccine and sargramostim (GM-CSF) in patients with unresectable locally advanced or metastatic pancreatic cancer.

Secondary

• To assess the toxicity of this regimen.
• To assess evidence of tumor response by imaging and tumor markers.
• To assess gene transfer to pancreatic tissue.
• To assess immunologic response to this regimen.

OUTLINE: This is a dose-escalation study of intratumoral recombinant fowlpox PANVAC vaccine (PANVAC-F; falimarev).

Patients receive an intratumoral injection of PANVAC-F vaccine using endoscopic ultrasound guidance. Patients also receive recombinant vaccinia PANVAC vaccine (PANVAC-V; inalimarev) subcutaneously (SC) on day 1 and sargramostim (GM-CSF) SC on days 1-4. Patients then receive PANVAC-F vaccine SC on days 15 and 29 and GM-CSF SC on days 15-18 and 29-32 in the absence of unacceptable toxicity. Beginning on day 43, patients with stable or improving pancreatic cancer receive PANVAC-F vaccine SC and GM-CSF SC (given on the day of and for 3 days after each PANVAC-F vaccination) monthly in the absence of disease progression or unacceptable toxicity. Beginning on day 71, patients with no irreversible or dose limiting toxicity , receive PANVAC-F vaccine SC (given on the day of and for 3 days after each PANVAC-F vaccination) monthly in the absence of disease progression or unacceptable toxicity.

Patients will undergo biopsy periodically for correlative studies.

After completion of study treatment, patients are followed every 3 months.

• Biological: falimarev
  Intratumoral falimarev priming and two peripheral boost injections over a period of one month prior to the initiation of other standard treatment. Dose escalation from from 1 x 10^8 pfu to 1 x 10^9 pfu
  Other Name: PANVAC-F (fowlpox)
• Biological: inalimarev
  Systemic inalimarev priming one month prior to initiating standard therapy.
  Other Name: PANVAC-V (vaccinia)
• Biological: sargramostim
  100 mcg subcutaneously following injection with systemic inalimarev on Day 1 or 2, followed by 100 mcg subcutaneously for 3 consecutive days. Then 100 mcg subcutaneously following injection with intratumoral falimarev on Day 15, followed by 100 mcg subcutaneously for 3 consecutive days. Then 100 mcg subcutaneously following injection with intratumoral falimarev on Day 29, followed by 100 mcg subcutaneously for 3 consecutive days.
  Other Name: GM-CSF

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed pancreatic adenocarcinoma, meeting one of the following criteria:

  • Locally advanced disease not amenable to curative resection

  • Newly diagnosed metastatic disease of small volume, limited to the following:

    • Liver involvement < 10% of volume and no metastasis > 2 cm
    • Pulmonary involvement with no respiratory compromise and no metastasis > 2 cm
    • Peritoneal disease and no metastasis > 2 cm with no ascites (as might be found on exploratory laparoscopy)
• Site of pancreatic cancer must be amenable to endoscopic ultrasound injection
• No known brain metastases

PATIENT CHARACTERISTICS:

• ECOG performance status (PS) 0-1 OR Karnofsky PS 80-100%
• Anticipated life expectancy ≥ 6 months
• Leukocyte count ≥ 3,000/mcL
• Hemoglobin ≥ 8 g/dL
• Absolute neutrophil count ≥ 1,500/mcL
• Platelet count ≥ 100,000/mcL
• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST/ALT ≤ 2.5 times ULN
• PT/PTT normal
• Amylase/lipase ≤ 1.5 times ULN
• Creatinine ≤ 1.5 times ULN
• Urine protein ≤ 1+ by urinalysis OR urine protein ≤ 1,000 mg by 24-hour urine collection
• No evidence of casts by urinalysis
• Not pregnant
• No nursing during and for ≥ 4 months after completion of study treatment
• Fertile patients must use effective contraception prior to, during, and for 4 months after completion of study treatment
• No active pancreatitis, defined as clinically symptomatic hyperamylasemia and/or hyperlipasemia
• No other active illness (e.g., uncontrolled infection, uncontrolled cardiac disease) that would preclude safe therapy
• No history of allergic reactions or severe adverse reactions attributed to compounds of similar chemical or biologic composition to the study vaccines including, but not limited to, vaccinia (small pox vaccination) or fowlpox viral vectors
• No allergy to sargramostim (GM-CSF) or eggs

• No other uncontrolled illness including, but not limited to, any of the following:

  • Active infection
  • Symptomatic congestive heart failure or documented cardiomyopathy
  • Cardiac arrhythmia
  • Myocardial infarction or cerebrovascular accident within the past 6 months
  • Unstable or uncontrolled angina requiring urgent cardiovascular intervention
  • Psychiatric illness/social situation that would preclude compliance with study requirements
• No HIV positivity
• No hepatitis B or C infection
• No evidence of immunodeficiency or immune suppression

• No autoimmune diseases, including any of the following:

  • Autoimmune neutropenia
  • Thrombocytopenia
  • Hemolytic anemia
  • Systemic lupus erythematosus
  • Sjögren syndrome
  • Scleroderma
  • Myasthenia gravis
  • Goodpasture syndrome
  • Addison disease
  • Hashimoto thyroiditis
  • Active Graves disease
• No prior or concurrent extensive eczema or acute, chronic, or exfoliative skin disorders (e.g., extensive psoriasis, burns, impetigo, disseminated zoster, varicella zoster, severe acne, or other open rashes or wounds)

• Must be able to avoid close contact or household contact with the following high-risk individuals for 3 weeks after vaccinia vaccination:

  • Children under the age of 3 years
  • Pregnant or nursing women
  • Individuals with active or a history of eczema, atopic dermatitis, or Darier disease
  • Individuals with other unresolved acute, chronic, or exfoliative skin conditions (e.g., burns, impetigo, varicella zoster, severe acne, contact dermatitis, psoriasis, herpes, or other open rashes or wounds)
  • Immunocompromised individuals (by disease or therapy), such as those with AIDS
• No other concurrent malignancy, except nonmelanoma skin cancer or in situ cervical cancer, unless the patient has been curatively treated and has been disease free for ≥ 2 years

PRIOR CONCURRENT THERAPY:

• Recovered from prior therapy

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C), radiotherapy, or systemic corticosteroid therapy

  • No prior radiotherapy to the pancreas
• No prior immunotherapy for unresectable pancreatic cancer
• No prior splenectomy
• More than 28 days since prior and no other concurrent investigational agents
• No other anticancer agents, including chemotherapy or biologic agents, during the first 35 days of study treatment
• No other concurrent vaccines or immunotherapy
• No systemic anticoagulation during the first 21 days of study treatment
• No topical steroids, steroid eye drops, or inhaled steroids for 2 weeks before, during, and for ≥ 4 weeks after vaccinia vaccination
• No concurrent routine use of systemic corticosteroid therapy