This study will evaluate the safety and side effects of vaccine treatment in patients with carcinomas that have metastasized (spread to other parts of the body). The vaccine consists of three parts: 1) a "priming vaccine" called PANVAC-V, which is made from vaccinia virus; 2) a "boosting vaccine" called PANVAC-F, made from fowlpox virus; and 3) sargramostim, or GM-CSF, a protein that boosts the immune system. Human genes are inserted into the vaccinia and fowlpox viruses to cause production of carcinoembryonic antigen (CEA) and mucin 1 (MUC-1) - two proteins that are normally produced by some patient's tumor cells and can be used as a target for the immune system to attack the cancer. Another type of DNA is inserted to cause production of other proteins that enhance immune activity.

Patients 18 years of age and older with metastatic carcinoma that is not controlled by standard treatments and whose tumors produce CEA or MUC-1 protein may be eligible for this study. Patients with colorectal cancer must have antigen type HLA-A2 and must have completed at least one chemotherapy regimen that includes the drug 5-fluorouracil. Candidates are screened with a medical history and physical examination, blood and urine tests, electrocardiogram (ECG), and computerized tomography (CT) or magnetic resonance imaging (MRI) scans.

Participants receive the priming vaccination on study day 1 and a boosting vaccine at 2, 4 and 6 weeks (study days 15, 29 and 43). With every vaccination patients also receive an injection of sargramostim to increase the number of immune cells at the vaccination site. Sargramostim injections are given on the day of vaccination and daily for the next 3 days after each vaccination (study days 1-4, 15-18, 29-32, and 43-46). All vaccine and sargramostim doses are given as injections under the skin. They have a clinic visit, with blood and urine tests every 2 weeks for safety monitoring.

Patients undergo apheresis, a procedure for collecting immune cells called lymphocytes, on study days 1 and 71. For this procedure, blood is collected through a needle in an arm vein. The blood circulates through a machine that separates it into its components by spinning, and the lymphocytes are extracted. The rest of the blood is returned to the patient through the same needle. The collected lymphocytes are studied to measure the immune response to treatment.

Four weeks after the final boosting vaccination, patients have a physical examination, including a review of laboratory data and treatment side effects. They may also undergo repeat imaging scans to assess the status of the tumor.

Patients who do not develop serious treatment side effects and whose cancer does not worsen with vaccine treatment are offered participation in an optional 12-month extension phase of the study to continue receiving monthly boosting vaccinations along with sargramostim injections.

Condition	Treatment or Intervention	Phase
Adenocarcinoma	Drug: PANVAC-V [Recombinant-Vaccinia-CEA (D609)/MUC-1(L93)/TRICOM]  Drug: PANVAC-F [Recombinant-Fowlpox-CEA (D609)/MUC-1(L93)/TRICOM]	Phase I

Further Study Details: 

Expected Total Enrollment:  25

This is a pilot trial of PANVAC-V (vaccinia) and PANVAC-F (fowlpox) vaccines in patients with metastatic carcinoma that express CEA or MUC-1 antigen. PANVAC-V (vaccinia) is a recombinant vaccinia virus that contains the transgenes for CEA and MUC-1 (both with modified HLA-A2 agonist epitopes) as well as 3 human T-cell costimulatory molecules, B7-1, ICAM-1, and LFA-3 (designated TRICOM). PANVAC-F (fowlpox) is a recombinant replication defective fowlpox virus that contains the identical 5 transgenes as PANVAC-V (vaccinia). This is a non-randomized two arm, open label safety trial. The first arm will enroll 10 patients with metastatic colorectal adenocarcinoma who will receive PANVAC-V (vaccinia) subcutaneously (s.c.) scheduled on day 1, followed by PANVAC-F (fowlpox) s.c. scheduled on days 15, 29, and 43 (Core Phase). Sargramostim (100 micrograms) will be given at the site of the vaccination on each vaccination day and for three consecutive days thereafter. The second arm will consist of 10-15 patients with any metastatic carcinoma that expresses either CEA or MUC-1. Patients on both arms will receive the identical vaccine regimen. These two arms will allow for preliminary comparison of immune responses and preliminary analysis of toxicity and clinical responses in different disease states. All vaccines and follow-up will be given at the National Naval Medical Center (NNMC) or at the Warren Magnuson Clinical Center.

An optional provision of up to 12 additional monthly boosting vaccinations (Extension Phase) with PANVAC-F (fowlpox) s.c. in combination with sargramostim (GM-CSF) will be offered to patients who have completed the Core Phase of the study and who have not experienced disease progression. In addition, for post study evaluation patients will be seen approximately one month after their final vaccination to evaluate toxicity. Patients will be followed for up to 15 years.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA:
A. Histologically confirmed carcinoma that is CEA or MUC-1 positive. Tumor that has been shown to express CEA or MUC-1 (greater than or equal to 20 % of cells) by immunohistochemical techniques or patients that have had an elevated serum CEA (greater than 5 microgram/L) at any point during their disease course.
B. Patients must have completed at least one 5-FU containing chemotherapy regimen (e.g. 5-FU/LV with or without either irinotecan or oxaliplatin) for the colorectal cancer arm, or either failed or not be a candidate for therapy of proven efficacy for their disease in the non-colorectal cancer arm.
C. 18 years of age or greater.
D. All patients on the colorectal adenocarcinoma cohort must be HLA-A2 positive.
E. At least 10 patients on the non-colorectal adenocarcinoma cohort must be HLA-A2 positive.
F. Metastatic disease (measurable or evaluable): metastatic disease documented by biopsy but not evaluable by imaging (e.g. small volume peritoneal disease), and patients with surgically resected metastatic disease at high risk of relapse.
G. Able to understand and give informed consent.
H. Able to avoid close household contact (close household contacts are those who share housing or have close physical contact) for at least three weeks after recombinant vaccinia vaccination with persons with active or a history of eczema or other eczematoid skin disorders; those with other acute, chronic or exfoliative skin conditions (e.g., atopic dermatitis, burns, impetigo, varicella zoster, severe acne, or other open rashes or wounds) until condition resolves; pregnant or nursing women; children 5 years of age and under; and immunodeficient or immunosuppressed persons (by disease or therapy), including HIV infection.
I. ECOG performance status of 0 - 1.
J. Serum creatinine within the institution limits of normal, and AST less than or equal to twice the upper limits of normal (at National Naval Medical Center this is a serum creatinine less than or equal to 1.5 mg/dL OR creatinine clearance on a 24 hour urine collection of greater than or equal to 60 mL/min, a total bilirubin less than or equal to 1.3, and AST less than or equal to 98 U/L and mg/DL).
K. Total bilirubin within the institution limits of normal OR patients with Gilbert's syndrome, a total bilirubin less than or equal to 3.0
L. Recovered completely from any reversible toxicity associated with recent therapy. Typically this is 3-4 weeks for patients who most recently received cytotoxic therapy except for the nitrosoureas and mitomycin C for which 6 weeks is needed for recovery.
M. Hematological eligibility parameters (within 16 days of starting therapy):
- Granulocyte count greater than or equal to 1,500/mm3
- Platelet count greater than or equal to 100,000/mm3
- Lymphocyte count greater than or equal to 500/mm3
- Hgb equal to 10 Gm/dL
N. Prior immune therapy with related vaccinia and fowlpox vaccines or antigen-specific peptides is allowed.
O. Men and women must agree to use effective birth control or abstinence during and for a period of 4 months after the last vaccination therapy.
P. Patients with prostate cancer must continue to receive GnRH agonist therapy (unless orchiectomy has been done).
INCLUSION CRITERIA FOR EXTENSION PHASE:
A. Completion of Core phase of the protocol.
B. Stable or responding disease (PR, CR).
C. No dose limiting toxicity (see below) in Core phase possibly, probably or definitely related to the vaccine.
Dose limiting toxicities include:
- Any Grade 2 generalized urticaria or Grade 3 or greater allergic reaction.
- Any Grade 2 or greater autoimmune response.
- Any Grade 3 or greater hematologic or non-hematologic reaction, including injection-site reaction.
EXCLUSION CRITERIA:
A. Patients should have no evidence of being immunocompromised as listed below.
- Human immunodeficiency virus positivity due to the potential for decreased tolerance and risk for severe side effects
- Active autoimmune diseases requiring treatment or a history of autoimmune disease that might be stimulated by vaccine treatment. This requirement is due to the potential risks of exacerbating autoimmunity. Patients with endocrine disease that is controlled by replacement therapy including thyroid disease and adrenal disease and vitiligo may be enrolled.
- Concurrent use of systemic steroids, except for physiologic doses for systemic steroid replacement or local (topical, nasal, or inhaled) steroid use. Limited doses systemic steroids to prevent IV contrast, allergic reaction, or anaphylaxis (in patients who have known contrast, allergic reaction, or anaphylaxis (in patients who have known contrast allergies) are allowed.
B. History of allergy or untoward reaction to prior vaccination with vaccinia virus
C. Pregnant or breast-feeding women
D. Altered immune function, including immunodeficiency or history of immunodeficiency; eczema; history of eczema, or other eczematoid skin disorders; or those with acute, chronic or exfoliative skin conditions (e.g. atopic dermatitis, burns, impetigo, varicella zoster, severe acne, or other open rashes or wounds)
E. Serious intercurrent medical illness which would interfere with the ability of the patient to carry out the treatment program, including, but not limited to, inflammatory bowel disease, Crohn's disease, ulcerative colitis, or active diverticulitis
F. Clinically active brain metastasis, or a history of seizures, encephalitis, or multiple sclerosis.
G. Medical conditions, which, in the opinion of the investigators would jeopardize the patient or the integrity of the data obtained
H. Concurrent chemotherapy.
I. Serious hypersensitivity reaction to egg products
J. Clinically significant cardiomyopathy requiring treatment.
K. Chronic hepatitis infection, including B and C, because of potential immune impairment
L. Although topical steroids are allowed, steroid eye drop are contraindicated.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  040246; 04-C-0246
Record last reviewed:  January 20, 2005
Last Updated:  April 2, 2005
Record first received:  July 23, 2004
ClinicalTrials.gov Identifier:  NCT00088413
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08