Protocol Number: 04-C-0167

Title:

A Phase I Trial of a CEA-TRICOM Based Vaccine and Radiation to Liver Metastasis with or without Celecoxib in Patients with CEA Positive Solid Tumors

Number:

04-C-0167

Summary:

This study will evaluate the effects of vaccine treatment plus radiation, either with or without addition of a drug called celecoxib, in patients with solid tumors that have spread to the liver. The vaccine treatment consists of three parts: 1) a priming vaccine made from vaccinia virus; 2) a boosting vaccine made from fowlpox virus; and 3) Sargramostim (GM-CSF), a protein that boosts the immune system. Human DNA is inserted into some of the vaccinia and fowlpox viruses to cause production of proteins that enhance immune activity and also to produce carcinoembryonic antigen (CEA), a protein that is normally produced by the patient's tumor cells. Celecoxib is an anti-inflammatory medicine approved for treating certain forms of arthritis. Laboratory and animal studies have shown that vaccines and celecoxib, used in combination with radiation, may be effective in killing cancer cells.

Patients 18 years of age and older who have a solid tumor that has spread to the liver may be eligible for this study. Candidates must have had at least one course of chemotherapy for metastatic disease; they must have four or more positive lymph nodes; and their tumor must produce CEA. Half of the patients must have HLA-A2 tissue type. Candidates are screened with a medical history and physical examination; blood and urine tests, imaging studies to assess the extent of tumor, and an electrocardiogram and cardiologic evaluation, if clinically indicated.

Participants are randomly assigned to one of two groups: Group 1 receives vaccine treatment plus radiation to the liver; Group 2 receives vaccine treatment, radiation to the liver, and celecoxib. All patients in both groups receive the priming vaccination on study day 1. After 3 weeks and then again every 2 weeks for 2 months (study days 21, 35, 49, and 63), they receive a boosting vaccine. All vaccines are injected under the skin. With each vaccination participant also receives an injection of Sargramostim to increase the number of immune cells at the vaccination site. The day after each of the first four boosting vaccinations, patients undergo 4 consecutive days of radiation to the tumor in the liver (study days 22-25, 36-39, 50-53, and 64-67). In addition to vaccine and radiation treatments, patients in group 2 take celecoxib in pill form every day of the study. All patients may continue treatment with monthly booster vaccinations and, for patients in group 2, daily celecoxib pills, as long as their cancer is not worsened and they do not develop serious treatment side effects.

Patients are monitored for safety and treatment response with the following tests and procedures:

- Blood and urine tests every 2 to 4 weeks.

- Periodic imaging scans to assess the status of the tumor.

- Apheresis (a procedure for collecting immune cells called lymphocytes): Apheresis is done around the first day of the study and again around study day 91. 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.

- Liver biopsy (optional): This test is done once before starting radiation treatment and again around 3 to 7 days after completing the first dose of radiation. The biopsy provides information on the type of cancer, the level of CEA produced by the tumor, and the immune status of the tumor. For this procedure, the skin over the liver is numbed with an anesthetic, a needle is placed in the liver tumor, and a small sample of tumor is withdrawn through the needle.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA

Solid Tumors expressing CEA positive cancer with radiographically visible metastatic liver lesions as the life-threatening aspect of the disease (as a guideline, metastatic liver lesions should be at least approximately 75% of total tumor burden). Tumor that has been shown to express CEA by positive immunohistochemical techniques (staining of at least 20% of cells will be considered positive) or have had an elevated serum CEA greater than 10 ng/ml at any point during their disease course.

Completed at least one chemotherapy regimen for metastatic disease.

18 years of age or greater.

Life expectancy greater than or equal to 6 months.

Able to understand and give informed consent.

ECOG performance status of 0 - 1.

Serum creatinine within the institution limits of normal OR creatinine clearance on a 24 hour urine collection of 60 mL/min or greater, total bilirubin within the institution limits of normal and AST less than or equal to twice the institution upper limits of normal.

Vaccinia-naive or vaccinia immune.

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.

At least 4 weeks after cytotoxic therapy with complete recovery of reversible toxicity.

At least 3 of the 6 patients in each cohort must be HLA-A2 positive. (If none of the first three patients in a cohort are A2 positive, then subsequent patients will be prescreened for A2 positivity prior to enrollment.)

Hematological eligibility parameters (within 16 days of starting therapy):

Granulocyte count of 1,500/mm3 or greater

Platelet count of 100,000/mm3 or greater

Hgb of 8 Gm/dL or greater

Absolute lymphocyte count of 400/mm3 or greater

PT/PTT within the institution limits of normal.

Prior Immunotherapy will be allowed

Serum Beta-HCG less than 5.0 microIU/mL in females (with child bearing potential).

EXCLUSION CRITERIA

Patients should have no evidence of being immunocompromised as listed below.

-Human immunodeficiency virus positivity due to the potential for decreased tolerance and may be at risk for severe side effects

-Autoimmune diseases such as, Addison's disease, Hashimoto's thyroiditis, or systemic lupus erythematous, Sjogren syndrome, scleroderma, myasthenia gravis, Goodpasture syndrome active Grave's disease. Altered immune function in prospective participants will be assessed through a thorough history and physical examination. Any clinical suspicion of autoimmune dysfunction will be worked up before enrollment on to the study. This requirement is due to the potential risks of exacerbating autoimmunity

-Hepatitis B or C positivity

-Prior radiation to greater than 50% of all nodal groups

-Prior whole liver radiation

-Concurrent use of nonsteroidal anti-inflammatory drugs

-Concurrent use of systemic steroids, except for physiologic doses for systemic steroid replacement or local (topical, nasal, or inhaled) steroid use. Steroid eye drops are contraindicated for at least 2 weeks prior vaccinia vaccination and at least 4 weeks post vaccinia vaccination.

-Prior splenectomy

History of allergy or untoward reaction to prior vaccination with vaccinia virus or to any component of the vaccinia vaccine regimen.

Pregnant or breast-feeding women.

Recombinant vaccinia vaccination should not be administered if any of the following apply to either recipients, or for at least three weeks after vaccination (i.e., until the scab has separated from the skin and the underlying skin has healed), their close household contacts (close household contacts are those who share housing or have close physical contact): 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.

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.

Known brain metastasis, history of seizures, encephalitis, or multiple sclerosis.

Concurrent chemotherapy.

Serious hypersensitivity reaction to egg products.

Clinically significant cardiomyopathy requiring treatment.

For Cohort II only: known hypersensitivity to celecoxib, or allergic reaction to sulfonamides.

For Cohort II only: History of peptic ulcer or gastrointestinal bleeding deemed as clinically significant by the investigator.

For Cohort II only: Known hypersensitivity to aspirin or other NSAID's and aspirin-sensitive asthma.

For Cohort II only: Concurrent use of inhibitors of P450 2C9, or concurrent fluconazole or lithium therapy.

Patients with cardiac disease that have fatigue, palpitation, dyspnea or angina with ordinary physical activity (New York Heart Association class 2 or greater) are not eligible.

Patients with pulmonary disease that have fatigue or dyspnea with ordinary physical activity are not eligible.

Patients who have objective evidence of congestive heart failure by physical exam or imaging are not eligible.

Chronic liver disease including end stage cirrhosis, or chronic active hepatitis as indicated by surface antigen or core antibody.

Special Instructions: Currently Not Provided

Keywords:

Colon Cancer

Gastrointestinal Cancer

Cytokines

Immunotherapy

Recruitment Keywords:

Cancer

Solid Tumor

Liver Metastasis

Conditions:

Liver Neoplasms

Investigational Drug(s):

rV-CEA(6D)/TRICOM

rF-CEA(6D)/TRICOM

Recombinant Fowlpox-GM-CSF

Celecoxib

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Rogers GT. Carcinoembryonic antigens and related glycoproteins. Molecular aspects and specificity.

Biochim Biophys Acta. 1983 Dec 29;695(3-4):227-49. Review. No abstract available.

Muraro R, Wunderlich D, Thor A, Lundy J, Noguchi P, Cunningham R, Schlom J. Definition by monoclonal antibodies of a repertoire of epitopes on carcinoembryonic antigen differentially expressed in human colon carcinomas versus normal adult tissues. Cancer Res. 1985 Nov;45(11Pt2):5769-80.

Steward AM, Nixon D, Zamcheck N, Aisenberg A. Carcinoembryonic antigen in breast cancer patients: serum levels and disease progress. Cancer. 1974 May;33(5):1246-52. No abstract available.

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