Protocol Number: 03-C-0040

Title:

A Phase I-II Study Of Tumor Vaccine Following Chemotherapy In Patients With Previously Untreated Metastatic Breast Cancer: Vaccine-Induced Bias Of T-Cell Repertoire Reconstitution After T-cell Re-Infusion

Number:

03-C-0040

Summary:

This study will evaluate the safety and effectiveness of a combination of vaccines and chemotherapy to treat metastatic breast cancer (breast cancer that has spread beyond the breast) in patients whose cancer cells have a surface protein called CEA. Patients who require surgery or radiation therapy, or both, will receive these treatments as well.

Patients 18 years of age and older with previously untreated metastatic breast cancer may be eligible for this study. Patients known or found to have metastases in the brain are not eligible for the study. Patients may be newly diagnosed with metastatic breast cancer or known to have breast cancer but newly diagnosed with metastatic disease. Newly diagnosed patients may not have received prior chemotherapy but they may have received hormonal therapy for stage IV disease. Patients previously diagnosed with local disease may have received chemotherapy or radiation therapy but at least 18 months before entering the current study. Candidates will be screened with blood and urine tests, x-rays, and heart and lung tests.

Participants undergo the following procedures:

1. Central venous line: Under local or general anesthesia, an intravenous catheter (plastic tube) is inserted into a major vein in the chest. It is used to give chemotherapy and other medications and to withdraw blood samples.

2. Apheresis: Before beginning chemotherapy, patients undergo apheresis to collect white blood cells (lymphocytes) for later re-infusion at the time of immunizations. For this procedure, blood is collected through the central venous catheter and circulated through a machine that separates the white cells from the rest of the blood. The rest of the blood is returned to the patient through the catheter. The white cells are removed and frozen for later use.

3. First vaccine: Before starting chemotherapy, patients receive one subcutaneous (under the skin) injection of a vaccine called rV-CEA-Tricom, along with subcutaneous injections of GM-CSF (Sargramostim), a drug that stimulates the response of the immune system to the vaccine.

4. Chemotherapy. Chemotherapy includes:

-Taxol (paclitaxel)/Cytoxan (cyclophosphamide) - Patients receive three to five cycles of Taxol and Cytoxan. Taxol is given as a continuous 72-hour intravenous (through a vein) infusion and Cytoxan is given daily for 3 days intravenously (IV). Cycles are 21 to 42 (usually 28) days. After each cycle, patients also receive G-CSF (a drug that helps boost white cell counts) by injection under the skin. The also receive Mesna, a drug that protects the bladder from harmful side effects of Cytoxan.

-Adriamycin (doxorubicin)/Cytoxan: Patients may receive additional chemotherapy with Adriamycin and Cytoxan for a maximum of 4 cycles. Adriamycin is given as a 10-minute IV bolus and Cytoxan is infused IV over 1 hour. Cycles are usually 21 days.

-Immune-depleting chemotherapy: Patients receive a final course of chemotherapy (following radiation, if needed) with Cytoxan and fludarabine to lower the immune system in preparation for receiving the white blood cells (lymphocytes) collected before the start of chemotherapy.

-Additional vaccines: Starting 3 weeks after immune-depleting chemotherapy, patients receive a series of immunizations once a month with a second type vaccine called rF-EA-Tricom). Starting 10 months after the immune-depleting chemotherapy, they will get a booster shot of the same vaccine every 6 months for four doses, along with four daily injections of Sargramostim. Along with the first series of immunizations, patients receive the white cells (lymphocytes) that were collected during apheresis to boost the body's response to the vaccines.

5. Hormonal treatment: Patients whose tumors are hormone receptor positive will receive hormonal therapy after all chemotherapies are completed.

The total length of treatment varies from about 25 to 41 months, depending on the number of cycles patients receive and whether or not they also undergo surgery or radiation therapy. (The last 18 months consist only of one vaccine injection every 6 months)

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): Children

Eligibility Criteria:

INCLUSION CRITERIA:

All patients must have a diagnosis of metastatic infiltrating carcinoma of the breast including hormone receptor testing. At least one site of metastatic disease must have been confirmed by pathologic or cytologic material. In the choice of a biopsy site, the PI will weigh the morbidity the diagnostic procedure against the probability of positive yield of the diagnostic procedure.

All pathologic material must be reviewed by the Pathology Laboratory of the NCI before treatment. The tumor MUST stain positive for CEA, by standard immuno-histochemistry performed at the Pathology Laboratory of the NCI.

Patients may be newly diagnosed with metastatic breast carcinoma or known to have breast carcinoma but newly diagnosed with metastatic disease.

-If newly diagnosed, patients may not have received any chemotherapy for this disease before entry on study.

-If previously treated for breast cancer, patients may have received chemotherapy or radiation as adjuvant treatment for non-metastatic disease but not in the previous 18 months.

-Patients may have been on hormonal therapy for stage IV disease. Patients with disease progression on hormonal therapy alone are eligible.

Karnofsky performance status of greater than 70% (ECOG 0 or 1).

Ejection fraction by MUGA or 2-D echocardiogram of greater than 45%. In case of insufficient ejection fraction, a stress echocardiogram will be performed. In case of an ejection fraction greater than 35% but less than 45%, the patient will remain eligible for the study if the increase of ejection fraction with stress is estimated at 10% or more.

Creatinine clearance greater than 60 cc/min.

Normal urinalysis; if proteinuria is present it must be quantified at less than 150 mg/24 h on a measured 24 h urine collection. Any other abnormalities in the urine sediment or the presence of hematuria should be evaluated by a nephrologist for evidence of underlying renal pathology. Patients may be eligible if the underlying cause of the abnormality is determined to be non-renal.

AST and ALT less than 3 x upper limit of normal except if believed to be due to tumor involvement of the liver prior to induction therapy.

Bilirubin less than 1.5 (except if due to tumor involvement prior to induction therapy or in cases of Gilbert's disease).

Absolute Neutrophil Count greater than 1000/mm(3) and Platelet count greater than 90,000.

Corrected DLCO greater than 50%.

No history of abnormal bleeding tendency or predisposition to repeated infections.

Patient must be able to avoid close contact with children under 5 years old, pregnant women, individuals with eczema or other skin conditions, and immuno-suppressed people for 2 weeks after initial vaccination. (Specific exclusion criteria for vaccinia administration). Patients must agree to make specific arrangements, if necessary, in order to comply and be eligible.

Patients must be able to give informed consent.

EXCLUSION CRITERIA:

Age less than 18 years.

Patients in whom an urgent or emergent clinical situation does not safely allow for the short delay in initiating the Concurrent Therapy necessary for the pre-treatment immunization and lymphocyte collection (at the discretion of the PI).

Patients requiring chronic immunosuppressive therapy (including corticosteroids) for any medical condition.

Patients with an autoimmune disease: autoimmune neutropenia, thrombocytopenia, or hemolytic anemia; Rheumatoid Arthritis, Systemic Lupus Erythematosus, Sjogren syndrome, Scleroderma, Systemic Sclerosis, Myasthenia Gravis; Multiple sclerosis, Goodpasture syndrome; Addison's disease, Hashimoto's thyroiditis, or active Graves' disease.

Any abnormality on the following tests suggestive of an autoimmune disease: ANA, anti-DNA, T3, T4, TSH.

Patients with active inflammatory bowel disease.

Patients with clinically significant cardiomyopathy requiring treatment.

Patients testing positive for HIV or Hepatitis B or C.

Patients known or found to be pregnant.

Patients of childbearing age who are unwilling to practice contraception.

Patients with brain metastases.

Patients with an active second malignancy (excluding treated skin cancers or carcinoma in-situ) will be ineligible.

Patients with a life expectancy reasonably estimated at less than 6 months.

Patients may be excluded at the discretion of the PI if it is deemed that allowing participation would represent an unacceptable medical or psychiatric risk.

History of splenectomy.

Allergy to eggs.

Several exclusion criteria are specific to vaccinia administration: The recombinant vaccinia vaccine should not be administered if the following apply to either recipients or, for at least two weeks after vaccination, to 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.

Persons 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 under 5 years of age.

Immunodeficient or immunosuppressed persons by disease or therapy, including HIV infection.

History of seizures, encephalitis, or multiple sclerosis.

History of allergy or complications with past vaccinia vaccination.

Special Instructions: Currently Not Provided

Keywords:

CEA vaccine

Metastatic Breast Cancer

T-cell Repertoire

High-dose Chemotherapy

Recruitment Keywords:

Breast Cancer

Conditions:

Breast Neoplasms

Metastases, Neoplasm

Investigational Drug(s):

rV-CEA (6D)/TRICOM

rF-CEA(6D)/TRICOM

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: Not Provided

• Questions about participating in a study, please contact the Patient Recruitment and Public Liaison Office, CC.
• Technical questions regarding the Clinical Center web site, please contact the Department of Networks and Applications, CC.

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