Protocol Number: 03-C-0040

Title:

A Multicenter Phase I-II Study of Tumor Vaccine Following Chemotherapy in Patients with Metastatic Breast Cancer Untreated with Chemo/Radiation in the Previous 18 Months: Vaccine-Induced Bias of T-Cell Repertoire Reconstitution After T-Cell Re-Infusion

Number:

03-C-0040

Summary:

This study will evaluate the effectiveness of chemotherapy and a combination of vaccines to treat metastatic breast cancer (breast cancer that has spread beyond the breast) in patients whose cancer cells have a protein called CEA on their surface. 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. Newly diagnosed patients may not have received prior chemotherapy. Patients previously diagnosed with local disease may have received chemotherapy or radiation therapy at least 18 months before entering the current study. Patients may have received hormonal therapy for stage IV disease. Candidates are screened with a medical history and physical examination, blood and urine tests, x-rays, heart and lung tests, and a test to determine the presence of CEA on their tumor cells.

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 treatment and at various times before and after chemotherapy, patients undergo apheresis to collect white blood cells for later re-infusion at the time of immunizations and to evaluate the body's response to the vaccines. 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 white cells are removed and frozen for later use. The rest of the blood is returned to the patient through the catheter.

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 bone marrow to release white blood cells and white cell precursors into the bloodstream.

4. Chemotherapy:

-Taxol (paclitaxel)/Cytoxan (cyclophosphamide): Patients receive three to five cycles of Taxol and Cytoxan. Taxol is given as a continuous 72-hour intravenous (IV, through a vein) infusion and Cytoxan is given daily for 3 days, intravenously, over 1 hour. 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 cells collected before the start of chemotherapy.

5. Additional vaccines: Starting 3 weeks after immune-depleting chemotherapy, patients receive a series of three monthly immunizations 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 that were collected during apheresis to boost the body's response to the vaccines.

6. Hormonal treatment: Patients whose tumors are estrogen- or progesterone-positive receive hormonal treatment, probably with Tamoxifen, after all chemotherapies are completed.

The total length of treatment varies, depending on the number of cycles patients receive and whether or not they also undergo surgery or radiation therapy.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Participants currently recruited/enrolled

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.

--Method: 5 microM formalin-fixed paraffin-embedded sections are deparaffinized and blocked with methanol-30% H2O2. After antigen retrieval by boiling in citrate buffer, or heating in a microwave oven for 10 minutes, slides are incubated with monoclonal antibodies anti-CEA (diluted 1/1000 Dako). Then, slides are immunostained with avidin-biotin-peroxidase complex and developed with diaminobenzidine. Harris' hematoxylin was used to counter stain the slides. Positivity is defined as greater than 30% of cells staining.

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

-- 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 or 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 or equal to 70% (ECOG 0 or 1)

Ejection fraction by MUGA or 2-D echocardiogram within normal institutional limits. 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 or equal to 60 cc/min

Normal urinalysis; if proteinuria is present it must be quantified at less than 1 g / 24 h on a measured 24 h urine collection

AST and ALT less than 3 times the 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 l000 / 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 3 years old, pregnant women, individuals with eczema or other skin conditions, and immuno-suppressed people for 2 weeks after initial vaccination. (see protocol for 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 (as defined in protocol) 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 after review with appropriate consultant. Patients with endocrine disease that is controlled by replacement therapy including, diabetes, thyroid and adrenal disease or vitiligo may be enrolled.

Patients with active inflammatory bowel disease

Patients with clinically significant cardiomyopathy requiring treatment or symptomatic CHF, symptomatic arrhythmia that is not controlled by medication, unstable CAD such as unstable angina who require active intervention, and patients with a recent infarction or CVA within the past 6 months

Patients testing positive for HIV or hepatitis B or C

Patients known or found to be pregnant or those unwilling to discontinue breastfeeding. The effects of the chemotherapy, vaccines, and the medications used in this study are highly likely to be harmful to a fetus. The effects upon breast milk are also unknown and may be harmful to the infant; therefore, women should not breastfeed while on this study.

Patients of childbearing age who are unwilling to practice an effective form of contraception. Patients of childbearing potential must use an effective method of contraception while they are on-study; effective methods include intrauterine device (IUD), hormonal (birth control pills, injections, or implants), tubal ligation/hysterectomy (self or partner), partner's vasectomy, or barrier methods (condom, diaphragm, or cervical cap), or abstinence.

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 3 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 Keyword(s):

Breast Cancer

Condition(s):

Breast Neoplasms

Metastases, Neoplasm

Investigational Drug(s):

rV-CEA (6D)/TRICOM

rF-CEA(6D)/TRICOM

Investigational Device(s):

None

Intervention(s):

Drug: rVaccinia/Fowlpox-CEA Tricom

Drug: rV-CEA (6D)/TRICOM

Drug: rF-CEA(6D)/TRICOM

Supporting Site:

National Cancer Institute

Contact(s):

NCI Referral Office
National Institute of Health Clinical Center (CC), 9000 Rockville Pike, Bethesda, Maryland 20892, United States: NCI Clinical Trials Referral Office
Phone: 1-888-NCI-1937
Fax: Not Listed
Electronic Address: ncicssc@mail.nih.gov

Citation(s): Not Provided

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