Vaccine and Chemotherapy for Previously Untreated Metastatic Breast Cancer

Phase 1

Terminated

Conditions: Breast Neoplasms
Metastases, Neoplasm

Registration Number: NCT00048893

Lead Sponsor: National Cancer Institute (NCI)

Brief 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 carcinoembryonic antigen (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 granulocyte macrophage colony stimulating factor (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 (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 growth colony stimulating factor (G-CSF) (a drug that helps boost white cells.

Detailed Description: BACKGROUND: Metastatic breast cancer remains to this day a mostly incurable disease, with less than 10% of patients reaching a long-term disease free survival. This study proposes using an immune-depleting chemotherapy as platform for immunotherapy. It is based on the following hypotheses and understanding:

* The combination of dose-intensive followed by immune-depleting chemotherapy provides a platform for subsequent immunotherapy by:

1. Lengthening the progression-free survival period, thus allowing time for a slow acting therapy such as vaccination to be effective.

2. Maximally decreasing the patient's tumor burden. This has been shown both in clinical and experimental settings to be desirable if not necessary for immunotherapy to be effective.

3. Decreasing the tumor burden which may also decrease a tumor-induced immuno-suppressive effect linked to tumor bulk.

4. Providing tumor antigen exposure following immune depletion in the form of repeated immunizations. This may take advantage of the pattern of immune reconstitution following immune depleting therapy at early time points (antigen-driven peripheral expansion of T-cells) and the renewal of a T-cell repertoire biased towards tumor antigens and anti-tumor responses at later time points.

* Low antigenicity of tumor antigens and immune tolerance may be overcome in a clinically relevant fashion by providing exposure to the tumor antigens (the carcino-embryonic antigen CEA) in a more immunogenic presentation along with added co-stimulatory signal (in the form of two poxvirus-based recombinant vaccines).

* Due to the post immune depletion defects and delay in immune reconstitution, an adequate immune response to vaccines may not occur unless the patients are provided, following immune depletion, with unaltered T-cells in the form of re-infusion of pre-chemotherapy lymphocytes.

The late recovery of thymic function (18 to 24 months) with reappearance of naive T-cells may play a determinant role in the prevention of later disease progression. It is the rationale for a late series of immunizations.

ELIGIBILITY: Patients with metastatic breast cancer untreated with chemotherapy or radiation in the previous 18 months with CEA positivity in either the tumor or the serum.

OBJECTIVES: The primary objectives are to evaluate biologically this immunization strategy by assessing CEA specific T-cell responses as well as clinically by comparing the patient event free survival (EFS) to our historical control (protocol 96-C-0104) in which patients have received the same conventional therapy but no immunization

DESIGN: Before any chemotherapy patients will be immunized with one of two tumor-specific, recombinant, poxvirus-based deoxyribonucleic acid (DNA) Tricom vaccines and sensitized lymphocytes will be cryopreserved. Patients will then receive conventional induction therapy with Paclitaxel, Cyclophosphamide and Doxorubicin, surgery and / or radiation as indicated for local control, then immune depleting chemotherapy with Fludarabine \& Cyclophosphamide. Following immune depletion, patients will receive 9 immunization boosts over the next 30 months. Patients whose disease progress through the vaccination schedule, may, under certain circumstances, receive further vaccinations under a more intensive schedule (monthly).

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 37

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Event-free Survival as Measured by Clinical Evaluation and Tumor Measurements by Imaging	time to progression, response rate: evaluation every 3 months for 3 years, then every 6 months for one year (fourth year), then yearly thereafter until taken off study	Complete response (CR) is the complete disappearance of all measurable and evaluable disease. Partial response (PR) is a decrease of greater than or equal to 50% in the sum of the products of the longest perpendicular dimensions of all measurable target lesions. Stable disease (SD) is any decrease of less than 50% or increase less than 25% in the sum of the longest perpendicular dimensions of measurable disease. Progressive disease (PD) is a greater than 25% increase in the sum of the longest perpendicular dimensions of any measurable disease.
Number of Participants With Adverse Events	91 months	Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

Secondary Outcome Measures

Name	Time	Method
Log Change in Precursor Frequency as Measured by Elispot.	time to progression, response rate: evaluation every 3 months for 3 years, then every 6 months for one year (fourth year), then yearly thereafter until taken off study	The log change in CEA-specific T cell precursor frequency will be calculated between values obtained at baseline and 5 months post immune depletion. A change equal to 1.0 standard deviation (SD) of the log change is significant.
Log Change of CD4 CEA-specific Immune Responses and Their Kinetics as a Surrogate Marker for Clinical Anti-tumor Activity of the Vaccines	Baseline and 5 months post immune depletion	Response is evaluated by CD4 response to CEA soluble protein. The log change in precursor frequencies will be calculated between values obtained at baseline and five months post immune depletion. By flow cytometry of peripheral blood lymphocyte frequency of potential killer cells directed to the CEA protein.
Immune Response to the Vaccine in Those Patients With Late Recovery of Thymic Function	2 years	It is expected that delayed administration of a vaccine will result in enhancement of immune response to the vaccine in those patients with later recovery of thymic function as evidenced by change in lymphocyte subsets in the blood.
Number of Months of Progression Free Survival	After the immune depletion cycle	The time period a participant remains free from progressive disease. Progressive disease (PD) is defined as a greater than 25% increase in the sum of the longest perpendicular dimensions of any measurable disease or the appearance of new disease or an increase in evaluable disease.
Number of Participants With an Immune Response as a Result of the Salvage Immunization Schedule	6 weeks, than 6, 12, 18, 24, 30, 36 (3y), 42, 48 (4y), 60 and 72 months after completion of immune chemotherapy	Patients showing disease progression or recurrence at any point after the start of the early immunizations series may continue on study in accordance to the off study criteria and will be receiving monthly rF immunizations for a total of 12 months or until further disease progression meets the off study criteria. Immune response as evidenced by change in lymphocyte subsets in the blood.
Number of Participants With a Clinical Response	At the beginning of each cycle of chemotherapy (every 4 weeks)	Defined as measurable disease (any solid lesion that can be measured accurately in at least one dimension), evaluable disease (disease not readily measurable but can be clinically assessed), complete response (complete disappearance of all measurable and evaluable disease), partial response (decrease of greater than or equal to 50%), stable disease (any decrease of less than 50% or increase less than 25% in the sum of the longest perpendicular dimensions), or progressive disease (greater than 25% increase in the sum of the longest perpendicular dimensions of any measurable disease).

Trial Locations

Locations (2): National Institutes of Health Clinical Center, 9000 Rockville Pike
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Bethesda, Maryland, United States
Hackensack University Medical Center
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Hackensack, New Jersey, United States