Vaccine and Chemotherapy for Previously Untreated Metastatic Breast Cancer

NCT00048893 | Terminated Phase 1 Results DMC

• 2 other identifiers: 03004003-C-0040
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 2

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. 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. 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. 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. 4.Chemotherapy:
5. 5.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.

Conditions

Breast Neoplasms; Metastases, Neoplasm

Keywords

CEA vaccine; Metastatic Breast Cancer; T- Cell Repertoire; High-dose Chemotherapy; Breast Cancer

Outcome Measures

Primary Outcomes (2)

• Event-free Survival as Measured by Clinical Evaluation and Tumor Measurements by Imaging

  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.

  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

• Number of Participants With Adverse Events

  Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.

  91 months

Secondary Outcomes (6)

• 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

• 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

• Immune Response to the Vaccine in Those Patients With Late Recovery of Thymic Function

  2 years

• Number of Months of Progression Free Survival

  After the immune depletion cycle

• 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

Interventions

recombinant fowlpox-CEA(6D)/TRICOM vaccine BIOLOGICAL

4 x 10\^8 pfu given monthly subcutaneously for three doses in the first series and three doses on each of the intermediate and late re-immunizations (total 9 doses).

recombinant vaccinia-CEA(6D)/TRICOM vaccine BIOLOGICAL

rV-CEA (6D)/Tricom concomitantly with sargramostim (rGM-CSF). 1.2 x 10\^8 pfu x 1 dose subcutaneously.

filgrastim BIOLOGICAL

5 mcg/kg/day subcutaneously

Also known as: Neupogen

sargramostim BIOLOGICAL

100 mcg daily for 4 consecutive days at the same site as the rF-CEA (6D)/Tricom vaccine. The first dose will be given with the vaccine.

Also known as: rGM-CSF, Leukine

cyclophosphamide DRUG

First induction chemotherapy: 2700 mg/m\^2 per cycle (900 mg/m\^2 per day intravenous over 1 hour for 3 consecutive days, days 1-3). Second induction: 600 mg/m\^2 per cycle (600 mg/m\^2 intravenous over 1 hour day 1. Immune depleting chemotherapy: 2400 mg/m\^2 per cycle (600 mg/m\^2 per day intravenous over 1 hour for 4 consecutive days, days 1-4).

Also known as: Cytoxan

doxorubicin hydrochloride DRUG

60 mg/m\^2 per cycle (60 mg/m\^2 slow intravenous push day 1).

Also known as: Adriamycin

fludarabine phosphate DRUG

120 mg/m\^2 (30 mg/m\^2 per day intravenous over 30 minutes for 4 consecutive days (days 1-4)).

Also known as: Fludara

paclitaxel DRUG

160 mg/m\^2 per cycle (53.3 mg/m\^2 per day by continuous intravenous infusion over 24 hours for 3 consecutive days 1-3).

Also known as: Taxol

Mesna DRUG

Percent equals fraction of total daily cyclophosphamide dose. Initial: 20% of cyclophosphamide dose given intravenously (IV) mixed with cyclophosphamide. 3 hours post completion of cyclophosphamide: 20% intravenously (IV) or 40% by mouth (PO) 6 hours post completion of cyclophosphamide: 20% intravenously (IV) or 40% by mouth (PO) 9 hours post completion of cyclophosphamide: 20% intravenously (IV) or 40% by mouth (PO)

Also known as: Mesnex

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 National Cancer Institute (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% hydrogen peroxide (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% (Eastern Cooperative Oncology Group (ECOG) 0 or 1)
• Ejection fraction by multi-gated acquisition scan (MUGA) or 2-dimensional (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
• Aspartate aminotransferase (AST) and alanine aminotransferase (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

You may not qualify if:

• Patients must be able to give informed consent.
• 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: anti-nuclear antibody (ANA), anti-deoxyribonucleic acid (DNA), triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (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 congestive heart failure (CHF), symptomatic arrhythmia that is not controlled by medication, unstable coronary artery disease (CAD) such as unstable angina who require active intervention, and patients with a recent infarction or cerebrovascular accident (CVA) within the past 6 months
• Patients testing positive for human immunodeficiency virus (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 principal investigator (PI) if it is deemed that allowing participation would represent an unacceptable medical or psychiatric risk.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (2)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Related Links

• Common Terminology Criteria for Adverse Events (CTCAE)

MeSH Terms

Conditions

Breast Neoplasms; Neoplasm Metastasis

Interventions

Filgrastim; sargramostim; Colony-Stimulating Factors; Cyclophosphamide; Doxorubicin; fludarabine phosphate; Paclitaxel; Mesna

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Granulocyte Colony-Stimulating Factor; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Diterpenes; Terpenes; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids

Limitations and Caveats

The study was closed to accrual due to very poor enrollment. No meaningful data analysis was possible on the small number of accrued subjects, so none was done.

Results Point of Contact

• Title: Claude Sportes, M.D.
• Organization: National Cancer Institute (NCI), National Institutes of Health (NIH)

csportes@mail.nih.gov

301-435-5280

Study Officials

• Claude Sportes, M.D.

  National Cancer Institute, National Institutes of Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH

Study Record Dates

• First Submitted: November 8, 2002
• First Posted: November 11, 2002
• Study Start: November 1, 2002
• Primary Completion: June 1, 2011
• Study Completion: June 1, 2011
• Last Updated: April 13, 2012
• Results First Posted: April 13, 2012

Record last verified: 2012-03

Locations

US (2)