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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

Phase 1/Phase 2
18 Years
Not Enrolling
Breast Neoplasms, Metastases, Neoplasm

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Trial Information

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

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

- 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).

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 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

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

- 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

Corrected carbon monoxide diffusing capacity (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.


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

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

- 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

- History of seizures, encephalitis, or multiple sclerosis

- History of allergy or complications with past vaccinia vaccination.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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

Outcome Description:

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.

Outcome Time Frame:

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

Safety Issue:


Principal Investigator

Claude Sportes, M.D.

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, National Institutes of Health


United States: Federal Government

Study ID:




Start Date:

November 2002

Completion Date:

June 2011

Related Keywords:

  • Breast Neoplasms
  • Metastases, Neoplasm
  • CEA vaccine
  • Metastatic Breast Cancer
  • T- Cell Repertoire
  • High-dose Chemotherapy
  • Breast Cancer
  • Breast Neoplasms
  • Neoplasms
  • Neoplasm Metastasis



National Institutes of Health Clinical Center, 9000 Rockville Pike Bethesda, Maryland  20892
Hackensack University Medical Center Hackensack, New Jersey  07601