Vaccine Therapy Before and After Dose-Intensive Induction Chemotherapy Plus Immune-Depleting Chemotherapy in Treating Patients With Metastatic Breast Cancer - Full Text View

Sponsor:	National Cancer Institute (NCI)
Information provided by:	National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:	NCT00053170

Purpose

RATIONALE: Vaccines may make the body build an immune response to kill tumor cells. Drugs used in chemotherapy, such as paclitaxel, cyclophosphamide, doxorubicin and fludarabine, work in different ways to stop tumor cells from dividing so they stop growing or die. Giving vaccine therapy with chemotherapy may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects, best way to give, and best dose of giving vaccine therapy with dose-intensive induction chemotherapy and immune-depleting chemotherapy and to see how well it works in treating patients with newly-diagnosed metastatic breast cancer.

Condition	Intervention	Phase
Breast Cancer	Biological: filgrastim Biological: recombinant fowlpox-CEA(6D)/TRICOM vaccine Biological: recombinant vaccinia-CEA(6D)-TRICOM vaccine Biological: sargramostim Biological: therapeutic autologous lymphocytes Drug: cyclophosphamide Drug: doxorubicin hydrochloride Drug: fludarabine phosphate Drug: paclitaxel	Phase I Phase II

Study Type:	Interventional
Study Design:	Treatment, Open Label
Official 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

Resource links provided by NLM:

Genetics Home Reference related topics: breast cancer

MedlinePlus related topics: Breast Cancer Cancer

Drug Information available for: Cyclophosphamide Fludarabine Doxorubicin Doxorubicin hydrochloride Paclitaxel Metronidazole hydrochloride Metronidazole phosphate Fludarabine monophosphate Myocet Filgrastim Sargramostim Metronidazole

U.S. FDA Resources

Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:

Event-free survival as measured by clinical evaluation and tumor measurements by imaging every 3 months for 3 years and then annually [ Designated as safety issue: No ]

Secondary Outcome Measures:

Overall survival [ Designated as safety issue: No ]

Estimated Enrollment:	62
Study Start Date:	November 2002
Estimated Primary Completion Date:	January 2007 (Final data collection date for primary outcome measure)

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Detailed Description:

OBJECTIVES:

Primary

Determine the efficacy of the CEA-TRICOM vector combination, comprising vaccinia-CEA-TRICOM vaccine and fowlpox-CEA-TRICOM vaccine, in eliciting a CEA-specific immune response after dose-intensive induction chemotherapy and immune depletion in patients with previously untreated metastatic breast cancer.
Determine a possible clinical benefit (e.g., time to progression or response rate) of this regimen in these patients.
Determine the safety of this regimen in these patients.

Secondary

Determine the validity of using CEA-specific immune responses and their kinetics as a surrogate marker for clinical antitumor activity of this regimen in these patients.
Determine whether delayed administration of a vaccine would result in enhancement of immune response in patients with late recovery of thymic function.
Evaluate, in a preliminary fashion, the impact of a monthly reimmunization schedule on the immune as well as the clinical responses.

OUTLINE: This is a mutlicenter study. Patients are stratified according to hormone receptor status (positive vs negative).

Prechemotherapy immunization: Patients receive vaccinia-CEA-TRICOM vaccine subcutaneously (SC) on day 1 and sargramostim (GM-CSF) SC on days 1-4.
Lymphapheresis: Patients undergo lymphapheresis 3 weeks after initial immunization.
Dose-intensive induction chemotherapy*: After lymphapheresis, patients receive paclitaxel IV continuously and cyclophosphamide IV over 1 hour on days 1-3. Patients then receive filgrastim (G-CSF) SC once daily beginning on day 5 and continuing until blood counts recover. Treatment repeats every 28 days for 3-5 courses.

If clinically indicated, patients may undergo definitive surgery.

Patients who have not received prior anthracycline therapy may receive additional dose-intensive induction chemotherapy comprising doxorubicin IV and cyclophosphamide IV over 1 hour on day 1. Treatment repeats every 21 days for up to 4 courses.

Radiotherapy*: If clinically indicated, patients undergo radiotherapy 4 weeks after the completion of dose-intensive induction chemotherapy.
Immune-depletion chemotherapy*: Beginning after recovery from dose-intensive induction chemotherapy or 3 weeks after the completion of radiotherapy, patients receive fludarabine IV over 30 minutes and cyclophosphamide IV over 1 hour on days 1-4. Patients then receive G-CSF SC beginning on day 5 and continuing until blood counts recover.
Lymphocyte reinfusions: Beginning 2 weeks after the completion of immune-depletion chemotherapy, patients undergo sensitized lymphocyte reinfusion over 30 minutes and again 1 month later.
Early reimmunizations: Beginning 4 weeks after the completion of immune-depletion chemotherapy (1 week after the first lymphocyte reinfusion), patients receive 3 immunizations with fowlpox-CEA-TRICOM vaccine (fCEA-TRI) SC 1 month apart (weeks 3, 7, and 11). Patients also receive GM-CSF SC concurrently with each vaccine and for 3 subsequent days.
Intermediate and late reimmunizations: Patients receive immunization with fCEA-TRI SC in week 3, week 7, and week 11, and at 6, 9, 12, 18, 24, and 30 months after immune-depletion chemotherapy. Patients also receive GM-CSF SC concurrently with the vaccine and for 3 subsequent days.
Salvage reimmunizations: At any time point after the start of the early reimmunization series, if there is evidence of disease progression or recurrence meeting predetermined conditions, the patient may receive 3 monthly immunizations with fCEA-TRI SC for a total of 12 months or until further disease progression is documented. After 12 monthly immunizations, patients will receive 4 immunizations every 3 months, then 4 immunizations every 6 months unless disease progression or recurrence is noted.
Hormonal therapy: Patients with hormone receptor-positive tumors receive hormonal therapy beginning after the completion of all chemotherapy and radiotherapy and continuing for 5 years.

NOTE: *May be administered by referring physician

Patients are followed every 3 months for 3 years, every 6 months for 1 year, and then annually thereafter.

PROJECTED ACCRUAL: A total of 62 patients (39 with hormone receptor-positive tumors and 23 with hormone receptor-negative tumors) will be accrued for this study within 18-36 months.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed metastatic infiltrating carcinoma of the breast
Meets one of the following criteria for newly diagnosed disease:
- Newly diagnosed with metastatic breast cancer
  - No prior chemotherapy for metastatic disease
- Known to have breast cancer
  - More than 18 months since prior adjuvant chemotherapy or radiotherapy for nonmetastatic or metastatic disease
CEA > 5 OR positive by standard immunohistochemistry
- Positivity defined as more than 30% of cells staining
Measurable or evaluable disease or no evidence of disease (postsurgery)
No brain metastases
Hormone receptor status:
- Positive or negative

PATIENT CHARACTERISTICS:

Age

18 and over

Sex:

Not specified

Menopausal status:

Not specified

Performance status

Karnofsky 70-100% OR
ECOG 0-1

Life expectancy

At least 6 months

Hematopoietic

Absolute neutrophil count > 1,000/mm^3
Platelet count > 90,000/mm^3
No history of abnormal bleeding tendency

Hepatic

Bilirubin < 1.5 mg/dL* (except in patients with Gilbert's disease)
AST and ALT < 3 times upper limit of normal*
Hepatitis B and C negative NOTE: *Except if due to tumor involvement of the liver prior to induction therapy

Renal

Urinalysis normal
- If proteinuria is present, must be < 1 g by 24-hour urine collection
Creatinine clearance ≥ 60 mL/min

Cardiovascular

Ejection fraction normal by MUGA or 2D echocardiogram
- If ejection fraction is between 35% and 45%, increase of ejection fraction with stress must be estimated at 10% or more
No clinically significant cardiomyopathy requiring treatment
None of the following:
- Cardiomyopathy or symptomatic congestive heart failure
- Symptomatic arrhythmia that is not controlled by medication
- Unstable coronary artery disease (i.e., unstable angina that require active intervention)
- Recent infarction or cerebrovascular accident within the past 6 months

Pulmonary

Corrected DLCO > 50%

Immunologic

No prior or active eczema or other eczematoid skin disorders
No predisposition to repeated infections
No allergy to eggs or egg products
No history of allergy or complications with prior vaccinia vaccination
No autoimmune disease, including any of the following:
- Autoimmune neutropenia, thrombocytopenia, or hemolytic anemia
- Rheumatoid arthritis
- Systemic lupus erythematosus
- Sjögren's syndrome
- Scleroderma
- Systemic sclerosis
- Myasthenia gravis
- Multiple sclerosis
- Goodpasture syndrome
- Addison's disease
- Hashimoto's thyroiditis
- Active Graves' disease
No abnormality of any of the following tests:
- Antinuclear antibody
- Anti-DNA
- T3, T4, and thyroid-stimulating hormone* NOTE: *Patients with endocrine disease that is controlled by replacement therapy including diabetes, thyroid and adrenal disease or vitiligo are eligible
No immunodeficiency or immunosuppression by disease or therapy
HIV negative

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during study therapy
No active inflammatory bowel disease
No acute, chronic, or exfoliative skin conditions, including any of the following:
- Atopic dermatitis
- Burns
- Impetigo
- Varicella zoster
- Severe acne
- Other open wounds or rashes
No history of seizures
No history of encephalitis
No other active malignancy except treated skin cancer or carcinoma in situ
No unacceptable medical or psychiatric risk
No urgent or emergent clinical situation that would preclude study participation
Must be able to avoid close household contact for at least 2 weeks after vaccination with the following individuals:
- Pregnant or nursing women
- Children under 3 years of age
- Individuals who are immunodeficient or immunosuppressed by disease or therapy (including HIV infection)
- Individuals with the following conditions:
  - Prior or active eczema or eczematoid skin disorders
  - Other acute, chronic, or exfoliative skin conditions (e.g., atopic dermatitis, burns, impetigo, varicella zoster, severe acne, or other open rashes or wounds)

PRIOR CONCURRENT THERAPY:

Biologic therapy

Not specified

Chemotherapy

See Disease Characteristics

Endocrine therapy

Prior hormonal therapy for stage IV disease allowed
- Disease progression on hormonal therapy alone allowed
No concurrent chronic corticosteroids

Radiotherapy

See Disease Characteristics

Surgery

See Disease Characteristics
No prior splenectomy

Other

No concurrent chronic immunosuppressive therapy

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00053170

Locations

United States, Maryland
NCI - Center for Cancer Research	Recruiting
Bethesda, Maryland, United States, 20892
Contact: Clinical Trials Office - NCI - Center for Cancer Research 888-624-1937
Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office	Recruiting
Bethesda, Maryland, United States, 20892-1182
Contact: Clinical Trials Office - Warren Grant Magnusen Clinical Center 888-NCI-1937
United States, New Jersey
Hackensack University Medical Center Cancer Center	Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Clinical Trials Office - Hackensack University Medical Center 201-996-2879

Sponsors and Collaborators

National Cancer Institute (NCI)

Investigators

Study Chair:

Claude Sportes, MD

National Cancer Institute (NCI)

More Information

Additional Information:

Clinical trial summary from the National Cancer Institute's PDQ® database This link exits the ClinicalTrials.gov site

Web site for additional information This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	NCI - Center for Cancer Research ( Claude Sportes )
Study ID Numbers:	CDR0000269292, NCI-03-C-0040, NCI-5762
Study First Received:	January 27, 2003
Last Updated:	July 7, 2009
ClinicalTrials.gov Identifier:	NCT00053170 History of Changes
Health Authority:	Unspecified

Keywords provided by National Cancer Institute (NCI):

recurrent breast cancer
stage IV breast cancer
male breast cancer

Additional relevant MeSH terms:

Antimetabolites
Anti-Infective Agents
Vidarabine
Antimetabolites, Antineoplastic
Immunologic Factors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Physiological Effects of Drugs
Cyclophosphamide
Antibiotics, Antineoplastic
Neoplasms by Site
Therapeutic Uses
Alkylating Agents
Breast Diseases
Skin Diseases

Mitosis Modulators
Breast Neoplasms
Antimitotic Agents
Fludarabine monophosphate
Antiviral Agents
Immunosuppressive Agents
Doxorubicin
Pharmacologic Actions
Neoplasms
Paclitaxel
Tubulin Modulators
Myeloablative Agonists
Fludarabine
Antineoplastic Agents, Alkylating
Antirheumatic Agents

ClinicalTrials.gov processed this record on November 25, 2009