Alternate Title
Basic Trial Information
Objectives
Entry Criteria
Expected Enrollment
Outcomes
Outline
Trial Contact Information
Related Information
Registry Information

Alternate Title

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

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase II, Phase I	Treatment	Active	18 and over	NCI	NCI-03-C-0040 NCI-5762, 03-C-0040, 5762, NCT00053170

Special Category: NIH Clinical Center trial

Objectives

Primary

1. 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.
2. Determine a possible clinical benefit (e.g., time to progression or response rate) of this regimen in these patients.
3. Determine the safety of this regimen in these patients.

Secondary

1. 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.
2. Determine whether delayed administration of a vaccine would result in enhancement of immune response in patients with late recovery of thymic function.
3. Evaluate, in a preliminary fashion, the impact of a monthly reimmunization schedule on the immune as well as the clinical responses.

Entry 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

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

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/mm³
• Platelet count > 90,000/mm³
• 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)

Expected Enrollment

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.

Outcomes

Event-free survival as measured by clinical evaluation and tumor measurements by imaging every 3 months for 3 years and then annually

Overall survival

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.

Trial Contact Information

Trial Lead Organizations

NCI - Center for Cancer Research

Claude Sportes, MD, Protocol chair		Ph: 301-435-5280 Email: csportes@mail.nih.gov

U.S.A.
Maryland
	Bethesda
	NCI - Center for Cancer Research
		Clinical Trials Office - NCI - Center for Cancer Research	Ph:  888-624-1937
	Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office
		Clinical Trials Office - Warren Grant Magnusen Clinical Center - NCI Clinical Trials Referral Office	Ph:  888-NCI-1937
New Jersey
	Hackensack
	Hackensack University Medical Center Cancer Center
		Clinical Trials Office - Hackensack University Medical Center Cancer Center	Ph:  201-996-2879

Related Information

Web site for additional information

Registry Information
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
Trial Start Date		2002-11-28
Trial Completion Date		2007-01-06 (estimated)
Registered in ClinicalTrials.gov		NCT00053170
Date Submitted to PDQ		2002-11-18
Information Last Verified		2008-11-30

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