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

Condition(s) targeted: Breast Cancer

Intervention: cyclophosphamide (Drug); doxorubicin hydrochloride (Drug); filgrastim (Drug); fludarabine phosphate (Drug); paclitaxel (Drug); recombinant fowlpox-CEA(6D)/TRICOM vaccine (Drug); recombinant vaccinia-CEA(6D)-TRICOM vaccine (Drug); sargramostim (Drug); therapeutic autologous lymphocytes (Drug)

Phase: Phase 1/Phase 2

Status: Recruiting

Sponsored by: NCI - Center for Cancer Research-Medical Oncology

Official(s) and/or principal investigator(s):
Claude Sportes, MD, Study Chair, Affiliation: NCI - Center for Cancer Research-Medical Oncology

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.

Official title: A 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

Study design: Treatment, Open Label

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

Secondary outcome: Overall survival

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: 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 3 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 at

10, 16, 22, and 28 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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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 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 80-100% 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 > 45% 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

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

- 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 5 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

NCI - Center for Cancer Research-Medical Oncology, Bethesda, Maryland 20892, United States; Recruiting
Clinical Trials Office - NCI - Center for Cancer Research, Phone: 888-624-1937

Warren Grant Magnuson Clinical Center - NCI Clinical Trials Referral Office, Bethesda, Maryland 20892-1182, United States; Recruiting
Clinical Trials Office - Warren Grant Magnusen Clinical Center, Phone: 888-NCI-1937

Clinical trial summary from the National Cancer Institute's PDQ® database

Web site for additional information

Starting date: November 2002
Last updated: October 22, 2008