Vaccine Therapy With or Without Cyclophosphamide and Doxorubicin in Women With Stage IV Breast Cancer

Sponsor

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Other)

Overall Status

Completed

CT.gov ID

NCT00093834

Collaborator

National Cancer Institute (NCI) (NIH)

Enrollment

Location

Study Details

Study Description

Brief Summary

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

PURPOSE: This phase I trial is studying the side effects and best dose of cyclophosphamide and doxorubicin when given with vaccine therapy in treating women with stage IV breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Biological: allogeneic GM-CSF-secreting breast cancer vaccine Drug: cyclophosphamide Drug: doxorubicin hydrochloride	Phase 1

Detailed Description

OBJECTIVES:

Primary

Determine the safety of vaccination comprising allogeneic sargramostim (GM-CSF)-secreting breast cancer cells with or without immunomodulation using cyclophosphamide and doxorubicin in women with stage IV breast cancer.
Determine the doses of cyclophosphamide and doxorubicin that maximize vaccine-induced immunity, in terms of immune response to HER2/neu, in patients treated with these regimens.
Compare in vivo immune response induced by these regimens, as measured by immunohistochemical analysis of vaccine site biopsies from these patients, with responses seen in prior preclinical and clinical studies.

Secondary

Determine the time to disease progression in patients treated with these regimens.

OUTLINE: This is a dose-finding study.

The first 6 patients receive 1 of 2 doses of vaccine comprising allogeneic sargramostim (GM-CSF)-secreting breast cancer cells intradermally (ID) on day 0. Subsequent patients receive cyclophosphamide IV on day -1, vaccine at the higher dose ID on day 0, and doxorubicin IV on day 7. Treatment in all patients repeats every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease after the third course receive a fourth course of treatment at approximately 4 months after completion of the third course.

Cohorts of 2-3 patients receive a fixed dose of vaccine in combination with escalating doses of doxorubicin and cyclophosphamide. Doses of cyclophosphamide and doxorubicin are escalated until an optimal dose of combination chemotherapy with a fixed dose of vaccine is achieved.

Patients are followed at 1 month and 4 months after completion of study therapy and then annually thereafter.

PROJECTED ACCRUAL: A total of 6-60 patients will be accrued for this study.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

60 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I Vaccine Safety and Chemotherapy Dose-Finding Trial of an Allogeneic GM-CSF-Secreting Breast Cancer Vaccine Given in a Specifically Timed Sequence With Immunomodulatory Doses of Cyclophosphamide and Doxorubicin

Study Start Date :

Jan 1, 2004

Actual Primary Completion Date :

Aug 1, 2008

Outcome Measures

Primary Outcome Measures

Toxicity of vaccine w/ & w/o cyclophosphamide+doxorubicin by history and phys. exam. at 28-42 days after each vaccination, 56-84 days after third vaccination, 6 months after first vaccination, and annually after first vaccination [4 years]
Toxicity of vaccine w/ & w/o cyclophosphamide+doxorubicin by CBC w/ differential at days 7, 14, 21, and 28-42 days after each vaccination, 56-84 days after third vaccination, 6 months after first vaccination, and annually after first vaccination [4 years]
Toxicity of vaccine w/ & w/o cyclophosphamide+doxorubicin by comprehensive metabolic panel at day 7 and 28-42 days after each vaccination, 56-84 days after third vaccination, 6 months after first vaccination, and annually after first vaccination [4 years]
Immune resp. of HER-2/neu by serum antibody titers, delayed hypersensitivity to HER-2/neu-derived peptides, and CD4+ T-cell resp. by ELISPOT at days 28-42 after each vaccination and days 56-84 after third vaccination [4 years]
Immune responses by immunohistochemical analysis of vaccine site biopsies at days 3 and 7 after the first and third vaccinations [4 years]

Secondary Outcome Measures

Time to disease progression by history and physical examination, computed tomography, bone scans, and tumor markers as appropriate at days 28-42 after third and fourth vaccinations and days 56-84 after third vaccination [4 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically confirmed adenocarcinoma of the breast
Stage IV disease
Stable disease for ≥ 28 days
Measurable or evaluable disease OR no evidence of disease
Not eligible for potentially curative therapy
Adequately treated CNS metastases are allowed
Hormone receptor status:
Not specified
HER-2/neu status:
Not specified

PATIENT CHARACTERISTICS:

Age

18 and over

Sex

Female

Menopausal status

Not specified

Performance status

ECOG 0-1

Life expectancy

Not specified

Hematopoietic

Absolute neutrophil count > 1,000/mm^3
Platelet count > 100,000/mm^3

Hepatic

Bilirubin ≤ 2.0 mg/dL (unless due to Gilbert's syndrome)
AST and ALT ≤ 2 times upper limit of normal (ULN)
Alkaline phosphatase ≤ 5 times ULN

Renal

Creatinine < 2.0 mg/dL

Cardiovascular

Ejection fraction ≥ 45% by echocardiogram or MUGA

Pulmonary

Asthma or chronic obstructive pulmonary disease allowed provided daily systemic corticosteroid therapy is not required

Immunologic

No active autoimmune disease requiring systemic immunosuppressive therapy, including any of the following:
Inflammatory bowel disease
Systemic vasculitis
Scleroderma
Psoriasis
Multiple sclerosis
Hemolytic anemia
Immune-mediated thrombocytopenia
Rheumatoid arthritis
Systemic lupus erythematosus
Sjögren's syndrome
Sarcoidosis
Other rheumatologic disease
HIV negative
No active acute or chronic infection
No allergy to corn

Other

No other malignancy within the past 5 years except carcinoma in situ of the cervix, superficial nonmelanoma skin cancer, or superficial bladder cancer
No active major medical or psychosocial problem that would preclude study participation
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 3 months after study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

More than 28 days since prior biologic therapy
No other concurrent biologic therapy, including trastuzumab (Herceptin®)

Chemotherapy

Prior adjuvant chemotherapy allowed
Prior doxorubicin and cyclophosphamide allowed
Prior doxorubicin dose combined with planned study therapy dose must not exceed a lifetime cumulative dose of ≥ 450 mg/m^2
More than 28 days since prior systemic chemotherapy
No other concurrent systemic chemotherapy

Endocrine therapy

More than 28 days since prior systemic corticosteroids
Concurrent hormonal or endocrine therapy allowed
No concurrent systemic corticosteroids

Radiotherapy

More than 28 days since prior radiotherapy
No concurrent radiotherapy

Surgery

Not specified

Other

More than 28 days since prior participation in another investigational drug trial
No other concurrent investigational drugs
Concurrent bisphosphonates allowed