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

This study has been completed.
Sponsor:
Collaborator:
Information provided by:
Sidney Kimmel Comprehensive Cancer Center
ClinicalTrials.gov Identifier:
NCT00093834
First received: October 6, 2004
Last updated: July 19, 2011
Last verified: April 2011
  Purpose

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 Intervention Phase
Breast Cancer
Biological: allogeneic GM-CSF-secreting breast cancer vaccine
Drug: cyclophosphamide
Drug: doxorubicin hydrochloride
Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by Sidney Kimmel Comprehensive Cancer Center:

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 [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
  • 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 [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
  • 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 [ Time Frame: 4 years ] [ Designated as safety issue: Yes ]
  • 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 [ Time Frame: 4 years ] [ Designated as safety issue: No ]
  • Immune responses by immunohistochemical analysis of vaccine site biopsies at days 3 and 7 after the first and third vaccinations [ Time Frame: 4 years ] [ Designated as safety issue: No ]

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 [ Time Frame: 4 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: January 2004
Primary Completion Date: August 2008 (Final data collection date for primary outcome measure)
Intervention Details:
    Biological: allogeneic GM-CSF-secreting breast cancer vaccine
    The first three patients will receive a dose of 5 X 107 cells, and the next three will receive a dose of 5 X 108 cells. Then, if these two doses of vaccine alone are found to be safe, a fixed vaccine dose of 5 X 108 cells will be tested in combination with chemotherapy based on the safety of the allogeneic breast vaccine alone and the safety and bioactivity of a dose of 5 X 108 cells in the allogeneic pancreatic vaccine trial
    Drug: cyclophosphamide
    This trial will be a dose ranging study of a fixed sequence of drug doses in a three by three factorial matrix modeled after the theories of Plackett and Burman (Plackett et al., 1946), and is designed to determine the doses of CY and DOX that maximize the immunologic response to vaccination
    Drug: doxorubicin hydrochloride
    This trial will be a dose ranging study of a fixed sequence of drug doses in a three by three factorial matrix modeled after the theories of Plackett and Burman (Plackett et al., 1946), and is designed to determine the doses of CY and DOX that maximize the immunologic response to vaccination
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.

  Eligibility

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

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00093834

Locations
United States, Maryland
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland, United States, 21231-2410
Sponsors and Collaborators
Sidney Kimmel Comprehensive Cancer Center
Investigators
Principal Investigator: Leisha A. Emens, MD, PhD Sidney Kimmel Comprehensive Cancer Center
  More Information

Additional Information:
Publications:
Responsible Party: Leisha Emens, MD., PHD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
ClinicalTrials.gov Identifier: NCT00093834     History of Changes
Other Study ID Numbers: J0085 CDR0000391826, R01CA093714, P30CA006973, JHOC-J0085, JHOC-RPN-01012502, JHOC-RAC-0304-578
Study First Received: October 6, 2004
Last Updated: July 19, 2011
Health Authority: United States: Food and Drug Administration

Keywords provided by Sidney Kimmel Comprehensive Cancer Center:
stage IV breast cancer
recurrent breast cancer

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Cyclophosphamide
Liposomal doxorubicin
Doxorubicin
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antirheumatic Agents
Therapeutic Uses
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 19, 2014