Trastuzumab, Cyclophosphamide, and Vaccine Therapy in Treating Patients With High-Risk or Metastatic Breast Cancer

NCT ID: NCT00847171

Last Updated: 2018-09-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-12-31
• Study Completion Date: 2013-06-30

Brief Summary

RATIONALE: Monoclonal antibodies, such as trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vaccines made from gene-modified tumor cells may help the body build an immune response to kill tumor cells. Giving trastuzumab together with cyclophosphamide and vaccine therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying the side effects of giving trastuzumab together with cyclophosphamide and vaccine therapy in treating patients with high-risk or metastatic breast cancer.

Detailed Description

OBJECTIVES:

Primary

• To evaluate the safety of allogeneic sargramostim (GM-CSF)-secreting breast cancer vaccine in combination with trastuzumab (Herceptin®) and cyclophosphamide in patients with high-risk or metastatic HER2/neu-overexpressing breast cancer.
• To measure the HER2/neu-specific CD4+ T-cell response by delayed-type hypersensitivity.
• To measure the magnitude of HER2/neu-specific CD8+ T-cell responses by ELISPOT.

Secondary

• To assess the impact of trastuzumab on immune priming in vivo by IHC.
• To measure the impact of cyclophosphamide pretreatment on CD4+CD25+ regulatory T cells by flow cytometry.
• To determine the time to disease progression.

Tertiary

• To develop the tandem tetramer/CD107a cytotoxicity assay for HER2/neu-specific CD8+ T cells.
• To measure novel T-cell responses induced by trastuzumab and cyclophosphamide-modulated vaccination.

OUTLINE: Patients receive trastuzumab (Herceptin®) IV over 30-90 minutes once weekly beginning on day -1 of the first course of vaccination and continuing until the completion of the last course of vaccination. Patients also receive cyclophosphamide IV over 30 minutes on day -1 and allogeneic sargramostim (GM-CSF)-secreting breast cancer vaccine intradermally on day 0. Treatment with cyclophosphamide and the vaccine repeats every 27-42 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth course of cyclophosphamide and vaccine approximately 6-8 months after the first course.

Patients undergo delayed-type hypersensitivity testing and blood sample collection at baseline and periodically during study for immunologic laboratory studies. Blood samples are analyzed for serum GM-CSF levels by pharmacokinetic studies and for immune monitoring by ELISPOT and flow cytometry. Skin punch biopsies are also performed periodically and analyzed by IHC.

After completion of study treatment, patients are followed periodically.

Conditions

Breast Cancer

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine

Participants receive Trastuzumab (T), Cyclophosphamide (CY), and an allogeneic GM-CSF-secreting whole cell breast cancer vaccine

Group Type: EXPERIMENTAL

allogeneic GM-CSF-secreting breast cancer vaccine

Intervention Type: BIOLOGICAL

Day 0 : Allogeneic GM-CSF-secreting Breast Cancer Vaccine administered as:

12 intradermal injections of a divided total dose of 5 x108 cells.

trastuzumab

Intervention Type: BIOLOGICAL

Patient HAS received prior Trastuzumab within the last two weeks, give Trastuzumab 2 mg/kg weekly on Day -1 for 5 weeks.

Patient has NOT received Trastuzumab within the last two weeks, give On Cycle 1, Day -1 ONLY, Loading dose 4 mg/kg

cyclophosphamide

Intervention Type: DRUG

Cyclophosphamide 200mg/m2 IV in NS 100ml over 30 minutes on Day -1 ONLY. Note: there are no dose modifications for Cyclophosphamide.

flow cytometry

Intervention Type: OTHER

Samples will be analyzed by flow cytometry using Cell Quest software

immunoenzyme technique

Intervention Type: OTHER

immunohistochemistry staining method

Intervention Type: OTHER

Measuring Immune Priming In Vivo By Vaccine Site Biopsies

laboratory biomarker analysis

Intervention Type: OTHER

pharmacological study

Intervention Type: OTHER

biopsy

Intervention Type: PROCEDURE

skin biopsy to be performed on day 3 and day 7 for cycle 1 and 3 only

Interventions

allogeneic GM-CSF-secreting breast cancer vaccine

Day 0 : Allogeneic GM-CSF-secreting Breast Cancer Vaccine administered as:

12 intradermal injections of a divided total dose of 5 x108 cells.

Intervention Type: BIOLOGICAL

trastuzumab

Patient HAS received prior Trastuzumab within the last two weeks, give Trastuzumab 2 mg/kg weekly on Day -1 for 5 weeks.

Patient has NOT received Trastuzumab within the last two weeks, give On Cycle 1, Day -1 ONLY, Loading dose 4 mg/kg

Intervention Type: BIOLOGICAL

cyclophosphamide

Cyclophosphamide 200mg/m2 IV in NS 100ml over 30 minutes on Day -1 ONLY. Note: there are no dose modifications for Cyclophosphamide.

Intervention Type: DRUG

flow cytometry

Samples will be analyzed by flow cytometry using Cell Quest software

Intervention Type: OTHER

immunoenzyme technique

Intervention Type: OTHER

immunohistochemistry staining method

Measuring Immune Priming In Vivo By Vaccine Site Biopsies

Intervention Type: OTHER

laboratory biomarker analysis

Intervention Type: OTHER

pharmacological study

Intervention Type: OTHER

biopsy

skin biopsy to be performed on day 3 and day 7 for cycle 1 and 3 only

Intervention Type: PROCEDURE

Other Intervention Names

Herceptin; Cytoxan

Eligibility Criteria

Inclusion Criteria

• HER2/neu-overexpressing disease, defined as HER2/neu positive by IHC 3+ staining or by FISH+ amplification
• Stable CNS disease allowed provided it has been adequately treated and is not under active treatment
• Hormone receptor status not specified

PATIENT CHARACTERISTICS:

• Menopausal status not specified
• ECOG performance status 0-1
• ANC > 1,000/mm^3
• Platelet count > 100,000/mm^3
• Serum creatinine < 2.0 mg/dL
• Serum bilirubin ≤ 2.0 mg/dL (unless elevation is due to known Gilbert's syndrome)
• AST/ALT ≤ 2 times upper limit of normal (ULN)
• Alkaline phosphatase ≤ 5 times ULN
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Cardiac ejection fraction normal by MUGA OR ≥ 45% by ECHO
• No other malignancies within the past 5 years, except for carcinoma in situ of the cervix, superficial nonmelanoma skin cancer, or superficial bladder cancer
• No prior or currently active autoimmune disease* requiring management with systemic immunosuppression, including any of the following:

• Inflammatory bowel disease
• Systemic vasculitis
• Scleroderma
• Psoriasis
• Multiple sclerosis
• Hemolytic anemia or immune-mediated thrombocytopenia
• Rheumatoid arthritis
• Systemic lupus erythematosus
• Sjögren syndrome
• Sarcoidosis
• Other rheumatologic disease
• No symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest
• HIV-negative
• No evidence of active acute or chronic infection
• No uncontrolled medical problems
• No active major medical or psychosocial problems that could be complicated by study participation
• No corn allergy
• No known severe hypersensitivity to trastuzumab (except for mild to moderate infusion reactions that are easily managed and do not recur) NOTE: *Asthma or chronic obstructive pulmonary disease that does not require daily systemic corticosteroids allowed

PRIOR CONCURRENT THERAPY:

• Any number of prior chemotherapy regimens for metastatic breast cancer allowed
• Prior or concurrent trastuzumab in the adjuvant or metastatic setting allowed
• More than 28 days since prior and no concurrent systemic oral steroids

• Topical, ocular, or nasal steroids allowed
• More than 28 days since prior and no concurrent chemotherapy, radiotherapy, or biologic therapy (except trastuzumab)
• More than 28 days since prior and no concurrent participation in another investigational clinical trial involving a new drug
• Concurrent endocrine therapy or bisphosphonates allowed

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 120 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Leisha A. Emens, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Locations

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, United States

Countries

United States

Other Identifiers

P30CA006973

Identifier Type: NIH

Identifier Source: secondary_id

View Link

NA_00021048

Identifier Type: OTHER

Identifier Source: secondary_id

CDR0000634155

Identifier Type: OTHER

Identifier Source: secondary_id

J0885

Identifier Type: -

Identifier Source: org_study_id