Clinical trial NCT00971737: Cyclophosphamide and Vaccine Therapy With or Without Trastuzumab in Treating Patients With Metastatic Breast Cancer
Official title: A Randomized, Open-Label Comparative Study of Combination Therapy With Cyclophosphamide and an Allogeneic GM-CSF-secreting Breast Tumor Vaccine With or Without Trastuzumab for the Treatment of Metastatic Breast Cancer That Does NOT Over-express HER-2/Neu
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Breast Cancer
Keywords: stage IV breast cancer
male breast cancer
Lead sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-09-04
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: RATIONALE: Vaccines made from gene-modified tumor cells may help the body build an effective immune response to kill tumor cells. Biological therapies, such as cyclophosphamide and trastuzumab, may increase the number of immune cells and make the immune response stronger. It is not yet known whether giving cyclophosphamide together with vaccine therapy is more effective with or without trastuzumab in treating patients with metastatic breast cancer.

PURPOSE: This randomized phase II trial is studying the side effects of giving cyclophosphamide together with vaccine therapy and to see how well it works compared with giving cyclophosphamide and vaccine therapy together with trastuzumab in treating patients with metastatic breast cancer.

Detailed description: OBJECTIVES:

Primary

* To evaluate the safety of cyclophosphamide-modulated vaccination with vs without trastuzumab in patients with breast cancer that does not overexpress HER-2/neu.
* To compare the clinical benefit of cyclophosphamide-modulated vaccination with vs without trastuzumab in these patients.
* To measure HER-2/neu-specific CD4+ and CD8+ T-cell immunity by delayed-type hypersensitivity (DTH) and ELISPOT.
* To measure the pharmacodynamics of CD4+CD25+ regulatory T cells by flow cytometry.

Secondary

* To assess the impact of trastuzumab on immune priming in vivo by immunohistochemistry of vaccine-site biopsies at day +3 and day +7 of courses 1 and 3 on the two study arms, comparing cellular infiltrates to those seen in previous preclinical and clinical models.
* To measure hTERT-specific CD8+ T-cell immunity by ELISPOT.
* To characterize the peripheral-memory T-cell pool.

Tertiary

* To determine baseline and change in vaccine site-draining lymph node immunohistology and gene expression profile.
* To develop the tandem tetramer/CD107a cytotoxicity assay for HER-2/neu-specific CD8+ T cells.
* To measure novel T-cell responses induced by trastuzumab and cyclophosphamide-modulated vaccination.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

* Arm I: Patients receive cyclophosphamide IV over 30 minutes on day -1 and allogeneic GM-CSF-secreting breast cancer vaccine intradermally on day 0. Courses repeat every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth vaccination at 6-8 months.
* Arm II: Patients receive cyclophosphamide and the vaccine as in arm I and trastuzumab IV over 30-90 minutes on day -1. Courses repeat every 4-6 weeks for 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive a fourth vaccination at 6-8 months.

Skin punch and lymph node biopsies are collected at baseline and on days +3 and +7 of courses 1 and 3 for biomarker analysis.

After completion of study treatment, patients are followed periodically.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed adenocarcinoma of the breast

  * Does not overexpress HER-2/neu, defined as FISH negative or 0, 1+, or 2+ by IHC
  * Stage IV disease
* Must not be eligible for therapy of known curative potential for metastatic breast cancer
* Measurable or evaluable disease
* Stable CNS disease allowed provided that it's adequately treated and 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
* Platelets \> 100,000/mm\^3
* Serum bilirubin \< 2.0 mg/dL (unless due to Gilbert syndrome)
* AST and ALT \< 2 times upper limit of normal (ULN)
* Alkaline phosphatase \< 5 times ULN
* Serum creatinine \< 2.0 mg/dL
* Ejection fraction normal by MUGA OR ≥ 50% by echocardiogram
* Not pregnant or nursing
* Fertile patients must use effective contraception
* HIV negative
* Asthma or chronic obstructive pulmonary disease that does not require daily systemic corticosteroids allowed
* No prior or concurrent 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
  * Sjogren syndrome
  * Sarcoidosis
  * Other rheumatologic disease
* No other malignancies within the past 5 years, except carcinoma in situ of the cervix, superficial nonmelanoma skin cancer, superficial bladder cancer, or tamoxifen-related endometrial cancer that has been adequately treated
* No active major medical or psychosocial problems that could be complicated by study participation
* No symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest
* No uncontrolled medical problems
* No evidence of active acute or chronic infection
* No known severe hypersensitivity to trastuzumab, except mild to moderate infusion reactions that are easily managed and do not recur
* No allergy to corn

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* More than 28 days since prior and no other concurrent chemotherapy, radiation therapy, or biologic therapy (except trastuzumab)

  * Concurrent endocrine therapy and supportive therapy with bisphosphonates allowed
* More than 28 days since prior and no other concurrent participation in an investigational new drug trial
* More than 28 days since prior and no other concurrent systemic oral steroids

  * Topical, ocular, and nasal steroids allowed
* No prior vaccination with the allogeneic GM-CSF-secreting breast tumor vaccine

Primary outcomes:
measure: Toxicity as Assessed by Number of Grade 3 or 4 Adverse Events
timeFrame: 3 years
measure: Clinical Benefit (CB) as Assessed by Progression Free Survival at Six Months
timeFrame: 6 months post-intervention
measure: HER-2/Neu-specific Immune Responses as Measured by Number of Participants With Positive for Delayed-type Hypersensitivity (DTH) Response
timeFrame: 3 years
measure: Pharmacodynamics of Peripheral CD4+CD25+ Regulatory T Cells
timeFrame: 3 years
Secondary outcomes:
measure: Immune Priming in In-vivo Vaccine-site Biopsies
timeFrame: 3 years
measure: Enumeration of CD8+ T Cells Specific for hTERT by ELISPOT
timeFrame: 3 years
measure: Characterization of the T-cell Memory Pool Pre- and Post-vaccination
timeFrame: 3 years
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Leisha A. Emens, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: