Cyclophosphamide and Vaccine Therapy With or Without Trastuzumab in Treating Patients With Metastatic Breast Cancer

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

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: cyclophosphamide; Biological: trastuzumab; Biological: allogeneic GM-CSF-secreting breast cancer vaccine

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.

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Cyclophosphamide and Vaccine only; 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.	Drug: cyclophosphamide; Given IV; Biological: allogeneic GM-CSF-secreting breast cancer vaccine; Given intradermally
Experimental: Cyclophosphamide, Vaccine and Trastuzumab; 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.	Drug: cyclophosphamide; Given IV; Biological: trastuzumab; Given IV; Biological: allogeneic GM-CSF-secreting breast cancer vaccine; Given intradermally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Toxicity as Assessed by Number of Grade 3 or 4 Adverse Events	Number of grade 3 or 4 nonhematologic toxicity (except alopecia), or any grade 4 hematologic toxicity as defined by NCI CTCAE v3.0	3 years
Clinical Benefit (CB) as Assessed by Progression Free Survival at Six Months	Progression-free survival is measured as percentage of participants with stable disease or complete response, as defined by RECIST criteria, six months after receiving last vaccination. Progressive disease (PD) will be defined by the appearance of a new lesion, or by an increase of at least 20% in the sum of the longest diameter of target lesions, taking as a reference that smallest sum longest diameter recorded since the study intervention began. In the case of bone lesions, progressive disease will be established after eight weeks of increasing or new lesions if there is subjective progressive disease as noted by increasing bone pain or decreasing performance status. These observations must be present for at least two measurement periods separated by at least four weeks.	6 months post-intervention
HER-2/Neu-specific Immune Responses as Measured by Number of Participants With Positive for Delayed-type Hypersensitivity (DTH) Response		3 years
Pharmacodynamics of Peripheral CD4+CD25+ Regulatory T Cells		3 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Immune Priming in In-vivo Vaccine-site Biopsies	3 years
Enumeration of CD8+ T Cells Specific for hTERT by ELISPOT	3 years
Characterization of the T-cell Memory Pool Pre- and Post-vaccination	3 years

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Leisha A. Emens, MD, PhD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study record dates

Study Major Dates

• Study Start: July 1, 2009
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: September 3, 2009
• First Submitted That Met QC Criteria: September 3, 2009
• First Posted (Estimate): September 4, 2009

Study Record Updates

• Last Update Posted (Actual): April 24, 2019
• Last Update Submitted That Met QC Criteria: April 10, 2019
• Last Verified: April 1, 2019

More Information

Terms related to this study

• Keywords: stage IV breast cancer; male breast cancer
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Cyclophosphamide; Trastuzumab
• Other Study ID Numbers: J0947; P30CA006973 (U.S. NIH Grant/Contract); JHOC-J0947; NA_00024527; GENENTECH-JHOC-J0947; CDR0000653173 (Other Identifier: other)