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

September 25, 2018 updated by: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

A Safety and Bioactivity Study of Combination Therapy With Trastuzumab, Cyclophosphamide, and an Allogeneic GM-CSF-Secreting Breast Tumor Vaccine for the Treatment of Patients With High Risk/ Metastatic HER-2/Neu- Overexpressing Breast Cancer With No Evidence of Disease

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
20

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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, meeting one of the following criteria:

    • Metastatic disease

    • High-risk disease, defined as early-stage disease with pathologic involvement of locoregional lymph nodes

      • Patients who are/will be receiving standard adjuvant trastuzumab [Herceptin®] for high-risk disease will participate in this study during the single-agent trastuzumab portion of their therapy
  • No clinical or radiographical evidence of active disease
  • Not eligible for therapy of known curative potential for metastatic breast cancer
  • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Trastuzumab, Cyclophosphamide, and a Breast Tumor Vaccine
Participants receive Trastuzumab (T), Cyclophosphamide (CY), and an allogeneic GM-CSF-secreting whole cell breast cancer vaccine
Other: pharmacological study
Other: laboratory biomarker analysis
Biological: 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.

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

Other Names:
  • Herceptin
Drug: cyclophosphamide
Cyclophosphamide 200mg/m2 IV in NS 100ml over 30 minutes on Day -1 ONLY. Note: there are no dose modifications for Cyclophosphamide.
Other Names:
  • Cytoxan
Other: flow cytometry
Samples will be analyzed by flow cytometry using Cell Quest software
Other: immunoenzyme technique
Other: immunohistochemistry staining method
Measuring Immune Priming In Vivo By Vaccine Site Biopsies
Procedure: biopsy
skin biopsy to be performed on day 3 and day 7 for cycle 1 and 3 only

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Safety as Assessed by Number of Participants Experiencing Toxicity
Time Frame: 4 years
Safety as assessed by number of participants who experienced drug-related local and systemic toxicity, as defined by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v3.0) in response to CY-modulated immunization with a novel breast cancer vaccine in the setting of weekly Trastuzumab therapy.
4 years
Number of Participants With Immunologic Response as Determined by Delayed-type Hypersensitivity (DTH) Response to HER2/Neu-derived Peptides
Time Frame: 4 years
4 years

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Clinical Benefit as Assessed by Number of Participants With Progression-free Survival
Time Frame: 4 years
Number of participants without evidence of disease progression.
4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
National Cancer Institute (NCI)

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Leisha A. Emens, MD, PhD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
December 1, 2008

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2013

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 1, 2013

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
February 18, 2009

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 18, 2009

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
February 19, 2009

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
September 26, 2018

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 25, 2018

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2018

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • J0885
  • P30CA006973 (U.S. NIH Grant/Contract)
  • NA_00021048 (Other Identifier: JHM IRB)
  • CDR0000634155 (Other Identifier: other)

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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