Effect of Trastuzumab on Disease Free Survival in Early Stage HER2-Negative Breast Cancer Patients With ERBB2 Expressing Disseminated Tumor Cells

October 31, 2022 updated by: Washington University School of Medicine

A Phase II Randomized Trial Evaluating the Effect of Trastuzumab on Disease Free Survival in Early Stage HER2-Negative Breast Cancer Patients With ERBB2 Expressing Bone Marrow Disseminated Tumor Cells

This phase II trial studies the efficacy of trastuzumab treatment in breast cancer patients with stage II-III human epidermal growth factor receptor 2 (HER2)-negative tumors and HER2-expressing bone marrow disseminated tumor cells (DTCs). Administering targeted trastuzumab therapy to these patients may result in the elimination of HER2 expressing disseminated tumor cells and improved disease free survival.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

7

Phase

  • 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
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington University School of Medicine

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

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Pre-Registration Inclusion Criteria:

  • Histologically confirmed HER2-negative primary invasive ductal or invasive lobular breast carcinoma. For patients enrolling for neoadjuvant treatment, diagnosis must be clinical stage II or III; for patients enrolling for adjuvant treatment, diagnosis must be pathologic stage IIA to IIIC. Standard HER2 testing will be performed in the surgical specimen at Washington University according to the standard of care in the Department of Pathology. A HER2-negative primary breast cancer sample from a patient eligible for randomization should have a HER2 IHC score of 0 or 1+ Those patients with IHC score of 2+ should be HER2 FISH-negative in standard testing. Patient will have undergone staging studies including a CT of the chest/abdomen/pelvis and bone scan and/or PET scan either prior to the initiation of treatment or prior to entry into the trial. In addition, patients with non-metastatic, HER2-negative, recurrent tumors who need chemotherapy are eligible.
  • Planning to receive best practice adjuvant or neoadjuvant chemotherapy according to institutional guidelines. Adjuvant tamoxifen or aromatase inhibitors treatment will be allowed for hormone receptor-positive patients. Patients who have failed neoadjuvant endocrine therapy will also be eligible.
  • At least 18 years old.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
  • Patient (or legally authorized representative) must be able to understand and willing to sign a written informed consent document.

Pre-Registration Exclusion Criteria:

  • Prior chemotherapy for this cancer (excluding initiation of best practice chemotherapy to be given as standard of care as described in this protocol, which may be initiated after the pre-registration bone marrow collection but before final confirmation of eligibility and randomization).
  • Previous treatment with trastuzumab or any other Her2 targeted therapy.
  • Presence of an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.

Registration Inclusion Criteria

  • Presence of bone marrow ERBB2 overexpressing DTCs at the time of diagnosis; bone marrow aspiration will be performed in consented patients to evaluate DTCs following pre-registration provided patients meet all eligibility criteria as described in this section.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1.
  • Adequate cardiac function as demonstrated by LVEF of >55% performed no more than 4 weeks prior to randomization.

  • Normal organ and marrow function as defined below:

    • leukocytes ≥3,000/mcL
    • absolute neutrophil count ≥1,500/mcL
    • platelets ≥100,000/mcL
    • hemoglobin ≥ 10 g/dL
    • total bilirubin within institutional upper limits of normal unless related to primary disease
    • AST(SGOT)/ALT(SGPT) ≤2.0 X institutional upper limit of normal
    • Creatinine ≤ 1.5 institutional upper limits of normal OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal
  • If a woman of childbearing potential, patient must use two forms of effective contraception for a minimum of 6 months following trastuzumab. Effective methods of birth control include use of established oral, injected, or implanted hormonal methods of birth control, IUD, IUS, and condoms.

Registration Exclusion Criteria

  • Evidence of distant metastasis present by CT scan, bone scan, or physical exam.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to trastuzumab.
  • Prior chemotherapy for this cancer (excluding initiation of best practice chemotherapy to be given as standard of care described in this protocol, which may be initiated after the pre-registration bone marrow collection but before final confirmation of eligibility and randomization).
  • History of other malignancy ≤ 5 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix.
  • Pregnant or breastfeeding. Patient must have a negative serum pregnancy test ≤ 7 days from date of registration (if a woman of childbearing potential).
  • Clinically important history of active liver disease, including viral or other hepatitis or cirrhosis.
  • Uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, or hypokalemia defined as less than the lower limit of normal for the institution despite adequate electrolyte supplementation.
  • Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs resulting in dyspnea at rest.

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: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Arm I (definitive therapy)

Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are:

  • doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel
  • docetaxel plus cyclophosphamide
  • single-agent paclitaxel
  • docetaxel plus carboplatin
  • fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel
Drug: Docetaxel
Other Names:
  • Taxotere, Docefrez
Drug: Epirubicin
Other Names:
  • Ellence, Pharmorubicin, Epirubicin ebewe
Drug: Cyclophosphamide
Other Names:
  • Cytoxan®, CPM, CTX, CYT
Drug: Doxorubicin
Other Names:
  • Adriamycin®, Rubex®, Hydroxydaunomycin Hydrochloride, Hydroxydoxorubicin Hydrochloride
Drug: Fluorouracil
Other Names:
  • 5-FU, Adrucil
Drug: Paclitaxel
Other Names:
  • Abraxane®, Onxol®
Experimental: Arm II (definitive therapy, trastuzumab)

Patients receive definitive surgery and best practice standard chemotherapy according to NCCN guidelines. The 5 chemo backbone options are:

  • doxorubicin or epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel
  • docetaxel plus cyclophosphamide
  • single-agent paclitaxel
  • docetaxel plus carboplatin
  • fluorouracil plus epirubicin plus cyclophosphamide followed by paclitaxel or docetaxel

Patients will also receive trastuzumab IV over 30-90 minutes for 52 weeks starting such that there is a minimum of 8 weeks of overlap with the standard of care chemotherapy. Trastuzumab may be given weekly, every 2 weeks, or every 3 weeks while overlapping with standard of care chemotherapy. Trastuzumab will be given every 3 weeks after all standard of care chemotherapy has concluded. Treatment continues in the absence of disease progression or unacceptable toxicity.
Drug: Docetaxel
Other Names:
  • Taxotere, Docefrez
Drug: Epirubicin
Other Names:
  • Ellence, Pharmorubicin, Epirubicin ebewe
Drug: Cyclophosphamide
Other Names:
  • Cytoxan®, CPM, CTX, CYT
Drug: Doxorubicin
Other Names:
  • Adriamycin®, Rubex®, Hydroxydaunomycin Hydrochloride, Hydroxydoxorubicin Hydrochloride
Drug: Fluorouracil
Other Names:
  • 5-FU, Adrucil
Drug: Carboplatin
Other Names:
  • cis-Diammine(1,1-cyclobutanedicarboxylato)platinum(II), Paraplatin, Paraplatin-AQ
Drug: Paclitaxel
Other Names:
  • Abraxane®, Onxol®
Biological: Trastuzumab
Other Names:
  • •Herceptin®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Disease Recurrence
Time Frame: Up to 3 years after completion of treatment (estimated to be 4 years)
-Disease recurrence is defined as the documented appearance of local (breast, chest wall, axillary, supraclavicular nodes) or distant disease.
Up to 3 years after completion of treatment (estimated to be 4 years)
Death Rate
Time Frame: Up to 3 years after completion of treatment (estimated to be 4 years)
Up to 3 years after completion of treatment (estimated to be 4 years)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Elimination of ERBB2 Overexpressing Bone Marrow DTCs
Time Frame: Before treatment and after treatment (estimated to be 6-18 months)
Bone marrow disseminated tumor cells (DTCs) are evaluated by RT-PCR performed on specimens collected 6-18 months apart (one before and one after therapy). The proportion of samples turned negative after therapy will be calculated. Samples will be considered negative for ERBB2-expression if expression from bone marrow collected from each iliac crest is less than 2 standard deviations above the ERBB2-level in pooled normal bone marrow specimens.
Before treatment and after treatment (estimated to be 6-18 months)

Collaborators and Investigators

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

Sponsor

Washington University School of Medicine

Collaborators

Genentech, Inc.

Investigators

  • Principal Investigator: Rebecca Aft, M.D., Ph.D., Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

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 (Actual)

December 19, 2013

Primary Completion (Actual)

September 1, 2021

Study Completion (Actual)

September 1, 2021

Study Registration Dates

First Submitted

January 25, 2013

First Submitted That Met QC Criteria

January 25, 2013

First Posted (Estimate)

January 29, 2013

Study Record Updates

Last Update Posted (Actual)

November 1, 2022

Last Update Submitted That Met QC Criteria

October 31, 2022

Last Verified

October 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 201309084

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

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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