Clinical trial NCT01779050: Effect of Trastuzumab on Disease Free Survival in Early Stage HER2-Negative Breast Cancer Patients With ERBB2 Expressing Disseminated Tumor Cells
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Breast Neoplasms
Lead sponsor: Washington University School of Medicine
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2013-01-29
Enrollment: 7
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Disease Recurrence
timeFrame: Up to 3 years after completion of treatment (estimated to be 4 years)
measure: Death Rate
timeFrame: Up to 3 years after completion of treatment (estimated to be 4 years)
Secondary outcomes:
measure: Elimination of ERBB2 Overexpressing Bone Marrow DTCs
timeFrame: Before treatment and after treatment (estimated to be 6-18 months)
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
Study officials:
affiliation: Washington University School of Medicine
name: Rebecca Aft, M.D., Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Siddappa CM, Watson MA, Pillai SG, Trinkaus K, Fleming T, Aft R. Detection of disseminated tumor cells in the bone marrow of breast cancer patients using multiplex gene expression measurements identifies new therapeutic targets in patients at high risk for the development of metastatic disease. Breast Cancer Res Treat. 2013 Jan;137(1):45-56. doi: 10.1007/s10549-012-2279-y. Epub 2012 Nov 6.
citation: Rack B, Juckstock J, Gunthner-Biller M, Andergassen U, Neugebauer J, Hepp P, Schoberth A, Mayr D, Zwingers T, Schindlbeck C, Friese K, Janni W. Trastuzumab clears HER2/neu-positive isolated tumor cells from bone marrow in primary breast cancer patients. Arch Gynecol Obstet. 2012 Feb;285(2):485-92. doi: 10.1007/s00404-011-1954-2. Epub 2011 Jun 30.
citation: Vincent-Salomon A, Pierga JY, Couturier J, d'Enghien CD, Nos C, Sigal-Zafrani B, Lae M, Freneaux P, Dieras V, Thiery JP, Sastre-Garau X. HER2 status of bone marrow micrometastasis and their corresponding primary tumours in a pilot study of 27 cases: a possible tool for anti-HER2 therapy management? Br J Cancer. 2007 Feb 26;96(4):654-9. doi: 10.1038/sj.bjc.6603584. Epub 2007 Jan 30.