Clinical trial NCT02326974: T-DM1+Pertuzumab in Pre-OP Early-Stage HER2+ BRCA
Official title: The Impact of HER2 Heterogeneity on the Treatment of Early-stage HER2-positive Breast Cancer: a Phase II Study of T-DM1 in Combination With Pertuzumab in the Preoperative Setting
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: HER-2 Positive Breast Cancer
Breast Cancer
Stage II Breast Cancer
Stage III Breast Cancer
Lead sponsor: Dana-Farber Cancer Institute
Sponsor class: OTHER
Collaborators: name: Genentech, Inc.
First posted: 2014-12-30
Enrollment: 164
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This research study is studying a combination of drugs as a possible treatment for breast cancer that has tested positive for a protein called HER2.

The names of the study interventions involved in this study are:

* Trastuzumab emtansine (also called T-DM1)
* Pertuzumab

Detailed description: This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved T-DM1 for pre-operative use in breast cancer but it has been approved for other uses in breast cancer. The FDA has approved pertuzumab as a pre-operative treatment.

Eligibility criteria: Inclusion Criteria:

* Patients must have HER2-positive Stage II or III histologically confirmed invasive carcinoma of the breast. A minimum tumor size of 2 cm determined by physical exam or imaging is required.
* HER-2 positive, confirmed by central testing (Clarient labs): IHC 3+ and/or FISH positive based on one of the three following criteria:
* Single-probe average HER2 copy number≥6.0 signals/cell OR
* Dual-probe HER2/CEP17 \<2.0 with an average HER2 copy number ≥6.0 signals/cell OR
* Dual-probe HER2/CEP17 ratio ≥2.0
* ER/PR determination is required.
* Bilateral breast cancers are allowed if both cancers are HER2-positive.
* Patients with multifocal or multicentric disease are eligible as long as one area meets eligibility criteria.
* Breast imaging should include the ipsilateral axilla. For subjects with a clinically negative axilla, a sentinel lymph node biopsy will be performed either before or after preoperative therapy at the discretion of the subject's physicians. For subjects with a clinically positive axilla, a needle aspiration, core biopsy or SLN procedure will be performed to determine the presence of metastatic disease in the lymph nodes.
* Men and women (with any menopausal status) ≥ 18 years of age
* ECOG performance status 0 or 1
* Required laboratory values:

  * ANC ≥1500/mm3
  * Hemoglobin ≥ 9 g/dl
  * Platelets ≥100,000/mm3
  * Serum creatinine \< 1.5 X ULN (institutional)
  * Total bilirubin ≤ 1.0 X ULN (institutional) For patients with Gilbert syndrome, the direct bilirubin should be within the institutional normal range.
  * AST and ALT ≤ 1.5x ULN (institutional)
  * Alkaline phosphatase ≤1.5x ULN (institutional)
* Documentation of hepatitis B virus (HBV) and hepatitis C virus (HCV) serologies is required: this includes hepatitis B surface antigen (HBsAg) and/or total hepatitis B core antibody (HBcAb) in addition to HCV antibody testing.
* Only for patients who test positive for hep B/C virus: PTT/INR \< ULN (institutional)
* Left ventricular ejection fraction (LVEF) ≥ 55%
* Premenopausal women must have a negative serum pregnancy test, including women who have had a tubal ligation and for women less than 12 months after the onset of menopause.
* Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of non-hormonal contraception or two effective forms of non-hormonal contraception by the patient and/or partner and continue its use for the duration of the study treatment and for 7 months after the last dose of study treatment.
* Potent CYP3A4 inhibitors, such as ketoconazole and erythromycin, should be avoided during the study treatment period with T-DM1.
* Excessive alcohol intake should be avoided (occasional use is permitted).
* Patients with a history of ipsilateral DCIS are eligible.
* Patients undergoing breast conservation therapy (i.e. lumpectomy) must not have any contraindications to radiation therapy.
* Willing and able to sign informed consent.
* Willing to provide tissue for research purposes.

Exclusion Criteria:

* Pregnant or nursing women due to the teratogenic potential of the study drugs.
* Active, unresolved infection.
* Receipt of intravenous antibiotics for infection within 7 days prior to enrollment.
* Patients with active liver disease, for example, due to hepatitis B virus, hepatitis C virus, autoimmune hepatic disorder, or sclerosing cholangitis.
* Uncontrolled hypertension (systolic \>180 mm Hg and/or diastolic \>100 mm Hg) or clinically significant (i.e. active) cardiovascular disease: cerebrovascular accident/stroke or myocardial infarction within 6 months prior to first study medication, unstable angina, congestive heart failure (CHF) of New York Heart Association (NYHA) Grade II or higher, or serious cardiac arrhythmia requiring medication.
* Significant symptoms (Grade ≥2) peripheral neuropathy.
* Other concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness, uncontrolled infections, uncontrolled diabetes.
* Any prior treatment for the current breast cancer, including chemotherapy, hormonal therapy, radiation or experimental therapy.

Primary outcomes:
measure: Rate of Pathologic Complete Response (pCR) by HER2 Amplification Status Non-Heterogeneous
timeFrame: Evaluate upon completion of breast surgery, up to approximately 24 weeks from study enrollment.
Secondary outcomes:
measure: Rate of Pathologic Complete Response (pCR)
timeFrame: Evaluate upon completion of breast surgery, up to approximately 24 weeks from study enrollment.
measure: Hormone Receptor (HR) Status by HER2 Amplification Status
timeFrame: Day 0 (baseline/at study entry)
measure: Median Disease-Free Survival
timeFrame: Post-surgery follow-up of disease and survival occurs every 6 months for 5 years and annually until year 10.
measure: Median Overall Survival
timeFrame: Post-surgery follow-up of disease and survival occurs every 6 months for 5 years and annually until year 10.
measure: Clinical Response Rate (Complete Response)
timeFrame: Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment.
measure: Clinical Response Rate (Partial Response)
timeFrame: Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment.
measure: Number of Participants With a Dose Reduction
timeFrame: Evaluate upon completion of neoadjuvant therapy, up to approximately 18 weeks from study enrollment.
measure: Treatment-Emergent Fatigue Rate
timeFrame: Adverse events are assessed every cycle of neoadjuvant therapy prior to surgery, up to approximately 18 weeks (6 cycles) from study enrollment.
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Nashville
country: United States
facility: Tennessee Oncology/Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Otto Metzger, MD
role: PRINCIPAL_INVESTIGATOR
References: