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T-DM1+Pertuzumab in Pre-OP Early-Stage HER2+ BRCA

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02326974
Recruitment Status : Active, not recruiting
First Posted : December 30, 2014
Last Update Posted : June 9, 2020
Genentech, Inc.
Information provided by (Responsible Party):
Ian E. Krop, MD, PhD, Dana-Farber Cancer Institute

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

Condition or disease Intervention/treatment Phase
HER-2 Positive Breast Cancer Breast Cancer Stage II Breast Cancer Stage III Breast Cancer Drug: T-DM1 Drug: Pertuzumab Procedure: Excision of tumor/mastectomy Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 164 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 29, 2014
Actual Primary Completion Date : June 18, 2018
Estimated Study Completion Date : April 2022

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: T-DM1 and Pertuzumab
T-DM1 via IV every 3 weeks for 6 doses and Pertuzumab loading dose via IV on Cycle 1 Day 1 followed by maintenance dose via IV every 3 weeks for 6 doses. Excision of tumor/mastectomy of biopsy residual tumor
Drug: T-DM1
Participants will receive Trastuzumab emtansine (T-DM1) by IV every 3 weeks for 6 doses; for a total of 18 weeks of treatment.
Other Name: Kadcyla

Drug: Pertuzumab
Participants will receive a loading dose of pertuzumab by IV on Cycle 1 Day 1 followed by maintenance dose of pertuzumab by IV every 3 weeks for a total of 6 doses; for a total of 18 weeks of treatment.
Other Name: Perjeta

Procedure: Excision of tumor/mastectomy
Definitive breast cancer surgery (excision or mastectomy) marks the end of protocol mandated therapy.

Primary Outcome Measures :
  1. Pathologic complete response (pCR) [ Time Frame: 2 years ]
    Pathologic response is determined by Residual Cancer Burden (RCB) as RCB= 0.

Secondary Outcome Measures :
  1. Intratumor heterogeneity of HER2 amplification [ Time Frame: 2 Years ]
    Intratumor heterogeneity will be assessed from two core biopsies at baseline from different geographic areas, and a dichotomous determination of heterogeneity will be made. HER2 genetic heterogeneity will be defined as the existence of an area of tumor cells with a HER2/CEP17 ratio ≥2.0 or a gene copy number of >6 and representing more than 5% but less than 50% of infiltrating tumor cells. HER2 regional heterogeneity will be defined as at least one of the six tumor areas being HER2 negative by ISH (HER2/CEP17 ratio <2 and CN <6, if IHC is <3+). A HER2-positive tumor will be considered HER2 heterogeneous if genetic heterogeneity and/or HER2 regional heterogeneity is identified

  2. Clinical response [ Time Frame: 2 Years ]
    Partial or complete response after preoperative T-DM1 plus pertuzumab

  3. Safety and tolerability of T-DM1 plus pertuzumab assessed by incidence of adverse events which will be reported by term and by maximum grade using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: 2 Years ]
  4. Enrichment for HER2-negativity or HER2 heterogeneity in residual tumors treated with T-DM1 plus pertuzumab preoperative therapy [ Time Frame: 2 years ]
    Enrichment will be measured as absolute change in HER2-negativity and HER2 heterogeneity between residual tumors and baseline biopsies.

  5. Disease-free and overall survival in patient groups defined by HER2 heterogeneity who are treated with T-DM1 plus pertuzumab [ Time Frame: 2 years ]
    Disease-free survival is defined as the interval from the date of definitive surgery to disease recurrence. Overall survival is defined as the interval from the date of registration to death from any cause.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02326974

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United States, Massachusetts
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114
Dana Farber Cancer Institute
Boston, Massachusetts, United States, 02215
United States, Tennessee
Tennessee Oncology/Sarah Cannon Research Institute
Nashville, Tennessee, United States, 37203
Vanderbilt-Ingram Cancer Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Dana-Farber Cancer Institute
Genentech, Inc.
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Principal Investigator: Ian Krop, MD, PhD Dana-Farber Cancer Institute
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Responsible Party: Ian E. Krop, MD, PhD, Principal Investigator, Dana-Farber Cancer Institute Identifier: NCT02326974    
Other Study ID Numbers: 14-409
First Posted: December 30, 2014    Key Record Dates
Last Update Posted: June 9, 2020
Last Verified: June 2020
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents