Trastuzumab Emtansine in Treating Patients With HER2-Positive Metastatic or Locally Advanced Breast Cancer That Cannot Be Removed by Surgery

Thrombokinetic Studies of Ado-Trastuzumab Emtansine

This phase I trial studies the side effects and best way of giving trastuzumab emtansine in treating patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer that has spread to other parts of the body or nearby tissue and cannot be removed by surgery. Biological therapies, such as trastuzumab emtansine, may stimulate the immune system in different ways and stop cancer cells from growing.

Study Overview

• Status: Completed
• Conditions: Stage IV Breast Cancer; Recurrent Breast Carcinoma; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; HER2/Neu Positive
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Biological: Trastuzumab Emtansine

Detailed Description

PRIMARY OBJECTIVES:

I. To assess change in thrombokinetics (platelet circulation life span).

SECONDARY OBJECTIVES:

I. Benefit rate (as defined by stable disease, partial response, or complete response by Response Evaluation Criteria in Solid Tumors [RECIST] v 1.1) at the end of study activities.

II. To evaluate the safety of trastuzumab emtansine (ado-trastuzumab emtansine) (non-platelet toxicity).

III. To evaluate the pharmacokinetics of ado-trastuzumab emtansine.

OUTLINE:

Patients receive trastuzumab emtansine intravenously (IV) over 30-90 minutes on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving response may continue treatment.

After completion of study treatment, patients are followed up periodically.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed study-specific informed consent form
• Histologically or cytologically documented breast cancer
• Metastatic or unresectable locally advanced/recurrent breast cancer
• HER2-positive disease documented as in situ hybridization (ISH)-positive and/or 3+ by immunohistochemistry (IHC) on previously collected tumor tissue
• Absolute neutrophil count (ANC) > 1500 cells/mm^3
• Platelet count > 100,000/mm^3
• Hemoglobin > 9.0 g/dL (patients are allowed to receive transfused red blood cells [RBC] to achieve this level)
• Total bilirubin =< 1.5 × upper limit of normal (ULN), except in patients with previously documented Gilbert's syndrome, in which case the direct bilirubin should be less than or equal to the ULN
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 2.5 × ULN
• Alkaline phosphatase =< 2.5 × ULN (patients with hepatic and/or bone metastases: alkaline phosphatase =< 5 × ULN)
• Serum creatinine < 1.5 × ULN
• International normalized ratio (INR) < 1.5 × ULN
• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
• Left ventricular ejection fraction (LVEF) >= 50% by either echocardiogram (ECHO) or multigated acquisition scan (MUGA)
• Negative results of serum pregnancy test for premenopausal women of reproductive capacity and for women < 12 months after entering menopause
• For women of childbearing potential and men with partners of childbearing potential, agreement by the patient and/or partner to use a highly effective, non-hormonal form of contraception or two effective forms of non-hormonal contraception; female patients of childbearing potential must agree to use two effective forms of non-hormonal contraception; effective methods of contraception include: intrauterine device (IUD); female condom; male condom; diaphragm with spermicide; cervical cap; or a sterile sexual partner; male patients with partners of childbearing potential must use barrier contraception; in addition, male patients should also have their partners use another method of contraception from the time of informed consent through the duration of study activity
• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including thrombokinetic studies and platelet function studies

Exclusion Criteria:

CANCER-RELATED CRITERIA

• Known platelet disorder, such as von Willebrand's disease or baseline platelet count of < 100,000/mm^3
• Chemotherapy =< 21 days before first study treatment
• Trastuzumab =< 21 days before first study treatment
• Lapatinib =< 14 days before first study treatment
• Investigational therapy or any other therapy =< 28 days before first study treatment
• Any prior ado-trastuzumab emtansine

• Previous radiotherapy for the treatment of unresectable, locally advanced/recurrent or metastatic breast cancer is not allowed if:

  • The last fraction of radiotherapy has been administered within 14 days of first on-study thormbokinetic study
  • The patient has not recovered from any resulting acute toxicity (to grade =< 1) prior to first on-study thormbokinetic study
• Brain metastases that are untreated or symptomatic, or require any radiation, surgery, or steroid therapy to control symptoms from brain metastases within 14 days of first on-study thrombokinetic study; for patients with newly diagnosed brain metastases or unequivocal progression of brain metastases on screening scans, localized treatment (i.e., surgery, radiosurgery, and/or whole brain radiotherapy) is required before study enrollment; subjects with known brain metastases must have clinically controlled neurologic symptoms, defined as surgical excision and/or radiation therapy followed by 14 days of stable neurologic function prior to the first thrombokinetic procedure; patients with small brain metastases not symptomatic and deemed requiring treatment by managing clinicians or study investigators may be permitted to enroll on study
• History of intolerance (including grade 3 or 4 infusion reaction) or hypersensitivity to trastuzumab or murine proteins
• Current peripheral neuropathy of grade >= 3 per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v. 4.0
• Current use of any platelet functioning inhibitors (including aspirin) within 14 days of first on-study thrombokinetic study

CARDIOPULMONARY FUNCTION CRITERIA

• Current unstable ventricular arrhythmia requiring treatment
• History of symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] classes II-IV)
• History of myocardial infarction or unstable angina within 6 months of enrollment
• History of a decrease in LVEF to < 40% or symptomatic CHF with previous trastuzumab treatment
• Severe dyspnea at rest due to complications of advanced malignancy or requiring current continuous oxygen therapy

GENERAL CRITERIA

• Current severe, uncontrolled non-cancer systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease) resulting in a life expectancy of < 6 months
• Major surgical procedure or significant traumatic injury within 28 days before enrollment or anticipation of the need for major surgery during the course of study treatment
• Current pregnancy or lactation
• Current known active infection with human immunodeficiency virus (HIV), hepatitis B, and/or hepatitis C virus; for patients who are known carriers of hepatitis B virus (HBV), active hepatitis B infection must be ruled out based on negative serologic testing and/or determination of HBV deoxyribonucleic acid (DNA) viral load per local guidelines
• Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (trastuzumab emtansine); Patients receive trastuzumab emtansine IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity. Patients achieving response may continue treatment.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Biological: Trastuzumab Emtansine; Given IV; Other Names: RO5304020; Kadcyla; Ado Trastuzumab Emtansine; PRO132365; T-DM1; Trastuzumab-DM1; Trastuzumab-MCC-DM1; Trastuzumab-MCC-DM1 Antibody-Drug Conjugate; Trastuzumab-MCC-DM1 Immunoconjugate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Platelet function, measured using a bleeding time test		Up to 30 days
Thrombokinetic changes	The actual analysis will fit a linear mixed effects model, using a two-sided Wald test to compare pre-therapy to the two post-therapy values, and should have greater power than a matched pairs design. Also, platelet lifespan may be measured in absolute terms (platelet lifespan) or relative terms (percentage relative to pre-therapy lifespan), and may be transformed to decrease the influence of extreme values.	Baseline up to 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cause of death		Up to 2 years
Clinical benefit rate	Defined as the proportion of patients who achieve an objective response (complete response or stable disease) based on investigator assessment using Response Evaluation Criteria in Solid Tumors version 1.1 criteria at the conclusion of study procedures.	Up to 2 years
Death		Up to 2 years
Incidence of abnormal laboratory values		Up to 30 days after completion of study treatment
Incidence of adverse events leading to study treatment discontinuation, modification, or interruption, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0		Up to 30 days after completion of study treatment
Incidence, type, and severity of adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0		Up to 30 days after completion of study treatment
Incidence, type, and severity of severe adverse events graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0		Up to 30 days after completion of study treatment
Left ventricular ejection fraction		Up to 2 years
Objective response rate, based on investigator assessment using Response Evaluation Criteria in Solid Tumors version 1.1		Up to 2 years

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Vijayakrishna Gadi, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start: June 1, 2014
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): April 1, 2017

Study Registration Dates

• First Submitted: March 19, 2013
• First Submitted That Met QC Criteria: March 19, 2013
• First Posted (Estimate): March 21, 2013

Study Record Updates

• Last Update Posted (Actual): May 23, 2017
• Last Update Submitted That Met QC Criteria: May 19, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Antineoplastic Agents, Immunological; Trastuzumab; Maytansine; Ado-Trastuzumab Emtansine; Immunoconjugates
• Other Study ID Numbers: 7900 (Fred Hutch/University of Washington Cancer Consortium); P30CA015704 (U.S. NIH Grant/Contract); NCI-2013-00552 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); CC-7900