A Study of Trastuzumab-MCC-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer Who Have Previously Received a Trastuzumab-Containing Regimen

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Genentech, Inc.
ClinicalTrials.gov Identifier:
NCT00932373
First received: June 30, 2009
Last updated: August 13, 2015
Last verified: August 2015
  Purpose

This is a phase I, multicenter, open-label, dose-escalation study of single-agent trastuzumab-MCC-DM1 administered by intravenous (IV) infusion in patients with HER2-positive metastatic breast cancer (MBC) who have previously received trastuzumab. The study will assess the safety, tolerability, and pharmacokinetics of trastuzumab-MCC-DM1 and determine the dose and schedule to be used in Phase II.


Condition Intervention Phase
Metastatic Breast Cancer
Drug: trastuzumab-MCC-DM1
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of Trastuzumab-MCC-DM1 (PRO132365) Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer Who Have Previously Received a Trastuzumab-Containing Regimen

Resource links provided by NLM:


Further study details as provided by Genentech, Inc.:

Primary Outcome Measures:
  • Percentage of Participants With Adverse Events (AE), Serious Adverse Events (SAE), AEs With Grade >=3, and AEs Related To Treatment [ Time Frame: Study treatment initiation until 30 or 90 days after last administration of study treatment ] [ Designated as safety issue: Yes ]

    The time frame for AEs is study treatment initiation until 30 days after last administration of study treatment or at the time of initiation of another anti-cancer therapy, which ever occurs first.

    The time frame for SAEs is study treatment initiation until 90 days after last administration of study treatment or at the time of initiation of another anti-cancer therapy, which ever occurs first.


  • Number of Patients With Dose Limiting Toxicities (DLTs) [ Time Frame: A minimum of 21 days after first dose of trastuzumab-MCC-DM1 ] [ Designated as safety issue: Yes ]

    DLT is defined as one of the following as per investigator related to study drug:

    • Grade ≥ 3 non-hematologic, non-hepatic major organ toxicity
    • Grade ≥ 3 cardiac toxicity, including cardiac troponin I elevation or any new segmental wall abnormality as determined by non-invasive cardiac imaging
    • Grade ≥ 4 thrombocytopenia
    • Grade ≥ 4 neutropenia (absolute neutrophil count < 500/μ L) lasting > 4 days or accompanied by fever
    • Grade ≥ 4 anemia
    • Grade ≥ 3 serum bilirubin, hepatic transaminase (alanine aminotransferase or aspartate aminotransferase), or alkaline phosphatase For patients with Grade 2 hepatic transaminase or alkaline phosphatase levels at baseline as a result of liver metastases or bone metastases, a hepatic transaminase or alkaline phosphatase level ≥ 10 times the upper limit of normal will be considered a DLT.
    • Weekly cohorts only: Toxicity preventing retreatment on Cycle 1, Day 8 or toxicity preventing re-treatment on Cycle 1, Days 15 and Day 22

  • Maximum Tolerated Dose (MTD) [ Time Frame: A minimum of 21 days after first dose of trastuzumab-MCC-DM1 ] [ Designated as safety issue: Yes ]
    The highest dose level resulting in a DLT in ≤ 1 of 6 patients was declared the MTD.

  • Pharmacokinetic (PK) Parameters After the First Dose: Maximum Observed Plasma Concentration Cmax for T-DM1 Concentrations [ Time Frame: 3-Week and Weekly Cohorts: Cycle 1 Day 1 Pre-dose 30 minutes and 4 hours after the end of infusion; Cycle 1 Day 2, 3, 4, 8 (Pre-dose 30 minutes after the end of infusion) 11, 15 (Pre-dose 30 minutes after the end of infusion) and 18 ] [ Designated as safety issue: No ]
  • PK Parameters After the First Dose: Area Under the Plasma Concentration-time Curve From 0 to Infinity (AUC[0-∞] for T-DM1 Concentrations [ Time Frame: 3-Week and Weekly Cohorts: Cycle 1 Day 1 Pre-dose 30 minutes and 4 hours after the end of infusion; Cycle 1 Day 2, 3, 4, 8 (Pre-dose 30 minutes after the end of infusion) 11, 15 (Pre-dose 30 minutes after the end of infusion) and 18 ] [ Designated as safety issue: No ]
  • PK Parameters After the First Dose: Terminal Half-life (t½) for T-DM1 Concentrations [ Time Frame: 3-Week and Weekly Cohorts: Cycle 1 Day 1 Pre-dose 30 minutes and 4 hours after the end of infusion; Cycle 1 Day 2, 3, 4, 8 (Pre-dose 30 minutes after the end of infusion) 11, 15 (Pre-dose 30 minutes after the end of infusion) and 18 ] [ Designated as safety issue: No ]
    Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma.


Secondary Outcome Measures:
  • Percentage of Participants With an Objective Response [ Time Frame: Baseline to the end of the study (up to 3 years 2 months) ] [ Designated as safety issue: No ]
    The occurrence of an objective response was determined by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST). An objective response was defined as a complete response or a partial response as determined on 2 consecutive occasions ≥ 4 weeks apart. A complete response was defined as the disappearance of all target lesions or the disappearance of all non-target lesions and normalization of tumor marker level. A partial response was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter of target lesions.

  • Duration of Objective Response [ Time Frame: Baseline to the end of the study (up to 3 years 2 months) ] [ Designated as safety issue: No ]
    Duration of objective response was defined as the time from the initial response to disease progression or death from any cause within 30 days of the last dose of trastuzumab emtansine.

  • Progression-free Survival [ Time Frame: Baseline to the end of the study (up to 3 years 2 months) ] [ Designated as safety issue: No ]
    Progression-free survival was defined as the time from first dose of trastuzumab emtansine to documented disease progression or death from any cause within 30 days of the last dose of trastuzumab emtansine, whichever occurred earlier. Progressive disease was defined as at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter of target lesions recorded since treatment started or the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.

  • Percentage of Participants With Anti-therapeutic Antibodies to Trastuzumab Emtansine [ Time Frame: Baseline to the end of the study (up to 3 years 2 months) ] [ Designated as safety issue: No ]
    After the start of trastuzumab emtansine treatment, serum samples were collected every 3 weeks prior to trastuzumab emtansine dosing for detection of anti-therapeutic antibodies using a validated assay. A bridging antibody electrochemiluminescence assay (ECLA) was used to detect antibodies to trastuzumab emtansine. The assay utilized trastuzumab emtansine conjugated to biotin and a ruthenium label to form a complex with anti-trastuzumab emtansine antibodies. The antibody complex was captured by streptavidin-coated paramagnetic beads.


Enrollment: 54
Study Start Date: April 2006
Study Completion Date: June 2009
Primary Completion Date: June 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 Drug: trastuzumab-MCC-DM1
Intravenous escalating dose

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically documented, incurable, locally advanced or metastatic breast cancer
  • Evaluable or measurable HER2-positive disease
  • History of progression during or within 60 days after treatment with any prior trastuzumab-containing chemotherapy regimen for HER2-positive breast cancer
  • Previous treatment with chemotherapy for MBC
  • Granulocyte count ≥ 1,500/μL, platelet count ≥ 100,000/μL, and hemoglobin ≥ 9 g/dL
  • Serum bilirubin ≤ 1.5 mg/dL; AST, ALT, and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN) except for: Patients with hepatic metastases: ALT and AST ≤ 5 × ULN Patients with hepatic and/or bone metastases: alkaline phosphatase ≤ 5 × ULN
  • Serum creatinine ≤ 1.5 mg/dL or creatinine clearance of ≥ 60 mL/min based on a 24-hour urine collection
  • Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2
  • Women of childbearing potential and men must agree to use an effective method of birth control (e.g., hormonal, barrier) while receiving study treatment

Exclusion Criteria:

  • History of significant cardiac disease, unstable angina, CHF, myocardial infarction, or ventricular arrhythmia requiring medication
  • History of Grade ≥ 3 hypersensitivity reaction to trastuzumab
  • History of any toxicity to trastuzumab that resulted in trastuzumab being permanently discontinued
  • Symptomatic brain metastases or any radiation or surgery for brain metastases within 3 months of first study treatment
  • Require supplemental oxygen for daily activities
  • Grade ≥ 2 peripheral neuropathy
  • Bisphosphonate therapy for symptomatic hypercalcemia
  • Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy for the treatment of breast cancer within 4 weeks of first study treatment
  • Any experimental therapy within 4 weeks of first study treatment
  • Any major surgical procedure within 4 weeks of first study treatment
  • History of clinically symptomatic liver disease, including viral or other hepatitis, current or history of alcoholism, or cirrhosis
  • Pregnancy or lactation
  • Cardiac troponin I ≥ 0.2 ng/mL
  • Ejection fraction < 50% or below the lower limit of normal determined by echocardiogram or MUGA scan
  • Prior cumulative doxorubicin dose of > 360 mg/m2 or equivalent
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00932373

Sponsors and Collaborators
Genentech, Inc.
Investigators
Study Director: Scott Holden, M.D. Genentech, Inc.
  More Information

No publications provided by Genentech, Inc.

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Genentech, Inc.
ClinicalTrials.gov Identifier: NCT00932373     History of Changes
Other Study ID Numbers: TDM3569g
Study First Received: June 30, 2009
Results First Received: July 1, 2015
Last Updated: August 13, 2015
Health Authority: United States: Food and Drug Administration

Keywords provided by Genentech, Inc.:
HER2-positive breast cancer
MBC
Trastuzumab emtansine
Herceptin
T-DM1

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms
Neoplasms by Site
Skin Diseases
Ado-trastuzumab emtansine
Maytansine
Trastuzumab
Antimitotic Agents
Antineoplastic Agents
Antineoplastic Agents, Phytogenic
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Tubulin Modulators

ClinicalTrials.gov processed this record on September 02, 2015