Clinical trial NCT00932373: A Study of Trastuzumab-MCC-DM1 Administered Intravenously to Patients With HER2-Positive Metastatic Breast Cancer Who Have Previously Received a Trastuzumab-Containing Regimen
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Metastatic Breast Cancer
Keywords: HER2-positive breast cancer
MBC
Trastuzumab emtansine
Herceptin
T-DM1
Lead sponsor: Genentech, Inc.
Sponsor class: INDUSTRY
First posted: 2009-07-03
Enrollment: 54
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility 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

Primary outcomes:
measure: Percentage of Participants With Adverse Events (AE), Serious Adverse Events (SAE), AEs With Grade >=3, and AEs Related To Treatment
timeFrame: Study treatment initiation until 30 or 90 days after last administration of study treatment
measure: Number of Patients With Dose Limiting Toxicities (DLTs)
timeFrame: A minimum of 21 days after first dose of trastuzumab-MCC-DM1
measure: Maximum Tolerated Dose (MTD)
timeFrame: A minimum of 21 days after first dose of trastuzumab-MCC-DM1
measure: Pharmacokinetic (PK) Parameters After the First Dose: Maximum Observed Plasma Concentration Cmax for T-DM1 Concentrations
timeFrame: 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
measure: PK Parameters After the First Dose: Area Under the Plasma Concentration-time Curve From 0 to Infinity (AUC[0-∞] for T-DM1 Concentrations
timeFrame: 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
measure: PK Parameters After the First Dose: Terminal Half-life (t½) for T-DM1 Concentrations
timeFrame: 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
Secondary outcomes:
measure: Percentage of Participants With an Objective Response
timeFrame: Baseline to the end of the study (up to 3 years 2 months)
measure: Duration of Objective Response
timeFrame: Baseline to the end of the study (up to 3 years 2 months)
measure: Progression-free Survival
timeFrame: Baseline to the end of the study (up to 3 years 2 months)
measure: Percentage of Participants With Anti-therapeutic Antibodies to Trastuzumab Emtansine
timeFrame: Baseline to the end of the study (up to 3 years 2 months)
Other outcomes:
Locations:
Study officials:
affiliation: Genentech, Inc.
name: Scott Holden, M.D.
role: STUDY_DIRECTOR
References:
citation: Beeram M, Krop IE, Burris HA, Girish SR, Yu W, Lu MW, Holden SN, Modi S. A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer. Cancer. 2012 Dec 1;118(23):5733-40. doi: 10.1002/cncr.27622. Epub 2012 May 30.