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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Drug: trastuzumab-MCC-DM1


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: trastuzumab-MCC-DM1<br>* Intravenous escalating dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Events (AE), Serious Adverse Events (SAE), AEs With Grade >=3, and AEs Related To Treatment | 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. | Study treatment initiation until 30 or 90 days after last administration of study treatment | 
| Number of Patients With Dose Limiting Toxicities (DLTs) | 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 | A minimum of 21 days after first dose of trastuzumab-MCC-DM1 | 
| Maximum Tolerated Dose (MTD) | The highest dose level resulting in a DLT in ≤ 1 of 6 patients was declared the MTD. | A minimum of 21 days after first dose of trastuzumab-MCC-DM1 | 
| Pharmacokinetic (PK) Parameters After the First Dose: Maximum Observed Plasma Concentration Cmax for T-DM1 Concentrations |  | 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 | 
| PK Parameters After the First Dose: Area Under the Plasma Concentration-time Curve From 0 to Infinity (AUC[0-∞] for T-DM1 Concentrations |  | 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 | 
| PK Parameters After the First Dose: Terminal Half-life (t½) for T-DM1 Concentrations | Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the plasma. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With an Objective Response | 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. | Baseline to the end of the study (up to 3 years 2 months) | 
| Duration of Objective Response | 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. | Baseline to the end of the study (up to 3 years 2 months) | 
| Progression-free Survival | 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. | Baseline to the end of the study (up to 3 years 2 months) | 
| Percentage of Participants With Anti-therapeutic Antibodies to Trastuzumab Emtansine | 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. | Baseline to the end of the study (up to 3 years 2 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MBC, HER2-positive breast cancer, Trastuzumab emtansine, Herceptin, T-DM1