Clinical Trial Result Information

Title of Study:
Trastuzumab (Ro 45-2317) in combination with epirubicin and docetaxel as first-line chemotherapy in metastatic breast cancer patients

Fast Facts:

Protocol number:	M77022
Sponsor:	Roche S.p.A. Italy
Company division:	Pharmaceutical
Product name:	Herceptin
Generic name:	trastuzumab
Phase of development:	II
Therapeutic area, approved indication:	Breast Cancer
Date of report:	3/11/2004

Clinical study summary:
This was an open-label, multi-center, Phase II study to evaluate the cardiac safety and tolerability of Herceptin plus epirubicin and docetaxel in patients with metastatic breast cancer. Herceptin was given until progressive disease, unacceptable toxicity, or patient refusal; for patients with stable disease, epirubicin and docetaxel were given for a maximum of 8 cycles.

Study center(s) :
8 sites in Italy.

Objectives:
Primary objective: To evaluate the cardiac safety of Herceptin in combination with epirubicin and docetaxel in patients with metastatic breast cancer and her-2/neu over-expression.

Secondary objectives: (1) To evaluate the feasibility and systemic tolerability of the combination; and (2) To determine the response rate, duration of response, and time to disease progression.

Methodology:
After screening and enrollment, patients received a 4mg/kg iv loading dose of Herceptin, then 2mg/kg weekly. Epirubicin and docetaxel 75mg/m2 were administered iv every 21 days. Patients were examined for signs of cardiotoxicity at intervals throughout the study, and routine safety evaluations were performed.

Number of patients (planned/analyzed):
2 stages: 29 patients to be enrolled and treated in stage 1; ≤30 patients enrolled in stage 2 if <4 patients (<15%) developed cardiotoxicity during stage 1. A total of 45 patients were enrolled.

Diagnosis and main criteria for inclusion:
Patients with metastatic breast cancer with HER-2/neu over-expression (2+, 3+ assessed by standardized immunohistochemistry using the DAKO Herceptest) who had not received prior chemotherapy for metastatic disease.

Test product, dose and mode of administration or test procedure:
Epirubicin and docetaxel: 75mg/m2 iv on Day 1, then every 21 days. Herceptin iv 4 mg/ kg on Day 0, then 2 mg/ kg weekly.

Duration of treatment:
Herceptin: until progressive disease, unacceptable toxicity, or patient refusal; epirubicin and docetaxel: maximum of 8 cycles for patients with stable disease

Reference therapy, dose and mode of administration or reference procedure:
Not applicable

Criteria for evaluation (efficacy, safety):
To assess cardiac safety, all patients were evaluated for left ventricular ejection fraction (LVEF) at baseline, every 2 cycles during the 2-drug chemotherapy regimen plus Herceptin, and every 3 months during Herceptin alone. Patients were removed from treatment if they developed cardiac toxicity defined as follows: signs and symptoms of congestive heart failure (CHF) classified as Grade III or higher, according to New York Heart Association classification; a decrease in resting LVEF (by multiple gated acquisition scan or ultrasonography) to ≤45%; a decrease from baseline resting LVEF of ≥20% EF units.

Statistical methods:
In the analysis of the primary endpoint, only patients who received ≥2 treatment cycles (or developed cardiotoxicity before the second cycle) were included. Patients who did not complete ≥2 LVEF evaluations were excluded as well. In the analysis of responses, all patients who received ≥1 cycle of the experimental regimen were included.

Safety analysis: A standard safety analysis was performed, and all adverse events and abnormal laboratory parameters were assessed according to the National Cancer Institute’s Common Toxicity Criteria grading system.

Efficacy analysis: Despite the fact that analysis of efficacy was not the aim of the study, patient response was assessed according to the World Health Organization criteria and the overall response achieved within the time from randomization to progressive disease or end of study reported, and time to disease progression computed.

Summary (efficacy, safety, other results):
Cardiac events – In the first stage of the study, <4 episodes of cardiotoxicity were observed (2 asymptomatic declines of LVEF and 1 CHF) in 29 patients, and recruitment continued. During follow-up of patients who continued Herceptin alone after chemotherapy, 7 additional cardiac events occurred. Three (3) patients experienced an asymptomatic decline of LVEF to 28%, 39%, and 43%, respectively, and 4 patients developed CHF. Therefore, recruitment was interrupted after the 45th patient.

Efficacy data – Complete and partial responses were observed in 9 (20%) and 21 (47%) patients, respectively, and the median time to disease progression was 15.7 months (95% confidence interval, 11.6–19.0 months).

Adverse events – The general safety profile of the combination therapy was as expected with these agents. The most frequent clinical adverse events were alopecia (93.3%), nausea (60.0%), mucositis (57.8%), asthenia (48.9%), pyrexia (48.9%), and vomiting (42.2%). Hematologic and laboratory abnormalities were also as expected, the most common being neutropenia (42.2%), febrile neutropenia (13.3%), and leukopenia (6.6%). The majority of adverse events were mild to moderate in intensity. The only Grade 3/4 treatment-related adverse events of note were alopecia (Grade 3, 44.4%; Grade 4, 2.2%) and neutropenia (Grade 3, 6.7%; Grade 4, 35.6%).

Serious adverse events – Serious adverse events were reported in 11 patients, including 16 events considered to be related to study treatment. These included febrile neutropenia (6.7% of patients), neutropenia (4.4%), cardiac failure (4.4%), alopecia (2.2%), diarrhea (2.2%), decreased LVEF (2.2%), infection (2.2%), and pyrexia (2.2%). The majority of patients with serious adverse events recovered either with or without dose reductions, with the exception of cardiac failure and decreased LVEF in 1 patient, and neutropenia and alopecia in a second patient.

Conclusions:
In light of the cardiac toxicity experienced by patients in this study, the results suggest that the use of Herceptin, epirubicin, and docetaxel in combination should be limited to controlled clinical trials.