Clinical Trial Result Information

Title of Study:
An open label randomised phase 2 study of trastuzumab (Herceptin) given with weekly paclitaxel (Taxol) versus weekly paclitaxel as single agent in first-line therapy for patients with HER-2/neu overexpressing advanced breast cancer (ABC).

Fast Facts:

Protocol number:	M77024
Sponsor:	F. Hoffmann-La Roche Ltd
Company division:	Pharmaceutical
Product name:	Herceptin
Generic name:	trastuzumab
Phase of development:	II
Therapeutic area, approved indication:	Breast Cancer
Date of report:	10/3/2005

Clinical study summary:
This was an open-label, multicenter study to compare the efficacy and safety of Herceptin + Taxol, versus Taxol alone, in the first-line treatment of locally advanced and metastatic breast cancer with HER-2/neu overexpression.

Study center(s) :
21 centers in Italy.

Objectives:
Primary: To determine the Overall Response Rate (ORR) in each treatment arm.
Secondary: To characterize the safety profile of the Taxol-Herceptin (T-H) combination and Taxol (T) alone. To determine time to progression (TTP), duration of response (DR), 1-year survival and overall survival (OS) of each treatment arm.

Methodology:
Eligible patients were randomized to receive either a combination of Herceptin (4mg/kg IV on day 1 followed by 2mg/kg IV weekly) + Taxol (80mg/m² IV weekly) or Taxol monotherapy. Treatment was to continue until disease progression. Efficacy was assessed at 8 weeks, 16 weeks, and subsequently every 3 months.

Number of patients (planned/analyzed):
176 planned; 124 enrolled.

Diagnosis and main criteria for inclusion:
Patients with locally advanced and metastatic breast cancer with HER-2/neu overexpression (IHC 2+/3+), treated as first line chemotherapy.

Test product, dose and mode of administration or test procedure:
Herceptin: Loading dose of 4mg/kg IV on day 1, administered as a 90-minute infusion followed by a weekly dose of 2mg/kg administered as a 30-minute infusion.
Taxol: 80mg/m² IV infusion over one hour, weekly, following Herceptin administration.

Duration of treatment:
Until disease progression.

Reference therapy, dose and mode of administration or reference procedure:
Taxol: 80mg/m² IV infusion over one hour, repeated every week.

Criteria for evaluation (efficacy, safety):
Efficacy: Overall response rate, time to progression, duration of response, 1 year survival, and overall survival. Safety: Adverse events, laboratory parameters.

Statistical methods:
The proposed sample size of 80 evaluable patients in each group was calculated to detect a difference in overall response rate between the groups with a precision (2-sided 95% confidence level) of approximately +/- 16%. Allowing for 10% of patients being unevaluable, the total number of patients required for randomisation was 88 per group.

The primary efficacy analysis, overall response rate, was calculated for each treatment arm, and compared descriptively. The effects were estimated with their 95% confidence interval, with binomial approximation. Other efficacy parameters were analysed descriptively.

Summary (efficacy, safety, other results):
Efficacy: As stated in the protocol, the anticancer efficacy (Tumor Response) was assessed according to WHO criteria every 8 weeks of treatment during the first 16 weeks and thereafter every 3 months.
The evaluation of Overall Response was possible in 118 out of 123 evaluable patients as 5 patients withdrew from the study before the 8-week visit (first assessment of response).
A Complete Response was obtained in 22% of patients (13 out of 60) in the T-H group and 14% (8 out of 58) in the T group. A further 57 patients (32 in the T-H group (53%) and 25 in the T group (43%)) showed a Partial Response. Moreover, Stable Disease was reported in 25 patients. Progressive disease was reported in 7% of patients treated with T-H (4 patients) and 19% (11 patients) treated with T alone. To summarize, Complete or Partial Response was obtained in 75% of patients treated with T-H and 56.9% of patients treated with T alone. The difference between groups was 18.1% with a 95% Confidence Interval ranging from 1.293 to 34.907.
Only 2 patients treated with T alone showed signs of Progressive Disease before 8 weeks; a further 14 patients (5 treated with T-H and 9 treated with T alone) were judged in Progression at the week 8-visit and 18 patients (8 T-H and 10 T alone) at the 16-week visit.
As regards Time to Progression, the mean value estimated by applying the product-limit method, was 278 days in the T-H group and 234 days in the T group.
The mean values estimated by applying the product-limit method, were 273 and 247 days in the T-H and T groups respectively.

Safety: The most frequently reported adverse events during treatment, in both groups, were alopecia (68% and 66% of patients in the T-H and T groups, respectively), peripheral neuropathy (68% T-H group and 59% T) and asthenia (56% in both groups).
During the trial 3 patients died. Two patients, both treated with T-H, died as a consequence of serious adverse events (head trauma and pulmonary failure with cardiopulmonary onset). The 3rd patient, in the T group, died of respiratory distress. 12 SAEs occurred during treatment with T-H and 6 SAEs occurred during treatment with T alone. The only SAEs considered related to treatment were erysipelas, reported by 1 patient in the T-H group, and diarrhea and fever, reported by 1 patient in the T group.

Conclusions:
The weekly regimen of Herceptin and Taxol showed better efficacy than Taxol monotherapy, in terms of inducing Complete or Partial Response. This result was more evident in patients with an IHC HER2 score of 3+.