Clinical Trial Result Information

Title of Study:
Pharmacokinetic Study of Herceptin® (H) and Doxorubicin (A) plus Paclitaxel (T) followed by weekly Paclitaxel (AT+/-H→TH) in Women with Metastatic Breast Cancer and HER2 Overexpression.

Fast Facts:

Protocol number:	M77004
Sponsor:	Hoffmann-La Roche
Company division:	Pharmaceutical
Product name:	Herceptin
Generic name:	trastuzumab
Phase of development:	II
Therapeutic area, approved indication:	Breast Cancer
Date of report:	9/1/2004

Clinical study summary:
This was an exploratory, non-randomized, open study to investigate the efficacy, safety and pharmacokinetics of combination treatment with Herceptin, doxorubicin and paclitaxel.

Study center(s) :
5 centers in Germany, Italy and Spain.

Objectives:
Primary: To examine the interactions between the pharmacokinetics of Herceptin, doxorubicin and paclitaxel (cohort 1).
Secondary: To compare the antitumor efficacy and safety of the doxorubicin plus paclitaxel combination when Herceptin was initiated with (cohort 1) and following (cohort 2) doxorubicin and paclitaxel administration.

Methodology:
Tumor assessment was made by CT-, MRI-scan, X-ray and ultrasound examination according to WHO criteria and the therapeutic response judged as complete response (CR), partial response (PR), no change stable disease (SD) or progressive disease (PD). Cardiac events were defined as type A (congestive heart failure, CHF), type B (cardiomyopathy with global decrease in LVEF) and type C (asymptomatic decrease of LVEF of at least 10 EF units to below 55% or to below 50%), and accrual procedures for cardiac toxicity were determined.

Number of patients (planned/analyzed):
Planned: 32. Actual: 32.

Diagnosis and main criteria for inclusion:
Patients with proof of metastatic breast cancer (stage IIIB/IV) and immunohistochemical evidence of HER2 overexpression who received no prior treatment with anthracyclines and/or taxanes; left ventricular ejection fraction (LVEF) >50% and no prior history of myocardial infarction.

Test product, dose and mode of administration or test procedure:
Herceptin: loading dose 4 mg/kg body weight by infusion; 2 mg/kg body weight by infusion from week 2. Weeks 1-52 (cohort 1), weeks 10-52 (cohort 2). Doxorubicin 60mg/m² i.v. bolus; paclitaxel 150 mg/m² infusion at cycle 1-3, 80mg/m² infusion at cycle 4-12. Weeks 1-9: doxorubicin plus paclitaxel every 3 weeks. Weeks 10-18: paclitaxel weekly.

Duration of treatment:
Until disease progression.

Reference therapy, dose and mode of administration or reference procedure:
N/A

Criteria for evaluation (efficacy, safety):
Efficacy: Response rate (overall response: complete response CR or partial response PR); time to progression; survival.
Safety: Adverse events; cardiac events; cardiac findings (ECG, echocardioagraphy, physical examination); vital signs, ECOG performance status; laboratory tests.
(Pharmacokinetics and pharmacodynamics will be reported separately).

Statistical methods:
As this was an exploratory, non-randomized and open study, no hypothesis was defined and tested. All analyses performed for cohorts 1 and 2 were descriptive and exploratory. Overall response rates and 95% confidence limits according to Pearson-Clopper were calculated for each cohort. Kaplan-Meyer estimates were calculated for time to progression, overall survival time and survival time for one year, progression-free survival and progression-free survival under treatment.

Summary (efficacy, safety, other results):
Pharmacokinetics: For paclitaxel and its major metabolite, and doxorubicin, the main pharmacokinetic measurements were similar with or without trastuzumab. However, exposure to doxorubicin metabolites was significantly greater in the presence of trastuzumab. Trastuzumab serum trough concentrations were similar and as expected in the two cohorts.

Efficacy: Overall the efficacy results demonstrated good antihumor activity in both cohorts with the same overall response rates (87.5%).

Differences in median response durations and median time to progression between the cohorts are largely attributable to the sequential enrollment, resulting in different observation periods (median of 608 and 402 days, respectively). Time to tumor progression showed a similar trend in the 2 cohorts over the interval when a comparison could be made. There were two deaths in cohort 2 during the first year, but no data were available at year 1 for 4 patients; this accounts for much of the apparent difference in 1 year survival between the two cohorts.

Cardiac Safety: Most patients in both cohorts had an absolute decrease in LVEF during the study; at cycle 12, LVEF decrease was observed in 75% and 33% of patients in cohorts 1 and 2, respectively. Congestive heart failure was not observed, and LVEF decreases were reversible in all cases. Four patients in Cohort 1 had a decrease in LVEF during treatment and follow-up of >50%. Study treatment was uninterrupted in 3 of these patients; doxorubicin treatment was discontinued in the fourth. In Cohort 2, no patients had a decrease in LVEF to <50%, and 6 showed an increase or no change in LVEF.

General Safety: Therapy was generally well-tolerated, with adverse events reflecting the well known side effect profile of the drugs administered. The majority of adverse events were mild or moderate in intensity, and occurred with a similar incidence in both cohorts. Only two NCI-CTC grade 4 events (diarrhea and malignant melanoma) were observed, both in Cohort 1 patients. The most common grade 3/4 events were amenorrhea, infection and hypertension. The most common treatment-related adverse events were mild to moderate alopecia, paresthesia and nausea. The majority of patients in both cohorts experienced hematological abnormalities (anemia, neutropenia and leukopenia), mostly of grade 1/2 intensity. No patient had to be withdrawn from the trial due to toxicity, and the need for dose modification was limited.

Conclusions:
Herceptin appeared to be highly effective when given concomitantly with doxorubicin + paclitaxel, or with paclitaxel alone after completion of doxorubicin + paclitaxel. Both treatment regimens demonstrated good antitumor activity. The plasma pharmacokinetics of doxorubicin and paclitaxel were not affected by trastuzumab. The results suggest that cardiotoxicity may be worse, but manageable with close cardiac monitoring, when Herceptin is administered concomitantly with doxorubicin + paclitaxel. Congestive heart failure was not observed in either treatment cohort, and LVEF decreases were reversible.

Publications (references, if available):
Pilot Trial of Trastuzumab, Starting with or after the Doxorubicin Component of a Doxorubicin plus Paclitaxel Regimen, for Women with HER2-positive Advanced Breast Cancer. Bianchi G, Albanell J, Eiermann W et al. Clinical Cancer Research 9: 5944-5951 (2003)