Clinical Trial Result Information
Title of Study:
An open-label, randomized phase II study of Herceptin (trastuzumab), Taxotere (docetaxel) and Xeloda (capecitabine) in combination, versus Herceptin (trastuzumab) plus Taxotere (docetaxel), in patients with advanced and/or metastatic breast cancers that overexpress HER2.
Fast Facts:
| Protocol number: | MO16419 |
| Sponsor: | Hoffmann-La Roche AG |
| Company division: | Pharmaceutical |
| Product name: | Herceptin |
| Generic name: | trastuzumab |
| Phase of development: | II |
| Therapeutic area, approved indication: | Breast Cancer |
| Date of report: | 4/1/2008 |
Clinical study summary:
This was an open-label, randomized, multi-center, multinational study comparing treatment with Herceptin + docetaxel + Xeloda vs. Herceptin + docetaxel in patients with advanced and/or metastatic breast cancer.
Study center(s) :
43 centers in Australia, Brazil, Canada, Cost Rica, Finland, France, Greece, Guatemala, Italy, Mexico, Panama, Poland, Spain, Sweden and United Kingdom.
Objectives:
Primary: To compare the overall response rate (complete and partial) in patients randomized to Herceptin, docetaxel plus Xeloda (HDX), with the response rate in patients randomized to Herceptin plus docetaxel (HD).
Secondary: To compare, in the two arms: progression-free survival; survival; duration of response; safety profile.
Methodology:
Patients were randomized to receive either Herceptin + docetaxel + Xeloda, or Herceptin + docetaxel, until disease progression, unmanageable toxicity or patient withdrawal. They were stratified according to previous anthracycline use, liver metastases and ECOG performance status. Disease assessment according to routine clinical practice was carried out at 1 year, and survival status was assessed at 18 months.
Number of patients (planned/analyzed):
225 patients enrolled
Diagnosis and main criteria for inclusion:
Female patients, at least 18 years old, with histologically confirmed locally advanced and/or metastatic breast cancer that overexpresses HER2 (measured as 3+ by immunohistochemistry or FISH positive).
Test product, dose and mode of administration or test procedure:
Herceptin was given as a loading dose of 8mg/kg by i.v. infusion over 90 minutes on Day 1. Thereafter, Herceptin was administered every 3 weeks at a dose of 6mg/kg by i.v. infusion.
Docetaxel was administered by i.v. infusion over 1 hour every 3 weeks, 75mg/m2.
Xeloda: 950mg/m2 twice daily. Two equal doses taken morning and evening for the first 14 days of each cycle.
Duration of treatment:
Until disease progression, unmanageable toxicity or patient withdrawal
Reference therapy, dose and mode of administration or reference procedure:
Herceptin was given as a loading dose of 8mg/kg by i.v. infusion over 90 minutes on Day 1. Thereafter, Herceptin was administered every 3 weeks at a dose of 6mg/kg by i.v. infusion.
Docetaxel was administered by i.v. infusion over 1 hour every 3 weeks, 100mg/m2.
Criteria for evaluation (efficacy, safety):
Efficacy: Tumor measurement/assessment (based on RECIST criteria) using CT or MRI scans, X-ray, bone scan, clinical examination. Survival.
Safety: Adverse events, cardiac failure; hematological and biochemical parameters; cardiac monitoring – ECG and LVEF (MUGA/echocardiography) at baseline then LVEF every 12 weeks.
Statistical methods:
Tumor response rates and 95% confidence limits were calculated according to Pearson-Clopper. The Hauck-Anderson approach was used to calculate confidence limits for the difference of two rates.
Summary (efficacy, safety, other results):
Efficacy: Both treatment arms achieved high overall response rates; 71% and 73% in HDX and HD arms respectively (p=0.717), with complete response in the HDX and HD arms of 23% and 16% respectively, and partial response of 47% and 56% respectively. A significant increase in time to progression (median 18.6 months (HDX) vs. 13.6 months (HD), p=0.033, hazard ratio 1.41, 95% CI 1.03; 1.94) and progression-free survival (median 17.9 months (HDX) vs. 12.8 months (HD), (p=0.045, hazard ratio 1.37, (95% CI 1.01; 1.87)) was obtained in the HDX arm.
Overall, neutropenia and febrile neutropenia were the most frequently reported grade 3/4 treatment-related adverse events in both study arms. The incidence of febrile neutropenia was however lower in the HDX arm (17 HDX vs. 30 HD), and probably due to the lower dose of docetaxel used in the HDX arm. Febrile neutropenia was the most common serious adverse event with 16 events in the HDX arm and 26 events in the HD arm. The incidence of palmar-plantar erythrodysesthesia and of diarrhea, both established side-effects of Xeloda, was higher in the HDX arm.
The incidence of cardiac dysfunction was the same in both treatment arms.
Five deaths in the HDX arm and 3 deaths in the HD arm were due to serious adverse events. The Investigator considered one death (due to bronchopneumonia) related to docetaxel treatment. The other 4 deaths in the HDX arm were considered unrelated to treatment. All 3 deaths on the HD arm (acute hepatic failure, febrile neutropenia and hypovolemic shock) were considered treatment-related.
Eleven patients in the HDX arm and 14 patients in the HD arm were withdrawn from treatment due to adverse events. Febrile neutropenia (4 incidents: 1 in the HDX arm and 3 in the HD arm) and LVEF decline (4 incidents: 1 in the HDX arm and 3 in the HD arm) were the most common reasons for premature withdrawal from the study.
The incidence of grade 3/4 leukopenia and neutropenia was slightly higher in the HD arm. There were no notable differences between the study groups in the incidence of anemia and thrombocytopenia and only rare, isolated incidents of changes, classified as grade 3 and grade 4, in laboratory parameters indicative of liver function, renal function or hypo- and hyper-calcemia.
Conclusions:
HDX combination therapy was shown to be an effective and well-tolerated first-line therapy for patients with HER-2 postive, locally advanced breast cancer or metastatic breast cancer. There was a statistically significant improvement of 5 months in the median time to progression and an improvement of 5.1 months (p=0.045) in progression-free survival in the HDX treatment arm. Febrile neutropenia (grade 3/4) was less frequent in the HDX arm; the occurrence of (grade 3/4) palmar-plantar erythrodysesthesia and (grade3/4) diarrhea, both recognized side-effects of Xeloda, was higher in the HDX arm. There was no notable difference in LVEF decline between the HDX and HD treatment arms.
Click here for the protocol registry listing of this trial.
