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Clinical Trial Result Information

Title of Study:
A phase III study comparing taxotere, epirubicin and Xeloda (TEX) versus epirubicin and taxotere (ET) in advanced breast cancer patients.

Fast Facts:

Protocol number:	ML16505
Sponsor:	Roche S.p.A. Italy
Company division:	Pharmaceutical
Product name:	Xeloda
Generic name:	capecitabine
Phase of development:	III
Therapeutic area, approved indication:	Breast Cancer
Date of report:	6/15/2007

Clinical study summary:
This was a prospective, randomized, open label, multicenter trial to compare therapy with taxotere + epirubicin with or without Xeloda (capecitabine) in patients with metastatic or locally advanced breast cancer.

Study center(s) :
26 centers in Italy.

Objectives:
Primary: To determine progression-free survival in the two treatment arms.
Secondary: To assess the efficacy in terms of response rate (RR), duration of response (DR) and overall survival (OS) in the two treatment arms; to evaluate the safety of the triple combination regimen.

Methodology:
A total of 342 patients with metastatic or locally advanced breast cancer (stage III or IV, respectively) were enrolled and randomized to either the triple combination regimen including Xeloda (2000mg/m²/day po bid on days 1-14 of each treatment cycle), docetaxel (75mg/m² i.v.  infusion on day 1 of each treatment cycle) and epirubicin (75mg/m² i.v. bolus on day 1 of each treatment cycle) (TEX regimen, group A) or the double combination regimen including the two latter drugs/doses/schedules (ET regimen, group B).
Cycles were repeated every 3 weeks, with treatment continued on the basis of tumor reassessment. Following surgery, the pathological tumor and regional lymph node stage was evaluated on tissue specimens from surgical intervention. After the end of treatment, for all patients but those discontinuing due to progression of disease (PD), tumor reassessment was repeated every 3 months during follow up visits until PD. After PD, follow up visits were continued up to a patient's death, for OS collection.

Number of patients (planned/analyzed):
340 patients planned, 342 patients recruited.

Diagnosis and main criteria for inclusion:
Metastatic or locally advanced histologically proven breast carcinoma (UICC stages III and IV); at least one evaluable lesion.

Test product, dose and mode of administration or test procedure:
Xeloda (capecitabine) + epirubicin + docetaxel.
Xeloda was administered orally at a split dose of 2000mg/m²/day within 30 minutes after the end of a meal (breakfast, dinner). Epirubicin and docetaxel were administered at a dose of 75mg/m² intravenously as slow bolus and one hour infusion, respectively. Treatments were administered in 3 week cycles. Epirubicin and docetaxel were given on day 1 of each cycle, while Xeloda was given twice daily from day 1 through day 14. Cycles were to be repeated every 3 weeks, with treatment continued on the basis of tumor reassessment. Patients with stage IV were to receive 6 to 8 cycles, while patients with stage III disease were to receive 4 to 6 cycles.

Duration of treatment:
Up to 8 x 3 weeks cycles of treatment

Reference therapy, dose and mode of administration or reference procedure:
Epirubicin + docetaxel (administered as above)

Criteria for evaluation (efficacy, safety):
Efficacy: Tumor response: complete response (CR),  partial response (PR), stable disease (SD), progressive disease (PD), overall response (OR); progression-free survival (PFS) (primary study endpoint); overall survival (OS); disease-free survival (DFS); duration of response (DR); response rate (RR).

Safety: AEs, laboratory parameters, ECG, LVEF (if clinically indicated).

Statistical methods:
Primary efficacy variables were to be analyzed in the ITT and STD populations. Secondary efficacy variables were to be analyzed in the ITT population.
Time dependent variables were analyzed according to Kaplan-Meier, with between treatment differences tested by log-rank test. Treatment-associated hazard ratios were estimated by a Cox model, with treatment and disease stage (metastatic vs locally advanced), as well as treatment by stage interaction included in the model. The proportion of responses in the two arms was compared by Mantel-Haenszel techniques, following adjustment for stage.

Summary (efficacy, safety, other results):
Efficacy: With regard to the primary study endpoint, the two treatment groups showed a similar PFS (from the Kaplan-Meier analysis), with a median value of 461 days (95% CI 373-545 days) in the total ITT population of group A vs 414 days in group B (95% CI 344-554 days (p=0.58, log rank test). Similar results were obtained from the STD population analysis. Consistent with the above findings, no significant between-treatment differences emerged from the Cox model analysis of PFS in both ITT and STD populations, while a highly significant (P<0.0001) stage effect was apparent, with a 4 times higher risk of progression in stage IV vs stage III disease (ITT population 95% CI 2.2-7.5), and no significant stage by treatment interaction.
In the secondary efficacy assessments, CR was seen more frequently in group A than in group B (15.4% vs 4.6% of total population groups), in both stage III (12.1% vs 2.6%) and stage IV patients (16.2% vs 5.2%), while PR was seen in 53.8% of patients in both group A and in group B, with similar frequency in stage IV patients (50.8% vs 47.4%), but was less frequent in group A than in group B in stage III cases (66.7% and 76.3%). In the total population the resulting RR was found to be significantly (p=0.04) more frequent in group A (69.2%) than in group B (58.4%), with a significantly higher relative risk of response in group A (1.19, 95% CI 1.01-1.39). While RR was similar in stage III patients in the two groups (78.8% vs 78.9%, group A vs B), in stage IV patients it was significantly (p=0.02) higher in group A (66.9%) than in group B (52.6%), with a significantly higher relative risk in group A (1.27, 95% CI 1.04-1.55). PD was not observed in stage III patient of either group, while in stage IV it was seen somewhat less frequently in group A (5.9%) than in group B (11.1%).
Median OS was similar in the total population of the two groups (1275 days vs 1329 days in group A and B, respectively), with no 95% CI upper limit estimate, and non-significant between-treatment differences in the log rank test (p=0.54).
No significant differences between treatment groups were detected in the Kaplan-Meier analysis of other time dependent variables, i.e. time to response and DR in responders and DFS in stage III patients after surgery.
The Kaplan-Meier analysis of PFS by overall response in the total ITT population showed in stage IV disease a direct positive relationship between PFS estimate and overall response, with median values increasing from 70 days in PD patients (95% CI 58-76), to 344 days in SD patients (95% CI 256-415), to 394 days in PR patients (95% CI 338-480), and to 614 days in CR patients (95% CI 398-na), with highly significant differences (p<0.0001) among overall response categories. The above pattern was present in both treatment groups, with no significant between-treatment differences over overall response strata (p=0.58). No significant differences among PFS estimates in the different overall response categories were detected in stage III disease, with a similar pattern in both treatment groups, and there were no significant between-treatment differences over overall response strata.

Safety: Three group A and 6 group B patients died during the study period, due to disease progression (1 group A and 2 group B patients), septic shock (1 patient per group), cardiorespiratory arrest, ARDS and suicide (3 group B patients), and pulmonary edema (1 group A patient), with AEs leading to death judged to be related to study medications for both septic shock cases and for the ARDS case. Study medications were discontinued due to AEs with similar frequency in group A (9 patients, 5.3%) and group B (12 patients, 6.9%). AEs causing discontinuation mostly included infection related AEs (febrile neutropenia or other infections) as well as allergic reactions (3 group A and 2 group B patients in both cases), or CV disorders (LVEF decrease, deep venous thrombosis or ischemia, 2 group A and 3 group B patients). SGPT increase caused discontinuation of 2 group B cases, while leukopenia, acute psychotic disorder in alcohol abuse, and abdominal pain caused discontinuation of single group B patients, and diarrhea caused discontinuation of a single group A patient.
The total number of AEs was greater in group A (18.2 AEs on average per patient with AEs) than in group B (15.0 AEs on average per patient), as was the total number of SAEs (1.47 SAEs on average per patient with SAEs in group A and 1.26 in group B). The most common SAEs included febrile neutropenia (37.7% of the SAEs in group A vs 27.3% in group B), other hematological toxicities (11.3% vs 25.0%), CV events (7.5% vs 11.4%), or GI events (9.4% vs 9.1%), with other SAEs in both groups including neurological events (9.4% vs 6.8%), pulmonary events (5.7% vs 2.3%), constitutional SAEs (5.7% vs 2.3%), or hepatic/metabolic SAEs (1.9% vs 6.8%). A total of 71.7% of group A SAEs and 77.3% of group B SAEs were considered drug-related.
Most frequent clinical AEs reported in both groups were alopecia (80.9% of group A vs 72.7% of group B patients), nausea (64.3% vs 61.6%) and asthenia (56.6% vs 56.4%). Several AEs occurred more frequently in group A, including stomatitis (61.3% vs 45.9%), diarrhea (48.2% vs 29.6%), edema (17.9% vs 9.9%), paresthesia (17.9% vs 11.6%), abdominal pain (14.9% vs 7.6%), and HFS (23.8% vs 1.7%). Other AEs reported with similar frequency in the two groups included vomiting (38.7% vs 30.8%), fever (36.9% vs 37.8%), epigastralgia (23.2% vs 17.4%), febrile neutropenia (20.8% vs 17.4%, mostly of maximum CTC grade 3 or 4 in either group), bone pain (17.3% vs 16.3%) and conjunctivitis (17.3% vs 16.9%). AEs more prevalent on TEX cycles (Group A) than on ET cycles (Group B) included diarrhea (15.3% vs 6.6%) and hand-foot syndrome affecting almost only TEX cycles (9.7% vs 0.4%).
Laboratory AEs occurring more frequently in group A than in group B included leukopenia (72.0% vs 62.2%), hemoglobin decrease (69.0% vs 59.9%), neutropenia (66.7% vs 54.6%) hyperglycemia (40.5% vs 26.2%) SGPT increase (31.6% vs 19.8%), SGOT increase (24.4% vs 17.4%) and thrombocytopenia (22.0% vs 11.6%). Other laboratory AEs had a similar incidence in both groups, including hypoalbuminemia (17.3% vs 14.4%), total protein decrease (13.1% vs 11.6%), and SAP increase (11.9% vs 10.5%). On the whole, the intensity of laboratory AEs tended to be greater in group A, with maximum NCI CTC grade 3 or 4 laboratory abnormalities more frequent than in group B, particularly leukopenia (53.8% vs 41.5%), and neutropenia (59.2% vs 49.9%). Other AEs were reported with similar frequency between the two groups. No clinically relevant changes in mean and/or median laboratory values were apparent. The proportion of patients with abnormal ECG findings at last assessment was similar in group A (11.4% of 44 evaluated cases) and B (7.5% of 53 evaluated cases). All assessed patients showed LVEF ≥50% at baseline, with mean percent changes at last assessment negligible in either group.

Conclusions:
The study failed to prove the hypothesis of a 30% increase of median PFS with addition of Xeloda to docetaxel and epirubicin in metastatic or locally advanced breast cancer. The difference in terms of the primary efficacy endpoint between the two regimens was maximal in worst prognosis stage IV patients, with a median PFS 20% increase in the triple regimen group. However, study results supported a significant RR advantage of Xeloda addition to docetaxel and epirubicin in the worst prognosis stage IV population, as well as a highly significantly PFS advantage following response to chemotherapy in the latter patient group. The triple regimen was associated with somewhat higher frequency and intensity of AEs, but proved feasible in terms of overall tolerability and safety.

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