Roche trials database

Protocol number:

ML16986

Title of Study:

A randomized, open-label study of the effect of Xeloda or intravenous 5-fluorouracil, both in combination with epirubicin and cyclophosphamide, on complete histological tumor response in patients with breast cancer before surgery

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

Xeloda

Generic name:

capecitabine [Xeloda]

Therapeutic area:

• Breast Cancer

Clinical study summary:

This was a randomized, phase II, open-label, parallel group, comparative, multicenter, French national study with direct individual benefit (DIB). Patients were randomized according to a centralized, balanced (1:1), adaptive randomization procedure using a minimization method and stratified by center and Scarff-Bloom Richardson grade (1 and 2 versus 3). Two neoadjuvant chemotherapy regimens were tested:

- Arm A consisting of the CEX regimen for 4 cycles each of 21 days duration

- Arm B consisting of the FEC 100 regimen for 4 cycles each of 21 days duration.

Following definitive surgery both study arms received 4 cycles of adjuvant docetaxel each of 21 days duration and if indication radiotherapy and/or hormonal therapy.

There were two study  periods: active treatment (neoadjuvant chemotherapy, surgery, and adjuvant chemotherapy) and 5-year follow-up.

 

Study center(s):

22 centers in France

Phase of development:

II

Objectives:

The primary objective was to demonstrate the non-inferiority of combination chemotherapy with capecitabine/epirubin/cyclophosphamide (CEX) versus 5-Fluorouracil/epirubicin/cyclophosphamide (FEC 100) in terms of pathological complete response rate at the time of definitive surgery.

The secondary objectives were to compare between the study arms, 1) the safety profile, 2) objective tumor response during and at end of neoadjuvant treatment, 3) breast conservation rate, 4) tumor expression of molecular determinants of activity (TP, DPD, TS) of the fluoropyrimidines and capecitabine in relation to treatment efficacy, 5) lymphocyte expression of DPD activity and its relation to treatment tolerability, 6) disease-free survival at 5 years, 7) overall survival at 5 years, and 8) overall safety at 5 years.

Methodology:

The study comprised a screening visit within 28 days prior to the inclusion/randomization visit on Day 1 (just before Cycle 1); followed by the 1st treatment period consisting of four cycles of 3-weekly CEX or FEC 100 neoadjuvant chemotherapy (including a study visit before administration of each cycle); followed thereafter within 4-6 weeks by definitive surgery with lymph node dissection; and followed thereafter, within a maximum of 6 weeks, by a 2nd treatment period consisting of four cycles of docetaxel adjuvant chemotherapy administered to patients in both Arms A and B (including a study visit before administration of each cycle). The post treatment follow-up period was for 5 years during which time patients were assessed annually on the anniversary date of randomization.

Total study duration was 7 years. The study was conducted under the supervision of a Scientific Committee.

Number of patients (planned/analyzed):

182 patients planned, 182 patients randomized

Diagnosis and main criteria for inclusion:

Females, 18 to 70 years of age, with measurable, operable, unilateral, non-inflammatory, histologically confirmed breast cancer, not considered candidates for conservative management, and with an ECOG performance status of  0-1.

Test product, dose and mode of administration or test procedure:

Period 1: Neoadjuvant systemic treatment with capecitabine, epirubicin and cyclophosphamide – CEX (Arm A)

Capecitabine, administered orally, at a dose of 900 mg/m², twice daily (i.e. total daily dose of 1800 mg/m²/day), from D1 to D14 followed by 7 days of rest (no treatment),

Epirubicin, administered by short intravenous (IV) infusion at a dose of 100 mg/m² on D1 of each cycle,

Cyclophosphamide, administered by short IV infusion at a dose of 500 mg/m2 on D1 of each cycle.

Cycles were repeated every 3 weeks for a total of 4 cycles.

Surgery with lymph node dissection was carried out 5 weeks (+ 1 week) after the last cycle of chemotherapy.

Period 2: Adjuvant treatment with docetaxel.

Adjuvant systemic treatment with docetaxel was initiated within a maximum of 6 weeks post-operatively at a dose of 100 mg/m2 as an IV infusion on Day 1 of each cycle.

Cycles were repeated every 3 weeks for a total of 4 cycles. 

If indication radiotherapy and/or hormonal therapy were administrated after docetaxel.

Duration of treatment:

Period 1: 4 cycles each of 21 days; Period 2: 4 cycles each of 21 days.

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

Period 1: Neoadjuvant systemic treatment with the reference therapy 5-FU, epirubicin and cyclophosphamide – FEC 100 (Arm B)

5-Fluorouracil, administered by short IV infusion at a dose of 500 mg/m² on D1 of each cycle,

Epirubicin and Cyclophosphamide were administrated as in Arm A

Cycles were repeated every 3 weeks for a total of 4 cycles.

Surgery with lymph node dissection was carried out 5 weeks (+ 1 week) after the last cycle of chemotherapy. 

Period 2: Adjuvant treatment with docetaxel

Adjuvant systemic treatment with docetaxel was initiated within a maximum of 6 weeks post-operatively at a dose of 100 mg/m2 as an IV infusion on Day 1 of each cycle.

Cycles were repeated every 3 weeks for a total of 4 cycles.

If indication radiotherapy and/or hormonal therapy were administrated after docetaxel.

Criteria for evaluation (efficacy, safety):

Efficacy
- Tumor assessment of pathologic complete response (pCR) was evaluated on surgical specimens following definitive surgery according to the Sataloff classification assessed by centralized independent expert blinded review.

- Objective tumor response (complete [CR] + partial [PR] response) as measured by ultrasound of the breast (using the same reproducible conditions each time) and assessed according to WHO criteria at 3 weeks after Cycle 4 of the neoadjuvant treatment period.

- Breast conservation was assessed on study Day 0 and following definitive surgery and defined as a binary variable (mastectomy / tumorectomy).

- Physical examination was performed at each study visit and quanitification of serum Cancer Antigen (CA 15.3) in those patients with baseline elevation. Chest X-ray, liver ultrasound, and bone scintigraphy were performed at baseline, thereafter if clinically indicated and at final study visit.

Post-treatment Follow-up:

- Patient status was recorded, at each follow-up visit until final visit.

- Disease status was recorded, at each follow-up visit until final visit.

Safety
Adverse events were recorded using the National Cancer Institute of Canada Common Terminology for Adverse Events classification (NCIC-CTCAE version 3.0 dated March 31, 2003) and a specific 3-point scale for Hand-Foot Syndrome [HFS], vital signs, and laboratory tests, at each study visit until final visit.

Statistical methods:

Efficacy analysis: Type one error set at 5% for one-sided tests (primary criterion) and at 10% for two-sided tests (secondary criteria).

Primary endpoint: (assessment of pCR rate according to the Sataloff classification TANA+ TANB ) after definitive surgery for Arms A and B. For the main analysis, all missing values were considered as treatment failure whatever the reason. 

Secondary endpoint: the primary endpoint analyses were repeated based on investigator evaluated pCR rate. Objective clinical response, best clinical response, breast conservation rate, disease recurrence/deaths during/after neoadjuvant treatment were evaluated. For the adjuvant treatment period, bilateral mammogram, echocardiogram LVEF, liver ultrasound, and chest X-ray findings and disease recurrence/deaths were evaluated at the Final Visit following Cycle 4 of docetaxel. 

Disease-Free Survival (from surgery) and Overall Survival (from randomization) were evaluated for the ITT and repeated for the PP population, using a Kaplan Meier method.

Safety analysis: Descriptive statistics and between-arm comparisons (if relevant).

Compliance: Descriptive statistics; between-arm differences were provided using a Chi-square test (or Fisher exact test) for qualitative parameters and a Wilcoxon test for quantitative parameters.

Summary (efficacy, safety, other results):

Efficacy
In the Per Protocol population (n=169), 17 patients (19.8%) in the CEX group and 11 patients (13.3%) in the FEC 100 group achieved the primary efficacy endpoint of pCR (TA + NA or TA + NB) based on independent expert blinded central review. The difference between the FEC 100 and CEX groups for pCR rate was -6.5%, the upper limit of the 95% one-sided CI (2.83%) was below the non-inferiority margin of 15%. Thus, the primary objective, to demonstrate non-inferiority of CEX to FEC 100 was met. The validity of these results was confirmed by a sensitivity analysis with the exclusion of non-evaluable patients (n=2). The primary endpoint of pCR was: CEX: 20.2% (17 patients) versus FEC 100: 13.8% (11 patients), the upper limit of the 95% one-sided CI (3.11%) below the non-inferiority margin of 15%.

In the Intent-to-Treat population (N =182), the pCR rate was 19.1% in the CEX (18 patients) and 13.6% in the FEC 100 group (12 patients). The difference between groups was -5.5% with the upper limit of the 95% one-sided CI (3.47%) below the non-inferiority margin of 15%. After exclusion of non-evaluable patients, the upper margin of the one-sided 95% CI (3.60%) remained below the non-inferiority margin of 15%, thus confirming the finding of non-inferiority for the PP population.

Secondary Efficacy Endpoints
In the Intent-to-Treat population (N=182), the pCR rate as evaluated by the investigator was 21.3% in the CEX group and 14.5% in the FEC 100 group for the ITT population. In the Per Protocol population (N=169), the pCR rate as evaluated by the investigator was 20.8% in the CEX group and 13.8% in the FEC 100 group. The investigators’ assessments were consistent for both populations and similar to those obtained after centralized independent blinded expert.

Objective clinical response (CR + PR) 3 weeks following Cycle 4 of neoadjuvant treatment, was similar in both groups: 51.1% (CEX) and 48.9% (FEC 100) p = 0.767 in the ITT population. When missing values were excluded, the CR+PR rate was 57.8% (CEX) and 54.4% (FEC 100) a difference of 3.4%. Results were similar for the PP population.

Breast conservation rate assessed after definitive surgery was: 61.5% (CEX) and 70.6% (FEC 100) of patients. The PP population analysis remained in favor of the FEC 100 group.

Disease progression was documented for 3 patients in the CEX group (3.4%) during the neoadjuvant treatment period and 1 patient in the FEC 100 group (1.2%).

There were no deaths during neoadjuvant treatment.

In the Adjuvant population (N=176), Mammography: 37% underwent mammography, approximately 35% of patients in both treatment groups had a normal evaluation at the Final Visit. No abnormalities were suspicious of malignancy and a large percent of the abnormal findings were post-surgical sequellae.

Cardiac function assessed by echocardiogram in 80% of the adjuvant ITT population revealed only 1 patient (1.1%) in the CEX group with a significant finding identified.

Liver ultrasound evaluation in 60% of the adjuvant ITT population, detected only non-malignant findings typical of the general female population in 23.1% (CEX) and 28.3% (FEC 100) group patients.

Chest X-ray in 60% of the adjuvant ITT population revealed only 1 patient (1.9%) in the CEX group with a non-malignant abnormality.

There were 4 patients deaths due to disease progression during the adjuvant  treatment period: 2 patients in the CEX group (2.2%) and 2 in the FEC 100 group (2.3%). 

Follow-up Period (Report Update 10-May-2012)

Therapeutic Management:

Among the 142 patients analyzed in the ITT population and followed over the 5-year follow-up period:

- 137 (97%) patients were treated with at least one course of radiotherapy

- 98 (69%) received at least one line of hormonal therapy

- 23 (16%) were treated with at least one chemotherapy line

- and 6 (4%) needed at least one surgery.

Among the 98 patients treated with at least one line of hormonal therapy over the follow-up period:

- 38 (39%) patients received an aromatase inhibitor only

- 27 (28%) were treated with an anti-estrogen only

- and 33 (34%) received both treatments.

In the 23 patients treated with chemotherapy over the follow-up period, the median number of chemotherapy lines received was 2 (range: 1-8; mean: 2.8±2.2). The main cancer treatments received by these 23 patients were taxanes (15 patients), anti-HER2 drugs (11), antiangiogenic agents (8), fluoropyrimidines (7), platinum salts (6), and anthracyclines (5).

In the Per Protocol population (N=132) and over the follow-up period, the findings were similar to those described for the ITT population.

Secondary Efficacy Endpoints

In the Intent-to-Treat population (N=182), 29 patients (16%) presented with at least one disease recurrence (defined as local/contralateral recurrence, development of metastases or disease-related death) from surgery to the end of the 5-year follow-up period.

At 5 years, the Disease-Free Survival rate was 84.4% in the total ITT population (85.4% in the CEX group versus 83.4% in the FEC 100 group, log rank test, p=0.66).

Fourteen (14) patients died over the study period:

- 4 patients died during the adjuvant treatment period, due to disease progression (2 in the CEX group and 2 in the FEC group) and 10 patients died during the follow-up period (5 in the CEX group and 5 in the FEC group).

- 13 deaths were related to disease progression and one patient died from another cause.

The patients survival rate at 5 years (from randomization) was 92% in the total ITT population (92.2% in the CEX group versus 91.8% in the FEC 100 group, logrank test, p=0.93).

In the Per Protocol population (N=169), the findings were similar to those described for the ITT population.

Safety
During the screening period, in the Safety population, a total of 4/182 patients (2.2%) experienced at least one adverse event for a total of 4 adverse events, none of which were grade 3-4 or serious in nature and all resolved completely.

The Safety population for the neoadjuvant period included a total of 181 patients (CEX: N=93; FEC 100: N=88). At least one dose adjustment was required by 42 patients (44.7%) in the CEX group compared with 6 patients (6.8%) in the FEC 100 group (p <0.001). This difference was attributed to the number of patients requiring capecitabine dose adjustment. Seventeen patients (18.1%) in the CEX group compared with 5 patients (5.7%) in the FEC 100 group required at least one dose adjustment due to adverse events (p <0.001). Thirty-five patients (37.2%) in the CEX group and 2 patients (2.3%) in the FEC 100 group required at least one dose adjustment for other reasons (p <0.001). A total of 178 patients (98.3%) experienced at least one AE, from a total of 2171 events, 1820/2171 were considered treatment-related (97.8% of patients). Adverse events leading to treatment discontinuation occurred in 3/181 patients (1.7%). A total of 351/2171 AEs were grade 3-4 (65.2% of patients), 323 events were both of grade 3-4 intensity and considered treatment-related (61.9% of patients). A total of 21/181 patients (11.6%) experienced 27 SAEs of which 21 SAEs were considered treatment-related (7.7% of patients). The main system organ classes affected were the gastrointestinal system (88.4% of patients), skin and subcutaneous tissues (72.4%), blood and lymphatic systems (59.7%), infections and infestations (28.2%), nervous system (26.5%), and general disorders and administration site conditions (72.4%). Grade 3-4 treatment-related emergent AEs occurred in 59.1% of the CEX group and 64.8% of the FEC 100 group patients. More CEX than FEC 100 patients experienced neutropenia (49.5% vs 39.8%) and febrile neutropenia (7.5% vs 3.4%), anemia (3.2% vs 0%), and mucosal inflammation (6.5% vs 1.1%), while more FEC 100 patients experienced nausea (14.8% vs 6.5%), vomiting (12.5% vs 5.4%), amenorrhea (13.6% vs 7.5%), and asthenia (2.3% vs 1.1%).

Serious adverse events were reported in a similar proportion of patients in the CEX and FEC 100 groups: 14 SAE events (11.8%) vs 13 events (14.8%), respectively. Serious febrile neutropenia was more frequent in the CEX than FEC 100 group (4 SAEs in 4.3% of patients vs 1 SAE in 1.1% of patients). Serious neutropenia was more common in the FEC 100 group (3 SAEs, 3.4% of patients vs 2 SAEs, 2.2% of patients). At least one treatment-related SAEs occurred in 2% of patients in the CEX and FEC 100 groups: neutropenia (2.2% vs 2.3%), and febrile neutropenia (4.3% vs 1.1%). Neoadjuvant treatment discontinuation for toxicity was rare, occurring only in 3 patients in the CEX group (3.2%) and none (0%) in the FEC 100 group. There were no deaths. 

The adjuvant Safety population included a total of 175 patients (CEX: N=91; FEC 100: N=84).A total of 172 patients (98.3%) experienced at least one AE for a total of 1689 events, of which 97.8% were judged as treatment-related. Overall, 10/175 patients (5.7%) discontinued adjuvant treatment due to an AE. A total of 209/1689 AEs were grade 3-4 (42.9% of patients), of which 191 events were both of grade 3-4 intensity and considered treatment-related (39.4% of patients). Nine patients (5.1%) experienced at least one SAE for a total of 12 SAEs of which 5 events were considered treatment-related (2.9% of patients). Almost all patients (98.3%) experienced at least one emergent adverse event but there were more events in the CEX group (1186 events) than in the FEC 100 group (985 events). In the CEX group, patients experienced more paresthesias  (19.8% vs 13.1%), increased lacrimation (7.7% vs 3.6%), Hand-foot syndrome (6.6% vs 4.8%), anemia (5.5% vs 0%), and febrile neutropenia (5.5% vs 2.4%) than in the FEC 100 group. In the FEC 100 group, patients experienced more asthenia (57.1% vs 51.6%), mucosal inflammation (38.19% vs 27.5%), myalgia (32.1% vs 25.7%), dysguesia (13.1% vs 5.5%), pyrexia (10.7% vs 6.6%), skin (10.7% vs 3.3%) and nail toxicity (8.3% vs 5.5%), conjunctivitis (8.3% vs 2.2%), and dyspnea (6.0% vs 2.2%). A total of 209 grade 3-4 treatment emergent AEs were experienced by 42.9% of patients: 103 events in 38 patients (41.8%) in the CEX group and 106 events in 37 patients (44.0%) in the FEC 100 group. In the CEX group, the following Grade 3-4 emergent AEs were observed more than in the FEC 100 group: febrile neutropenia (5.5% vs 2.4%), asthenia (4.4% vs 2.4%), mucosal inflammation (3.3% vs 2.4%), and Hand-foot syndrome (3.3% vs 1.2%). In the FEC 100 group, grade 3-4 emergent AEs were observed more frequently than in the CEX group: arthralgia (7.16% vs 1.1%), myalgia (3.6% vs 2.2%), abdominal pain (2.4% vs 0%), diarrhea (2.4% vs 0%), and nail toxicity (2.4% vs 0%). Serious adverse events were reported in a similar proportion in the CEX group and in the FEC 100 group: 4 events (4.4% of patients) versus 8 events (6.0% of patients). Serious blood and lymphatic system disorders were marginally more frequent in the CEX group than in the FEC 100 group (3 SAEs, 3.3% of patients vs 1 SAE, 1.2% of patients). Serious febrile neutropenia was more frequent in the CEX group than in the FEC 100 group (3 SAEs in 3.3% of patients vs 0%). Adjuvant treatment was discontinued in 5 patients (5.5%) in the CEX group (14 AEs: 6-Grade 2, 6-Grade 3, 1-Grade 4 [agranulocytosis]) and 5 patients (6.0%) in the FEC 100 group (16 AEs: 10-Grade 2, 5-Grade 3). There were 4 deaths during the study (1 during and 3 at the completion of the adjuvant treatment period): 2 patients in each study group. All died of disease progression.

Over the 5-year follow-up period, 14 non serious adverse events were reported in 11 patients (in 7 CEX and 4 FEC 100 patients) and 2 serious adverse events (grade 3 lymphoedema and lymphangitis) were reported in one CEX patient.

Conclusions:

The primary efficacy endpoint of pathological complete response rate was 19.8% in the CEX group and 13.3% in the FEC 100 group for the PP population. The ITT population analysis confirmed the finding of non-inferiority for the PP population analysis. The ITT and PP populations analyses of the secondary efficacy criteria confirmed the non-inferiority of CEX to FEC 100 for investigator evaluated tumor response while objective clinical response and disease progression rates lend further support to the efficacy of the CEX regimen when used in the neoadjuvant setting. The primary objective of the study was met. CEX was non-inferior to FEC 100 in terms of pathological complete response (pCR) rate in both the PP and ITT populations and confirmed by sensitivity analyses. The pCR was assessed by centralized independent blinded expert review according to the Sataloff classification of pathological tumor response. The safety findings of the present study confirm the well known tolerability profile of capecitabine when used as monotherapy or in combination regimens for the treatment of breast cancer. No new or unexpected capecitabine toxicity emerged in this study when combined with cyclophosphamide and epirubicin and administered in the neoadjuvant setting. The incidence, nature, and severity of treatment-emergent adverse events in patients in the CEX group were similar to that observed for FEC 100, differing only in the time of presentation over the course of treatment. This study demonstrates that CEX is non-inferior to FEC 100 when administered as neoadjuvant treatment for operable breast cancer, that the safety profile of the CEX and FEC 100 regimens is similar, that surgery following neoadjuvant CEX chemotherapy does not result in an increase in post-operative complications, and that CEX does not compromise the administration of adjuvant docetaxel in terms of dose intensity or toxicity profile.

After the 5-year follow-up period, no relevant difference was observed between study groups in terms of Disease-Free Survival and Overall Survival. Furthermore, safety data were similar over this period.

Publications (references, if available):

Roché H, Deporte R, Berton-Rigaud D, et al. Capecitabine + epirubicin + cyclophosphamide (CEX) has comparable safety to 5-FU + epirubicin + cyclophosphamide (FEC) as neoadjuvant therapy in patients (pts) with operable breast cancer (BC): Early safety findings from a randomized phase II trial. J Clin Oncol, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 10655. 

- Roché H, Deporte R, Berton-Rigaud D, et al. Updated safety findings from a randomized phase II trial of capecitabine + epirubicin + cyclophosphamide (CEX) vs. 5-FU + epirubicine + cyclophosphamide (FEC) as neoadjuvant therapy in patients (pts) with operable breast cancer (BC). ESMO 2006 Istanbul Turkey. Ann Oncol 17 (Supplement 9): 2006 Abstract 261P.

- Deporte R, Milano G, Renee N, et al. Randomized phase II trial of cyclophosphamide (C), epirubicin (E) and capecitabine (Cap) (CEX) vs 5-fluorouracil (5-FU), E and C (FEC) as neoadjuvant therapy in patients (pts) with operable breast cancer (BC): pharmacokinetic (PK) analysis. 98th Annual Meeting of the American Association for Cancer Research Meeting; 2007 Apr 14-18; Los Angeles, CA. AACR Meeting Abstracts, Apr 2007; 2007: 3513.

- Roché H, Penault-Llorca F, Berton-Rigaud D, et al. Efficacy and safety results from a randomized, phase II trial of neoadjuvant capecitabine + epirubicin + cyclophosphamide vs 5-FU + epirubicin + cyclophosphamide in operable breast cancer. Poster 5057. Breast Cancer Research and Treatment, Special Issue, 30^th Annual San Antonio Breast Cancer Symposium 2007, Vol. 106, Supplement 1, December 2007 SABCS 2007. 

- Milano G, Deporte R, Renée N, et al. Pharmacokinetic and pharmacodynamic analysis of cyclophosphamide, epirubicin and capecitabine vs 5-FU, epirubicin and cyclophosphamide as neoadjuvant therapy in breast cancer patients. Poster 5064. Breast Cancer Research and Treatment, Special Issue, 30^th Annual San Antonio Breast Cancer Symposium 2007, Vol. 106, Supplement 1, December 2007 SABCS 2007 

- Berton-Rigaud D, Roché H, Penault-Llorca F, et al. Benefit of neoadjuvant capecitabine + epirubicin + cyclophosphamide (CEX) versus 5-FU + epirubicin + cyclophosphamide (FEC) for operable breast cancer (BC) followed by adjuvant docetaxel (T). J Clin Oncol 26: 2008 (May 20 suppl; abstr 598).

Date of report:

29.10.2009

Click here for the protocol registry listing of this trial.