Roche trials database

Protocol number:

M66011

Title of Study:

An open label, phase II, study of capecitabine (RO 09-1978) in combination with pre-operative standard radiotherapy in rectal cancer patients.

Sponsor:

Hoffmann-La Roche

Company division:

Pharmaceutical

Product name:

Xeloda

Generic name:

capecitabine

Therapeutic area:

• Colorectal Cancer

Clinical study summary:

This was a non-comparative, open label study to assess the efficacy of Xeloda (capecitabine) in combination with standard pre-operative radiotherapy of the pelvic region in patients with primary rectal cancer. All patients received neo-adjuvant treatment with Xeloda 825 mg/m² b.i.d. and radiotherapy.

Study center(s):

6 centers in Italy

Phase of development:

II

Objectives:

Primary: to determine the pathological complete response (pCR) rate in patients treated with Xeloda plus standard technique radiotherapy of the pelvic region when optimal surgery is applied.
Secondary: to assess the clinical tumor and lymph node response rate to chemo-radiotherapy and to evaluate the safety profile of Xeloda (capecitabine) in combination with pelvic radiotherapy.

Methodology:

A total of 52 eligible patients received a neo-adjuvant treatment with Xeloda 825 mg/m² b.i.d. and radiotherapy (planned total dose 50.4 Gy given with five weekly fractions, with daily fraction dose of 1.8 Gy) for 38 days, followed by surgery. Neo-adjuvant treatment was completed in 45 patients. Treatments were continued on the basis of tumor reassessment and/or disease status, with weekly safety assessments and end of neo-adjuvant treatment efficacy evaluations (pelvic and abdomen computer tomography; endosonography of the rectum and/or rectosigmoidoscopy).
After surgery, 4-cycle Xeloda adjuvant treatment (1250 mg/m² b.i.d. on days 1-14 every 3 weeks) was given to 29 patients expected to benefit from post-operative therapy, with safety assessments repeated at the end of each cycle, and efficacy evaluations repeated at the end of adjuvant treatment as well as at 3 to 6 month intervals during long term off-study follow-up. Adjuvant treatment was completed in 23 patients.

Number of patients (planned/analyzed):

Planned: 43 patients. Recruited: 53 patients

Diagnosis and main criteria for inclusion:

Patients with locally advanced, non-metastatic, resectable primary rectal cancer stage cT3 or cT4, subject to combined chemo-radiotherapy of the pelvic region in the pre-operative setting. No prior chemotherapy for colorectal cancer.

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

Neo-adjuvant treatment Xeloda (capecitabine) 825 mg/m² p.o. b.i.d. .Adjuvant treatment: Xeloda monotherapy 1250 mg/m² b.i.d. given after surgery to patients considered to potentially benefit from post-operative therapy.

Duration of treatment:

Neo-adjuvant¿for 38 days from the first to the last day of radiotherapy. Adjuvant¿days 1-14 every 3 weeks, for 4 cycles

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

N/A

Criteria for evaluation (efficacy, safety):

Efficacy: Primary study endpoint: pCR (absence of viable tumor cells in the surgical tumor specimen, including regional lymph nodes, determined with standard histologic procedures).
Second efficacy variables: Clinical objective response (as defined) after neo-adjuvant and adjuvant treatment; overall survival, disease free survival, local disease free survival at follow-up.
Safety: AEs, laboratory parameters, with toxicities graded by NCI CTC; ECG (if clinically indicated).

Statistical methods:

The sample size was calculated according to the Two-stage Min-Max Design .Considering as clinically relevant a 15% difference between standard chemo-radiation (5-FU continuous infusion or 5-FU plus LV) (expected pCR rate 10%) and a new therapy warranting further investigation (expected pCR rate 25%), and fixing error probabilities at α=0.05 and ß=0.20, 18 patients were to be observed in the first stage. If ≤2 responses were seen in these first 18 patients, then the trial had to be terminated. Otherwise, the accrual was to be continued up to a total of 43 patients.
Descriptive statistics of pathological response and objective response for neo-adjuvant and adjuvant study phase were calculated. Kaplan-Meier analysis was performed for the time dependent variables overall survival, disease free survival and local disease free survival (LDFS).
Efficacy analysis was based on the ITT population (all registered patients who had received at least one dose of the study drug). Descriptive safety parameters analysis was carried out in the safety population (i.e. after exclusion from ITT population of patients with no follow-up safety information).

Summary (efficacy, safety, other results):

Efficacy: Primary Endpoint: A total of 52 patients underwent surgery, which was successfully completed in 51 cases (1 patient was found to have unresectable disease at operation). Pathological complete response of the primary tumor was seen in 21.1% of patients (21.6% of surgery completed cases). Regional lymph node involvement was found to be absent in 37 patients (71.1%), while 1 to 3 lymph nodes and ≥4 lymph nodes were reportedly involved in 5 cases (9.6%) and 6 cases (11.5%), respectively, with regional lymph node involvement classified as Nx in 3 patients (5.8%). Nodal downstaging was found to be present in 19 of the 27 patients with N1-N2 disease (70.4%). Tumor downstaging was seen in 27 of 51 patients who had surgery completed as planned (52.9%). On the whole, at histological post-surgical examination, stage grouping was improved in 32 patients (62.7%), among which pCR was seen in 10 cases (19.6%).
Secondary Efficacy Variables: At the end of neo-adjuvant treatment, objective tumor response was classified as CR and PR in 2 patients (3.8% of the total 53 patients sample) and 28 patients (52.8%), respectively. Therefore, objective response was seen at the end of neo-adjuvant treatment in 56.6% of the 53 patients studied.
All patients had at least one post study follow-up evaluation. DFS and LDFS were calculated on the 50 patient sample submitted to radical surgery. A total of 27 patients had either disease progression (25 patients) or died due to causes other than disease progression (second primary pancreatic tumor and cardiogenic shock, respectively), while 23 patients had data censored at last progression free observation. DFS ranged between 13-1102 days, with a median value of 833 days, and a mean value of 736.3 days.
LDFS analysis showed presence of the event in only 6 patients, with 44 patients censored at last local progression free observation, including the largest LDFS value. LDFS ranged between 13-1102 days, with a mean value of 1023.2 days.
Among the 53 patients participating in the study, 17 died during the off-study follow-up period, while 36 patients were censored at last observation, including the largest observation value. OS ranged between 115-1202 days, with a mean value of 1032.1 days.

Safety: No deaths occurred during the study. Four SAEs were reported in 3 patients, two of which (hemoglobin decrease and febrile neutropenia) were judged to be related to study medications.
During neo-adjuvant treatment the clinical AEs most frequently reported were diarrhea (29.6% of 53 patients), proctitis (26.4%), radiation dermatitis and dysuria (24.5%), nausea (22.6%), and asthenia (20.7%). The most frequently reported laboratory AEs were lymphocytopenia (88.7%), leukopenia (75.5%), hemoglobin decrease (54.7%), hyperglycemia (39.6%) and thrombocytopenia (30.2%). Grade 3-4 AEs included lymphocytopenia (43.4%), leukopenia and hemoglobin decrease (2 cases each) and single instances of hyperglycemia, neutropenia and SGPT increase.
During adjuvant treatment, the clinical AEs most frequently reported were diarrhea, (31.0% of 29 patients), and asthenia (24.1%). The most frequently reported laboratory AEs were leukopenia and hemoglobin decease (69.0%), lymphocytopenia (51.7%), and neutropenia (31.0%). Grade 3 AEs included single instances of leukopenia, hemoglobin decrease and thrombocytopenia.
Hematological parameters showed a limited decrease over time, with mean hematocrit decreased from 40.1% (SD 4.1) at baseline to 36.6% (SD 4.3) at day 43, mean hemoglobin decreased from 13.4 g/dL (SD 1.7) to 12.3 g/dL (SD 1.8) at day 43, mean WBC decreased from 7.20 thousands/μL (SD 1.82) to 4.17 thousands/μL (SD 1.30) at day 43, with decreased absolute mean values of both lymphocytes and neutrophils, as well as platelets decreased on average from 274.29 thousands/μL (SD 92.27) to 212.60 thousands/μL (SD 61.35) at day 43. Mean and/or median changes vs baseline of blood chemistry and coagulation parameters were minimal at all assessment intervals, with the possible exception of total bilirubin, slightly increased on average from 0.62 mg/dL (SD 0.28) at baseline to 0.90 mg/dL (SD 0.58) at day 43. 

Conclusions:

The results of the study support the efficacy of Xeloda in combination with radiotherapy as neo-adjuvant treatment of locally advanced resectable rectal cancer. The combination regimen proved feasible in terms of tolerability and safety. Prognosis of patients with pCR following neo-adjuvant radio-chemotherapy was more favorable in terms of both DFS and OS.
No firm conclusions can be drawn on the efficacy of adjuvant Xeloda therapy following surgery; however, DFS and OS were more favorable in the subgroup of 29 patients who received adjuvant treatment than in non-treated cases. Tolerability and safety of adjuvant Xeloda was satisfactory in the vast majority of cases.

Publications (references, if available):

De Paoli, A, Chiara S, Luppi G, et al. (2006) Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study. Ann Oncol 17: 246-251.

Date of report:

01.11.2006

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