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Clinical Trial Result Information
Protocol number
ML16323
Title of Study
A phase II study of oral Xeloda (capecitabine) in combination with intravenous irinotecan for patients with locally advanced and/or metastatic colorectal cancer (ROXI trial).
Sponsor
Roche Laboratories Inc.
Company division
Pharmaceutical
Product name
Xeloda
Generic name
capecitabine
Therapeutic area
Colorectal Cancer
Clinical study summary
This was a single-arm, open-label, multicenter study of Xeloda (capecitabine) administered as an oral twice-daily intermittent treatment (Days 2 through 15) every 3 weeks combined with intravenous irinotecan (Days 1 and 8) every 3 weeks in patients with locally advanced and/or metastatic colorectal cancer.
Study center(s)
15 centers in the United States.
Phase of development
II
Objectives
Primary: To evaluate the overall objective response rate (complete and partial responses) of Xeloda and irinotecan as first-line treatment of patients with locally advanced and/or metastatic colorectal cancer.
Secondary: To evaluate time to progression, time to overall response, duration of overall response, duration of overall complete response and time to treatment failure; to determine 1-year survival and overall survival; to evaluate toxicity and the safety profile of the combination of Xeloda and irinotecan in this patient population; to evaluate the feasibility of predicting responses to Xeloda and irinotecan by the molecular profile of patient tumor tissues.
Methodology
Xeloda was administered as an oral twice-daily intermittent treatment (Days 2 through 15) q3w. Irinotecan was administered as a 90-minute IV infusion on Days 1 and 8 q3w. The initial treatment regimen was Xeloda 1000 mg/m² bid for 14 days with irinotecan 125 mg/m² on Day 1 and Day 8 in 3-week cycles. Due to an unacceptable toxicity in the first 15 patients (Cohort 1), the protocol was amended to reduce the starting dose for Xeloda to 900 mg/m² twice daily (total dose 1800 mg/m²) on Days 2 through 15, and the starting dose for irinotecan to 100 mg/m² on Days 1 and 8 (Cohort 2; 52 patients). The 2-stage study design was applied to patients enrolled after this protocol amendment became effective.
Patients with documented progressive disease were taken off treatment at time of progression. Patients who were responding or whose disease was stable were treated until progression of disease, intolerable toxicity or patient refusal to continue with the study. A total of 12 cycles of treatment was planned. Patients who were responding or whose disease was stable were permitted to continue Xeloda/irinotecan combination therapy until progressive disease was documented in the post-study treatment phase.
Tumor measurements were conducted every 2 cycles (6 weeks) during treatment and at the end of treatment. Safety was monitored throughout the study. Expression of TS, TP, and DPD in the primary tumor and metastatic lesions was measured and correlated with clinical responses to therapy.
Clinical cut off for the primary analysis of the data was 40 weeks after the last patient enrolled.
Number of patients (planned/analyzed)
Planned: 50 patients. Actual: 67 patients.
Diagnosis and main criteria for inclusion
Patients ≥18 years of age with histologically confirmed, measurable, locally advanced (including locally recurrent disease) and/or metastatic colorectal cancer which had not been previously treated (except for neoadjuvant or adjuvant treatment completed ≥12 months prior to initiation of study treatment).
Test product, dose and mode of administration or test procedure
Xeloda (capecitabine) 150 mg and 500 mg tablets. Initial regimen: 1000 mg/m² orally, twice daily (total daily dose of 2000 mg/m²), Days 2-15 (14 days) every 3 weeks/12 cycles. Amended regimen: 900 mg/m² orally, twice daily (total daily dose of 1800 mg/m²) Days 2-15 (14 days) every 3 weeks/12 cycles.
Duration of treatment
12 x 3 week cycles planned, and then until disease progression
Reference therapy, dose and mode of administration or reference procedure
Irinotecan. Initial regimen: 125 mg/m², 90-minute IV infusion, Days 1 and 8 every 3 weeks/12 cycles. Amended regimen: 100 mg/m², 90-minute IV infusion, Days 1 and 8 every 3 weeks/12 cycles.
Criteria for evaluation (efficacy, safety)
Efficacy: Primary: Tumor response rate based on tumor measurement (per RECIST criteria).
Secondary: Time to progression; time to treatment failure; 1-year survival; overall survival; time to response; duration of overall response; duration of overall complete response.
Pharmacodynamics: The expression of thymidine phosphorylase (TP), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD); ratio of TP/DPD; TS and DPD polymorphism; UPD-glucuronosyltransferase (UGT)1A1, (UGT)1A6, and (UGT)1A7 polymorphisms.
Safety: Adverse events, Karnofsky Performance Status, clinical laboratory tests, vital signs, and physical examination.
Statistical methods
The study was conducted using a 2-stage design to detect a response rate of 20% improvement from the null response rate of 30% (1-sided 5% level of significance) with at least 81% power. The first stage was to accrue 14 evaluable patients. If 3 or more responses were observed in the first stage, an additional 31 evaluable patients were to be accrued in the second phase for a total of 45 valuable patients. A total of at least 50 patients were to be recruited to allow for an estimated 10% dropout or non-evaluable rate.
Primary and secondary efficacy variables were summarized by cohort. The efficacy analysis included all patients who received at least 1 dose of both Xeloda and irinotecan. Safety analyses included all patients who received at least 1 dose of any study medication and had post-baseline safety measurements. An exact 90% confidence interval was calculated for the primary efficacy parameter, using the Clopper-Pearson formula. Kaplan-Meier product limit method was applied for all time-to-event/duration variables.
The associations between biomarker parameters and efficacy endpoints were evaluated in all enrolled patients who completed at least 2 cycles of study treatment. Logistic regression analysis with cohort and biomarker parameters as independent variables was used to assess the association between the binary tumor response and the biomarker parameters. The Cox’s regression with cohort and biomarker parameters as independent variables was performed to assess the association between the biomarkers and the time-to-event efficacy endpoints.
Summary (efficacy, safety, other results)
Efficacy: The objective tumor response rate was 47% (90% CI=24%, 70%) in Cohort 1 (N=15), 44% (90% CI=32%, 57%) in Cohort 2 (N=52), which included 1 complete response and 22 partial responses, and was 45% (90% CI=34%, 56%) in all cohorts combined (N=67), which included 2 complete responses and 28 partial responses. Based on the data from Cohort 2, the null hypothesis that the response rate would be less than 30% was rejected, and it as concluded that the treatment regimen of Xeloda 900 mg/m² bid in combination with irinotecan 100 mg/m² for 12 cycles was efficacious for treating patients with locally-advanced and/or metastatic colorectal cancer.
The median time to disease progression was 6.1 months (95% CI=3.4, 9.0 months) for patients in Cohort 1 and 7.6 months (95% CI=5.8, 8.7 months) for patients in Cohort 2. The median time to treatment failure was 5.8 months (95% CI=2.4, 9.2 months) in Cohort 1 and 7.3 months (95% CI=4.6, 9.5 months) in Cohort 2. The median overall survival was 22.9 months (95% CI=10.1, 28.2 months) for Cohort 1 and 20.5 months (95% CI=14.9, 30.0 months) for Cohort 2.
Pharmacodynamic (biomarker): With respect to tumor markers associated with capecitabine metabolism, expression of TP protein in primary tumors (OR=4.77; 95% CI=1.25, 18.18) was significantly positively associated with response to therapy, and near significant association was observed with metastatic tumors (OR=8.67, 95% CI=0.95, 79.1). Patients expressing TP protein at metastatic sites had significantly superior time to disease progression compared to patients who did not express TP protein (P=0.001). Patients expressing TP protein in the primary tumor and at metastatic sites had superior survival time to patients who did not express TP protein (P=0.035 and P=0.002, respectively). Thymidine phosphorylase gene expression in primary tumors was significantly positively associated with response to therapy (OR=4.53; 95% CI=1.08, 19.01) when the value exceeded the 25th percentile or when it exceeded the mean (OR=12.38; 95% CI=1.99, 77.06). Neither TS nor DPD protein or gene expression was significantly associated with clinical response to therapy.
Expression of TP, TS or DPD protein in primary tumors or metastatic tumors was not significantly associated with the occurrence of Grade 3 or 4 diarrhea or neutropenia during the first 2 cycles of treatment. Thymidine phosphorylase gene expression in the primary tumor was not associated with categorical 25th percentile, mean or median values for Grade 3 to 4 diarrhea during the first 2 cycles. However, TP gene expression in metastatic tumors was significantly negatively associated with Grade 3 or 4 diarrhea (OR=0.18; 95% CI=0.04, 0.79), when measured by the 25th percentile as a cut-off value. On the other hand, TS and DPD gene expression in primary and metastatic tumors was not associated with Grade 3 or 4 diarrhea. Gene expression of TP, TS and DPD in primary and metastatic tumors was not associated with Grade 3 or 4 neutropenia.
With respect to tumor markers associated with irinotecan metabolism, patients with UGT1A7 alleles 2.2 or 3.3 were more likely to exhibit an objective response to treatment (OR=0.15; 95% CI=0.03, 0.74) than patients with UGT1A7 alleles 1.1, 1.2, 1.3 or 2.3. None of the UGT1A1 or UGT1A6 alleles evaluated was associated with clinical response to therapy. Also, none of the UGT1A1, -A6, or –A7 alleles were associated with the incidence of Grade 3 or 4 diarrhea or neutropenia during the first 2 cycles of treatment.
Safety: The most frequent treatment-related AEs were diarrhea, nausea, fatigue, vomiting, HFS, abdominal pain, anemia, alopecia, neutropenia, dehydration and anorexia. The most frequent treatment-related SAEs were diarrhea, dehydration, pulmonary embolism, and febrile neutropenia. Three deaths were reported during the study, all in Cohort 2, due to CNS bleeding/haemorrhaging, colon cancer metastasis to the liver, and pulmonary embolism.
Reducing the initial dose of oral Xeloda 1000 mg/m² twice daily with parenteral irinotecan 125 mg/m² (Cohort 1) to oral Xeloda 900 mg/m² twice daily with parenteral irinotecan 100 mg/m² (Cohort 2) led to reductions of 20% (from 53% to 33%) in Grade 3 or 4 diarrhea, 14% (27% to 13%) in Grade 3 or 4 dehydration, 12% (from 20% to 8%) in Grade 3 or 4 neutropenia, and 9% (from 13% to 4%) in Grade 3 or 4 pulmonary embolism, without loss of efficacy (as measured by activity or survival).
Conclusions
Combination therapy with 3-week cycles of oral Xeloda 900 mg/m² twice daily on Days 2 to 15 and parenteral irinotecan 100 mg/m² on Day 1 and Day 8 was efficacious, inducing an overall response rate of 44% in patients with metastatic colorectal cancer treated in a first-line setting. Median time to disease progression was 7.6 months, median time to treatment failure was 7.3 months, median survival was 20.5 months, and 1-year survival rate was 71%.
Toxicity with Xeloda and irinotecan was predictable and tolerable. Reducing the initial dose of Xeloda and irinotecan led to reductions in Grade 3 or 4 diarrea, dehydration, neutropenia and pulmonary embolism.
Expression of thymidine phosphorylase (TP), in primary tumors was significantly positively associated with favourable response to clinical therapy. Patients expressing TP protein at metastatic sites had significantly superior time to disease progression compared to patients who did not express TP protein (P=0.001). Patients expressing TP protein at primary or metastatic tumors had significantly superior survival than patients who did not express TP protein (P=0.035 and P=0.002, respectively).
Publications (references, if available)
Meropol NJ, Gold PJ, Diasio RB et al. Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer. J. Clin. Oncol. 2006 Sep 1; 24(25): 4069-77.
Date of report
11/1/2005
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