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Simulations to Assess Phase II Noninferiority Trials of Different Doses of Capecitabine in Combination With Docetaxel for Metastatic Breast Cancer.

ABSTRACT: A phase II trial in metastatic breast cancer (MBC) (NO16853) failed to show noninferiority (progression-free survival, PFS) of capecitabine 825?mg/m(2) plus docetaxel 75?mg/m(2) to the registered capecitabine dose of 1,250?mg/m(2) plus docetaxel 75?mg/m(2). We developed a modeling framework based on NO16853 and the pivotal phase III MBC study, SO14999, to characterize the link between capecitabine dose, tumor growth, PFS, and survival to simulate response to a range of capecitabine doses and determine a minimum capecitabine dose noninferior to 1,250?mg/m(2). Simulation showed NO16853 had little power to demonstrate noninferiority (69%). The power reached 80% with a 1,000?mg/m(2) starting dose and an increased number of PFS events. A starting dose of 1,000?mg/m(2) could be established as noninferior in terms of efficacy to the registered dose in the second-line MBC setting, with a potentially improved safety, in line with medical practice.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e19; doi:10.1038/psp.2012.20; advance online publication 26 December 2012.

SUBMITTER: Bruno R

PROVIDER: S-EPMC3600724 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Simulations to Assess Phase II Noninferiority Trials of Different Doses of Capecitabine in Combination With Docetaxel for Metastatic Breast Cancer.

Bruno R R Lindbom L L Schaedeli Stark F F Chanu P P Gilberg F F Frey N N Claret L L

CPT: pharmacometrics & systems pharmacology 20121226

A phase II trial in metastatic breast cancer (MBC) (NO16853) failed to show noninferiority (progression-free survival, PFS) of capecitabine 825 mg/m(2) plus docetaxel 75 mg/m(2) to the registered capecitabine dose of 1,250 mg/m(2) plus docetaxel 75 mg/m(2). We developed a modeling framework based on NO16853 and the pivotal phase III MBC study, SO14999, to characterize the link between capecitabine dose, tumor growth, PFS, and survival to simulate response to a range of capecitabine doses and det ...[more]

PMID: 23835839

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Project description:Purpose: Treatment of advanced pancreatic cancer with a single therapeutic at a maximal dose has been largely ineffective at increasing survival. Combination therapies are commonly studied but often limited by toxicity. We previously showed that low-dose multiagent therapy with gemcitabine, docetaxel (taxotere), capecitabine (xeloda), and cisplatin (GTX-C) was safe, well tolerated, and effective (NCT01459614). Here, we hypothesize that adding irinotecan to GTX-C may improve survival with minimal toxicity. Experimental Design: Patients with treatment-naïve metastatic pancreatic adenocarcinoma were treated with gemcitabine, docetaxel (taxotere), capecitabine (xeloda), cisplatin, and irinotecan (GTX-CI). Treatment consisted of capecitabine 500 mg twice daily on days 1–14 and gemcitabine 300 to 500 mg/m2, docetaxel 20 mg/m2, cisplatin 15 to 20 mg/m2, and irinotecan 20 to 60 mg/m2 on days 4 and 11 of a 21-day cycle. The primary objective was 9-month overall survival (OS). Secondary objectives included response rate (RR), disease control rate (DCR), progression-free survival (PFS), and OS. Results: The regimen was well tolerated. The recommended phase II dose was gemcitabine 500 mg/m2, docetaxel 20 mg/m2, capecitabine 500 mg po bid, cisplatin 20 mg/m2, and irinotecan 20 mg/m2. Median follow-up in phase II was 11.02 months (2.37–45.17). Nine-month OS rate was 57% [95% confidence interval (CI): (41–77)]. RR was 57% [95% CI: (37–75) 50% PR and 7% CR]. DCR was 87% [95% CI: (69–96)]. Median OS and PFS were 11.02 [95% CI: (8.54–21.09)] and 8.34 [95% CI: (6.34–NA)] months, respectively. Conclusions: The addition of irinotecan to GTX-C was safe and well tolerated. While the study did not meet its primary objective, the responses were clinically meaningful using a well-tolerated regimen. Significance: We aimed to optimize the previously reported efficacious regimen of low-dose multiagent therapy with GTX-C for the treatment of metastatic pancreatic ductal adenocarcinoma by adding irinotecan. The primary objective was not met, but GTX-CI was well tolerated. The RR of 57%, median PFS of 8.3 months, median OS of 11 months, and 36-month OS rate of 19% suggest clinical benefit. Further optimization of this regimen is warranted.

Project description:IntroductionCurrent treatment options for advanced esophagogastric cancer (AEGC) are still unsatisfactory. The aim of this prospective phase Ib/II study was to evaluate the safety and efficacy of a novel regimen, AVDCX, consisting of weekly docetaxel and cisplatin together with capecitabine and bevacizumab, in AEGC.MethodsPatients with AEGC received treatment with different dose levels of AVDCX (cisplatin and docetaxel 25-35 mg/m2, days 1,8, capecitabine 1,600 mg/m2 days 1-14, bevacizumab 7.5 mg/kg, day 1, Q:21 days). The study's primary objectives were to establish the recommended phase II doses of docetaxel and cisplatin in AVDCX (phase Ib part) and to determine the tumor response rate (phase II part).ResultsThe study was closed early, after the accrual of 22 patients, due to accumulating toxicity-related deaths. The median age was 59 years and 77% of patients had gastric or gastroesophageal adenocarcinomas. Grade ≥3 adverse events were documented in 18 patients (82%), usually neutropenia (36%), fatigue (54%) or diarrhea (23%). There were three fatal toxicities (14%): mesenteric thromboembolism, gastric perforation and pancytopenic sepsis. The recommended phase II doses of cisplatin and docetaxel were determined to be 25 mg/m2 and 30 mg/m2, respectively. Twenty-one patients were evaluable for response: 12 (54%) had partial response (PR), 4 (18%) had stable disease (SD) and none had complete response (CR). Hence, the objective response rate (CR+PR) was 54% and the disease control rate (CR+PR+SD) was 72%. For the 17 patients treated at the MTD, the objective response rate was 41% and the disease control rate was 88%. The median overall survival (OS) for these patients was 13.9 months (range, 1.5-52.2 months) and the median progression-free survival was 7.6 months (range, 1.3-26.6 months). The 2-year OS rate reached 23.7%.ConclusionsAVDCX was associated with a high rate of regimen related fatal adverse events and is not appropriate for further development in AEGC patients.Trial registrationClinicalTrials.gov NCT00845884.

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Simulations to Assess Phase II Noninferiority Trials of Different Doses of Capecitabine in Combination With Docetaxel for Metastatic Breast Cancer.

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Simulations to Assess Phase II Noninferiority Trials of Different Doses of Capecitabine in Combination With Docetaxel for Metastatic Breast Cancer.

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