Phase I Study of Axitinib in Combination with Cisplatin and Capecitabine in Patients with Previously Untreated Advanced Gastric Cancer
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Purpose This phase I trial evaluated the question of whether the standard starting dose of axitinibcould be administered in combination with therapeutic doses of cisplatin/capecitabine inpatients with previously untreated advanced gastric cancer, and assessed overall safety,pharmacokinetics, and preliminary antitumor activity of this combination. Materials and MethodsPatients in dose level (DL) 1 received axitinib 5 mg twice a day (days 1 to 21) with cisplatin80 mg/m2 (day 1) and capecitabine 1,000 mg/m2 twice a day (days 1 to 14) in 21-daycycles. Maximum tolerated dose (MTD) was the highest dose at which ! 30% of the first 12patients experienced a dose-limiting toxicity (DLT) during cycle 1. Ten additional patientswere enrolled and treated at the MTD in order to obtain additional safety and pharmacokineticdata. ResultsThree DLTs occurred during cycle 1 in three (25%) of the first 12 patients: ruptured abdominalaortic aneurysm, acute renal failure, and > 5 consecutive days of missed axitinib dueto thrombocytopenia. DL1 was established as the MTD, since higher DL cohorts were notplanned. Common grade 3/4 non-hematologic adverse events in 22 patients treated atDL1 included hypertension (36.4%) and decreased appetite and stomatitis (18.2% each). Cisplatin/capecitabine slightly increased axitinib exposure; axitinib decreased capecitabineand 5-fluorouracil exposure. Eight patients (36.4%) each had partial response or stable disease. Median response duration was 9.1 months; median progression-free survival was3.8 months. ConclusionIn patients with advanced gastric cancer, standard doses of axitinib plus therapeutic dosesof cisplatin and capecitabine could be administered in combination. Adverse events weremanageable.
Abstract
Purpose This phase I trial evaluated the question of whether the standard starting dose of axitinibcould be administered in combination with therapeutic doses of cisplatin/capecitabine inpatients with previously untreated advanced gastric cancer, and assessed overall safety,pharmacokinetics, and preliminary antitumor activity of this combination. Materials and MethodsPatients in dose level (DL) 1 received axitinib 5 mg twice a day (days 1 to 21) with cisplatin80 mg/m2 (day 1) and capecitabine 1,000 mg/m2 twice a day (days 1 to 14) in 21-daycycles. Maximum tolerated dose (MTD) was the highest dose at which ! 30% of the first 12patients experienced a dose-limiting toxicity (DLT) during cycle 1. Ten additional patientswere enrolled and treated at the MTD in order to obtain additional safety and pharmacokineticdata. ResultsThree DLTs occurred during cycle 1 in three (25%) of the first 12 patients: ruptured abdominalaortic aneurysm, acute renal failure, and > 5 consecutive days of missed axitinib dueto thrombocytopenia. DL1 was established as the MTD, since higher DL cohorts were notplanned. Common grade 3/4 non-hematologic adverse events in 22 patients treated atDL1 included hypertension (36.4%) and decreased appetite and stomatitis (18.2% each). Cisplatin/capecitabine slightly increased axitinib exposure; axitinib decreased capecitabineand 5-fluorouracil exposure. Eight patients (36.4%) each had partial response or stable disease. Median response duration was 9.1 months; median progression-free survival was3.8 months. ConclusionIn patients with advanced gastric cancer, standard doses of axitinib plus therapeutic dosesof cisplatin and capecitabine could be administered in combination. Adverse events weremanageable.
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