Phase I Study of Axitinib in Combination with Cisplatin and Capecitabine in Patients with Previously Untreated Advanced Gastric Cancer

Abstract

Purpose: This phase I trial evaluated the question of whether the standard starting dose of axitinib could be administered in combination with therapeutic doses of cisplatin/capecitabine in patients with previously untreated advanced gastric cancer, and assessed overall safety, pharmacokinetics, and preliminary antitumor activity of this combination.

Materials and methods: Patients in dose level (DL) 1 received axitinib 5 mg twice a day (days 1 to 21) with cisplatin 80 mg/m(2) (day 1) and capecitabine 1,000 mg/m(2) twice a day (days 1 to 14) in 21-day cycles. Maximum tolerated dose (MTD) was the highest dose at which ≤ 30% of the first 12 patients experienced a dose-limiting toxicity (DLT) during cycle 1. Ten additional patients were enrolled and treated at the MTD in order to obtain additional safety and pharmacokinetic data.

Results: Three DLTs occurred during cycle 1 in three (25%) of the first 12 patients: ruptured abdominal aortic aneurysm, acute renal failure, and > 5 consecutive days of missed axitinib due to thrombocytopenia. DL1 was established as the MTD, since higher DL cohorts were not planned. Common grade 3/4 non-hematologic adverse events in 22 patients treated at DL1 included hypertension (36.4%) and decreased appetite and stomatitis (18.2% each). Cisplatin/capecitabine slightly increased axitinib exposure; axitinib decreased capecitabine and 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 was 3.8 months.

Conclusion: In patients with advanced gastric cancer, standard doses of axitinib plus therapeutic doses of cisplatin and capecitabine could be administered in combination. Adverse events were manageable.

Trial registration: ClinicalTrials.gov NCT00842244.

Keywords: Axitinib; Capecitabine; Cisplatin; Clinical trial; Pharmacokinetics; Phase I; Stomach neoplasms.

Conflict of interest statement

Ying Chen, Liqiang Yang, and Olga Valota are Pfizer employees and hold Pfizer Inc. stock. Yung-Je Bang has performed consulting services for and received honoraria and research funding from Pfizer Inc. Do-Youn Oh, Toshihiko Doi, Kuniaki Shirao, Sook Ryun Park, and Keun-Wook Lee have no conflicts of interest to disclose. This study was sponsored by Pfizer Inc. Medical writing support was provided by Lilliam Poltorack, PharmD, and Joanna Bloom, PhD, of Engage Scientific Solutions, and was funded by Pfizer Inc.

Figures

Fig. 1.

Study design for patients in the pharmacokinetic (PK) subgroup. b.i.d., twice a day; D, day; C, cycle. a)Morning doses on day 1 were administered at the start of cisplatin infusion, b)1,000 mg/m2, c)80 mg/m2.

Fig. 2.

Median plasma concentration-time profiles, semi-log scale, for steady-state axitinib (A), cisplatin (platinum in plasma ultrafiltrate [PUF]) (B), capecitabine (C), and 5-fluorouracil (5-FU) (D). The lower limit of quantification was 0.500 ng/mL for axitinib, 1.00 ng/mL for platinum in PUF, 20.0 ng/mL for capecitabine, and 5.00 ng/mL for 5-FU. Two patients were excluded from median concentration profile plots for platinum in PUF, capecitabine, and 5-FU because cycle 2 (C2), day 1 (D1) pharmacokinetic samples were not collected.

Fig. 3.

Waterfall plot of tumor response for each patient (n=20) with at least one post-baseline scan. Two patients were not evaluable, and one patient had a maximum percent change from baseline of 0.