Phase I study of axitinib combined with paclitaxel, docetaxel or capecitabine in patients with advanced solid tumours

Abstract

Background: Axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors, enhanced the efficacy of chemotherapy in human xenograft tumour models. This phase I study investigated the safety, tolerability, pharmacokinetics and antitumour activity of axitinib combined with chemotherapy.

Methods: A total of 42 patients with advanced solid tumours received a continuous axitinib starting dose of 5 mg twice daily (b.i.d.) plus paclitaxel (90 mg m(-2) weekly), docetaxel (100 mg m(-2) every 3 weeks) or capecitabine (1000 or 1250 mg m(-2) b.i.d., days 1-14).

Results: Common treatment-related adverse events across all cohorts were nausea (45.2%), hypertension (45.2%), fatigue (42.9%), diarrhoea (38.1%), decreased appetite (33.3%) and hand-foot syndrome (31.0%). There was one complete response, nine partial responses and seven patients with stable disease. Ten patients (23.8%) remained on therapy for >8 months. Paclitaxel and capecitabine pharmacokinetics were similar in the absence or presence of axitinib, but docetaxel exposure was increased in the presence of axitinib. Axitinib pharmacokinetics were similar in the absence or presence of co-administered agents.

Conclusions: Axitinib combined with paclitaxel or capecitabine was well tolerated; no additive increase in toxicities was observed. Antitumour activity was observed for each treatment regimen and across multiple tumour types.

Figure 1

Treatment schedule. C=cycle; CT=chemotherapy; PK=pharmacokinetic.

Figure 2

Plasma concentration–time curves. (A) Axitinib/paclitaxel: Left panel, one patient excluded because cycle 2 day 1 pharmacokinetic (PK) samples were not collected. Right panel, two patients excluded because cycle 1 day 1 pharmacokinetics samples were not collected. (B) Axitinib/docetaxel: Left panel, two patients excluded because matching cycle 1 and cycle 2 PK evaluations were not completed. (C) Axitinib/capecitabine: Upper left panel, three patients excluded because matching cycle 1 and cycle 2 PK evaluations were not completed. Upper right panel, two patients excluded because matching cycle 1 and cycle 2 PK evaluations not completed and six patients excluded because of dose change from cycle 1 to cycle 2. Lower left panel, one patient excluded because matching cycle 1 and cycle 2 PK evaluations were not completed and one patient excluded because of dose reduction. Lower right panel, three patients excluded because matching cycle 1 and cycle 2 PK evaluations were not completed and two patients excluded because of dose reduction. *1000 mg m⁻²; ^†1250 mg m⁻².