Phase I dose-escalation study of cabazitaxel administered in combination with cisplatin in patients with advanced solid tumors

Summary Introduction Cabazitaxel is a second-generation taxane with in vivo activity against taxane-sensitive and -resistant tumor cell lines and tumor xenografts. Cabazitaxel/cisplatin have therapeutic synergism in tumor-bearing mice, providing a rationale for assessing this combination in patients with solid tumors. Methods The primary objectives of this study were to determine dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a cabazitaxel/cisplatin combined regimen (Part 1) and to assess antitumor activity at the MTD (Part 2). Safety and pharmacokinetics (PK) were also examined. Results Twenty-five patients with advanced solid tumors were enrolled (10 in Part 1; 15 in Part 2). In Part 1, two dose levels were evaluated; the MTD for cabazitaxel/cisplatin (given Q3W) was 15/75 mg/m 2 . DLTs occurring during Cycle 1 at the maximum administered dose (20/75 mg/m 2 ; acute renal failure and febrile neutropenia) and the MTD (febrile neutropenia and hypersensitivity despite pre-medication) were as expected for taxane/platinum combinations. For the 18 patients treated at the MTD, the most frequent possibly related non-hematologic treatment-emergent adverse events (Grade ≥3) were nausea (16.7 %), fatigue, acute renal failure and decreased appetite (each 11.1 %). Neutropenia was the most frequent treatment-emergent Grade ≥3 hematologic laboratory abnormality at the MTD (77.8 %). The best overall response at the MTD was stable disease, observed in 66.7 % of patients. PK results of the combination did not appear to differ from single-agent administration for each agent. Conclusion Combination treatment with cabazitaxel/cisplatin had a manageable safety profile; no PK interactions were evident. The recommended Phase II dose for this combination is cabazitaxel/cisplatin 15/75 mg/m 2 administered every 3 weeks. Antitumor activity findings suggest that further evaluation of this combination in disease-specific trials is warranted.