A phase 1 study of nilotinib in combination with paclitaxel in patients with advanced solid tumors.

Purpose: We assessed the safety, maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), efficacy, pharmacokinetic, and pharmacodynamics of the nilotinib-paclitaxel combination in 44 patients with solid tumors.

Patients and methods: Paclitaxel was administered intravenously (days 1, 8, and 15) and nilotinib was administered twice daily orally beginning on cycle 1 day 2 (C1D2, escalation) or C1D3 (expansion) in 28-day cycles using a 3+3 dose escalation design. Pharmacodynamic biomarkers of drug action were assessed in paired tumor biopsies and circulating tumor cells (CTCs) at the RP2D.

Results: The RP2D was 300 mg nilotinib twice daily with 80 mg/m2 paclitaxel. Grade 4 (Gr4) neutropenia and Gr3 rash, photosensitivity, and transaminase elevation were dose-limiting. The most common Gr3-4 toxicities were hematological and hypophosphatemia; 1 patient (2%) experienced Gr3 peripheral neuropathy. Three patients (2 with adult ovarian granulosa cell tumors [AOGCT] and 1 with endometrial carcinoma) had confirmed partial responses (cPR); the patients with AOGCT remained on study for 5 and 6+ years and mesenchymal-like CTCs were measured prior to progression or during treatment holiday (patients 12 and 10, respectively).

Conclusions: This study determined the MTD of this combination, demonstrated sustained cPRs in patients with AOGCT, and profiled molecular pharmacodynamic responses that will inform further mechanism of action studies. The rate of peripheral neuropathy suggests enhanced tolerability of this combination.