A Phase I Study of Nilotinib in Combination with Paclitaxel in Patients with Advanced Solid Tumors

Abstract Purpose: We assessed the safety, maximum tolerated dose, and recommended phase 2 dose (RP2D), efficacy, pharmacokinetics, 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 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 hematologic and hypophosphatemia; one patient (2%) experienced Gr3 peripheral neuropathy. Three patients [two with adult ovarian granulosa cell tumors (AOGCT) and one with endometrial carcinoma] had confirmed partial responses (cPR); the patients with AOGCT remained on study for 5 and 6+ years, and mesenchymal-like circulating tumor cells were measured prior to progression or during treatment holiday (patients 12 and 10, respectively). Conclusions: This study determined the maximum tolerated dose 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.