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

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.

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.

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).

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.