Safety, pharmacodynamic, and clinical response evaluation of nilotinib and paclitaxel in adults with refractory solid tumors.
Authors: Shin Sarah , O'Sullivan Coyne Geraldine Helen , Kummar Shivaani , Hogu Murielle , Rubinstein Larry V. , Miller Sarah , Takebe Naoko , Juwara Lamin , Anderson Larry , Collins Jerry M. , Piekarz Richard , Sharon Elad , Ji Jiuping Jay , Miller Brandon , Wilsker Deborah , Srivastava Apurva K. , Ferry-Galow Katherine V. , Parchment Ralph E. , Doroshow James H. , Chen Alice P. 
Published: June 2022

3026 Background: The combination of the BCR-Abl kinase inhibitor nilotinib and the anti-tubulin agent paclitaxel was identified in the NCI-ALMANAC study to have greater-than-additive activity in the NCI-60 cell line panel and greater-than-single-agent antitumor activity in xenograft models, in which this combination induces tumor epithelial-mesenchymal transition (EMT). A phase 1 study was initiated to establish the safety, tolerability, and recommended phase 2 dose (RP2D) of this combination in patients (pts) with advanced solid tumors and to examine the pharmacokinetic (PK) and pharmacodynamic (PD) effects of the combination to understand the mechanism of action (NCT02379416). The dose escalation phase established the RP2D as 300 mg oral nilotinib twice daily and 80 mg/m2 intravenous paclitaxel on days (D) 1, 8, and 15 of each 28-day cycle. Here, we report the safety, preliminary PD, and efficacy data for this combination. Methods: Nilotinib and paclitaxel were administered as noted above, with a 1-day (escalation cohort) or 2-day (expansion cohort) paclitaxel-only run-in during the first cycle to enable comparison of the PK and PD effects of the combination vs. single-agent paclitaxel. Paired biopsies to assess tumor molecular response were collected from expansion cohort pts at baseline, cycle (C) 1 D2, and C1D28, with an optional biopsy at progression; accrual continued until ≥ 12 sufficient-quality paired biopsies were obtained. Blood specimens to assess molecular responses in circulating tumor cells (CTCs) were obtained at several timepoints during C1 and longitudinally every cycle thereafter. EMT biomarkers were measured in tumor and CTC specimens using quantitative immunofluorescence microscopy assays. Results: A total of 44 pts were enrolled. Three pts had partial responses (PR), and 1 had an unconfirmed PR (9%); 23 pts (52%) had a best response of stable disease (SD), including 7 pts on study for ≥ 10 cycles. The most common grade (Gr) 3-4 treatment-related adverse events were hematologic and hypophosphatemia. No pts experienced Gr ≥ 3 peripheral neuropathy. The median time on treatment was 67 days. Two pts with granulosa cell ovarian carcinoma had durable responses, completing 74+ and 64 cycles. Multiple patient biopsies and corresponding CTC specimens exhibited treatment-induced EMT. Longitudinal analysis of CTC EMT phenotypes in the 2 pts with extended PR revealed a substantial increase in mesenchymal-like CTCs prior to progression for the pt on study for 64 cycles; such increases were not observed in the pt still on study after 74+ cycles. Further PD analyses are ongoing. Conclusions: The combination of nilotinib and paclitaxel demonstrates promising disease control with durable response in select patients. Tumor PD analyses to discover the underlying pharmacology of this active regimen are ongoing. Funded by NCI Contract No. HHSN261201500003I. Clinical trial information: NCT02379416.