A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors.

Abstract

3152 Background: Paclitaxel resistance in patients is a clinical challenge that limits the durability of clinical benefit in patients with taxane-responsive advanced solid tumors. One proposed mechanism for this resistance is overexpression of spleen tyrosine kinase (SYK); which can be inhibited with new molecules including TAK-659. In this phase I study, we have investigated the combination of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors; hypothesizing that use of TAK-659 would help to overcome resistance to prior taxane-based therapy. Methods: We included patients with advanced solid tumors who received and progressed on prior taxane-based therapy. Patients received treatment with intravenous paclitaxel on day 1,8, and 15 in addition of daily TAK-659 in 28-day cycles. Six cohorts were treated during dose escalation at different dose levels followed by a dose expansion phase in patients with advanced ovarian cancer. We used the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 for evaluation of toxicity and Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for assessment of preliminary efficacy. Results: We included 49 patients with advanced solid tumors. The maximum tolerated dose was not reached in this study; and no patients experienced treatment-related deaths. Most adverse events were either grade 1 or 2. Grade 3 or more adverse events were reported in 47% of patients (n=23). The most common grade ≥3 adverse events were decreased neutrophil count (n=7; 14%), elevated lipase (n=6; 12%), anemia (n=5; 10%), increased amylase (n=4; 8%), and decreased white blood cell counts (n=4; 8%). In 44 patients with taxane-refractory tumors who were evaluable for efficacy, 9% (n=4) had RECIST partial response and 27% (n=12) had RECIST stable disease, including 3 patients with prolonged stable disease for at least 6 months. Conclusions: The combination of paclitaxel and TAK-659 was well tolerated and showed preliminary modest efficacy which could be possibly overcoming resistance to taxane-based therapy in patients with advanced solid tumors. Clinical trial information: NCT03756818 .