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Published on: May 14, 2018
A phase I study of TAK-659 and paclitaxel in patients with taxane-refractory advanced solid tumors
M A Gouda1, J Shunyakova1, A Naing1
1Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston.
Background:
Paclitaxel resistance limits durability of response in patients with initial clinical benefit. Overexpression of spleen tyrosine kinase (SYK) has been proposed as a possible resistance mechanism. This phase I trial evaluated the safety and preliminary activity of the SYK inhibitor TAK-659 combined with paclitaxel in patients with advanced taxane-refractory solid tumors.
Patients And Methods:
Patients with advanced solid tumors and prior progression on taxane-based therapy received intravenous infusion of paclitaxel on days 1, 8, and 15 plus oral TAK-659 daily in 28-day cycles. The dose-escalation phase included six cohorts treated at different dose levels; the dose-expansion phase included patients with ovarian cancer treated at the highest dose level. Toxicity was graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Efficacy was evaluated using Response Evaluation Criteria in Solid Tumors version 1.1.
Results:
Our study included 49 patients. Maximum tolerated dose was not reached, but higher rates of adverse events were observed at higher dose levels. There were no treatment-related deaths. The most common treatment-related adverse events of any grade were increased aspartate aminotransferase (n = 31; 63%), increased alanine aminotransferase (n = 26; 53%), decreased neutrophil count (n = 26; 53%), and decreased white blood cell count (n = 26; 53%). Most adverse events were either grade 1 or 2. In the 44 patients with evaluable disease, 12 (27%) had stable disease as the best overall response, including three patients with prolonged stable disease, and 4 patients (9%) achieved a partial response.
Conclusions:
The combination of paclitaxel and TAK-659 showed preliminary activity possibly overcoming resistance to taxane-based therapy as well as a tolerable safety profile in patients with advanced solid tumors.
Insights
This study combined paclitaxel with TAK-659 in advanced solid tumors, showing preliminary activity against taxane resistance. The combination demonstrated a tolerable safety profile, suggesting potential for overcoming treatment resistance.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Paclitaxel resistance is a significant challenge in treating advanced solid tumors.
- Overexpression of spleen tyrosine kinase (SYK) is a potential mechanism of paclitaxel resistance.
- This study investigated the SYK inhibitor TAK-659 in combination with paclitaxel.
Purpose of the Study:
- To evaluate the safety and preliminary activity of TAK-659 plus paclitaxel in patients with advanced solid tumors resistant to taxanes.
- To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the combination therapy.
- To assess the preliminary efficacy of the combination in patients with advanced solid tumors.
Main Methods:
- Phase I dose-escalation and dose-expansion trial in patients with advanced solid tumors and prior taxane progression.
- Paclitaxel administered intravenously on days 1, 8, and 15, with oral TAK-659 daily in 28-day cycles.
- Toxicity assessed using NCI CTCAE v5.0; efficacy evaluated by RECIST v1.1.
Main Results:
- 49 patients were enrolled; MTD was not reached, but higher adverse event rates occurred at higher doses.
- No treatment-related deaths were observed.
- Most common adverse events included elevated liver enzymes and cytopenias (neutropenia, leukopenia), mostly grade 1-2.
- In 44 evaluable patients, 12 (27%) achieved stable disease (3 prolonged) and 4 (9%) had a partial response.
Conclusions:
- The combination of paclitaxel and TAK-659 demonstrated a tolerable safety profile in patients with advanced solid tumors.
- Preliminary activity suggests the combination may overcome resistance to taxane-based therapies.
- Further investigation is warranted to confirm the efficacy of this combination regimen.
