Phase I Dose-Escalation Study of Pilaralisib (SAR245408, XL147) in Combination with Paclitaxel and Carboplatin in Patients with Solid Tumors
Lessons Learned: Although activation of the PI3K pathway is implicated in tumorigenesis of solid tumors, single-agent PI3K inhibitors have shown limited clinical effectiveness. Preclinical studies suggest that combining PI3K inhibitors with chemotherapy may enhance antitumor activity. In clinical trials, the PI3K inhibitor pilaralisib exhibited a favorable safety profile, but it did not improve the antitumor effects of paclitaxel plus carboplatin. Further clinical studies are needed to explore more effective combination strategies involving PI3K pathway inhibitors.
Background: Pilaralisib (SAR245408) is an oral, pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I dose-escalation study aimed to evaluate the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics of pilaralisib in both capsule and tablet forms, when combined with paclitaxel and carboplatin in patients with advanced solid tumors.
Methods: The study followed a 3 + 3 design. Pilaralisib was administered once daily (QD), while paclitaxel (up to 175 mg/m²) and carboplatin (up to area under the curve [AUC] of 6) were administered on day 1 of 21-day cycles. An MTD expansion cohort of patients with endometrial carcinoma was included.
Results: Fifty-eight patients were enrolled, with six patients (10.3%) experiencing dose-limiting toxicities. Rash was the only adverse event occurring in more than one patient (3.4%). The MTD of pilaralisib tablets, when combined with paclitaxel and carboplatin, was determined to be 200 mg QD. The most common adverse events (AEs) of any grade were neutropenia (67.2%) and thrombocytopenia (67.2%). PK data indicated no interaction between pilaralisib and paclitaxel/carboplatin. Tumor tissue showed moderate inhibition of both PI3K and mitogen-activated protein kinase (MAPK) pathways. Seven of 52 evaluable patients (13.5%) achieved a partial response (PR).
Conclusion: While pilaralisib demonstrated a favorable safety profile, it did not enhance the antitumor activity of paclitaxel plus carboplatin in patients with solid tumors.