A phase I safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with paclitaxel (P) and carboplatin (C) in patients (pts) with advanced solid tumors.

Abstract

3078 Background: Upregulation of PI3K pathway signaling is associated with tumor resistance to P and C. The oral selective Class I PI3K inhibitor XL147 potentiates the antitumor efficacy of P and C without exacerbated toxicity in preclinical xenograft tumor models. Methods: A standard 3 + 3 design was used. Pts receive intravenous P/C on day 1 of each 21-day cycle, and oral XL147 qd. Prior P and/or C were permitted. Maximum tolerated dose (MTD) expansion cohorts will include patients with endometrial, ovarian and non-small cell lung cancer. Dose limiting toxicities are determined using cycle 1 safety data. Tumor response is evaluated every 6 weeks. Results: 19 pts with advanced solid tumors (including 5 breast, 2 cervical, and 1 endometrial) have been enrolled. Pts have been treated at 6 dose levels up to 600mg XL147/175mg.m−2 P/AUC 6 C. The MTD has not yet been established. One grade 4 thrombocytopenia assessed as study treatment related was reported. The most frequently reported related AEs were neutropenia and fatigue (each 65%), thrombocytopenia (53%), and anemia (47%). Four pts had a confirmed PR with the following reductions (sum of tumor target lesions): 72% (tongue), 63% (tonsillar), 45% (esophageal), and 42% (cervical). One Merkel cell cancer pt had an unconfirmed PR (47% reduction of a single target lesion). In addition, 12 pts continued on treatment ≥ 12 weeks, with 4 pts ≥ 24 weeks. All PRs occurred in pts who had been previously treated with a platinum-containing regimen. No major PK interaction between XL147 and P/C was evident across cohorts based on comparison with single agent data. Inhibition of PI3K pathway signaling has been demonstrated. For example, post-dose reductions in pAKT-T308 (67%), p4EBP1 (64%), and pERK (73%) were observed at day 49, with an associated reduction in Ki67 (32%) and induction of apoptosis (2.4-fold), in paired tumor biopsies from a colon cancer pt. Conclusions: XL147 at doses up to 600 mg in combination with P at 175 mg.m−2 and C at AUC 6 is generally well tolerated, with no major PK interaction or emergent toxicities, and results in robust pharmacodynamic activity and tumor regression in heavily pretreated pts. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Exelixis Exelixis Exelixis