Abstract B247: A phase 1 safety and pharmacokinetic (PK) study of the PI3K inhibitor XL147 (SAR245408) in combination with paclitaxel (P) and carboplatin (C) in patients with advanced solid tumors
Authors: Wheler Jennifer J. , Traynor Anne M. , Bailey Howard H. , Attia Steven , Falchook Gerald S. , Laird A. Douglas , Nguyen Linh , Scheffold Christian , Kurzrock Razelle 
Published: June 2012

Abstract
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: Patients (pts) enrolled in successive cohorts of 3 receive intravenous P/C on Day 1 of each 21-day cycle, and oral XL147 qd. This study consists of two parts. In Part A, P and C will be dose-escalated up to 175 mg.m2 and AUC 6, respectively, in pts with solid tumors (MTD expansion in endometrial and ovarian cancer). In Part B, P and C will be dose-escalated up to 225 mg.m−2 and AUC 6, respectively, in NSCLC pts. Dose limiting toxicities (DLTs) are determined using Cycle 1 safety data. Tumor response is evaluated every 6 weeks.
Results: As of 01Aug2009, 15 pts with advanced solid tumors have been enrolled: breast (5), cervical (2), vulvar, tonsillar, parotid, peritoneal, colorectal, esophageal, melanoma, and tongue (1 each). Pts have been treated at 5 dose levels up to 400mg XL147/175mg.m−2 P/AUC 6 C. The MTD has not yet been established. Four pts experienced one or more SAEs. Of these, one pt experienced Grade 4 thrombocytopenia which was assessed as related to study treatment (XL147 and P/C). The most frequently reported related AEs were neutropenia, anemia, fatigue (each 31%), and peripheral neuropathy (23%). Three pts have experienced a confirmed PR with the following maximal reductions (sum of tumor target lesions): 63% (tonsillar), 45% (esophageal), and 42% (cervical). In addition, 11 pts continued on study ≥ 12 weeks, with 3 pts remaining on study ≥ 24 weeks. All PRs occurred in pts who had been previously treated with a platinum-containing regimen. In addition, a platinum-naïve pt with triple-negative, inflammatory breast cancer (mutant p53 and LKB-1) experienced regression of cutaneous lesions after two cycles. When given in combination with P/C, XL147 PK was consistent with that of XL147 given alone (Exelixis Study XL147-001). Likewise, XL147 does not have an apparent effect on PK of P or C. Pharmacodynamic modulation of the PI3K pathway was evident in tumor biopsies at plasma exposures consistent with those associated with PI3K inhibition in tumors in an ongoing single-agent Phase 1 trial of XL147 (Exelixis Study XL147-001). For example, post-dose reductions in pAKT-T308 (76%) and p4EBP1 (69%), with associated reductions in pERK (70%) and Ki67 (33%), and induction of apoptosis (2.3-fold), were evident in paired tumor biopsies from the pt with cervical adenocarcinoma (dosed at 200mg XL147/175mg.m−2 P/AUC 6 C) who experienced a PR.
Conclusions: XL147 at doses up to 400 mg in combination with paclitaxel at 175 mg.m−2 and carboplatin at AUC 6 is generally well tolerated, with no apparent drug-drug PK interaction or emergent toxicities, and results in robust pharmacodynamic activity in tumors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B247.