Abstract A174: Results from the phase 1 portion of a phase 1/2 study of the irreversible PI-3K inhibitor PX-866 and cetuximab.
Authors: Senzer Neil , Bowles Daniel , Cohen Roger B. , Vo Alex , Klucher Kevin , Peterson Scott , Hausman Diana F. , Jimeno Antonio 
Published: June 2012

Abstract
Background: Inhibition of the EGFR pathway by the monoclonal antibody cetuximab is an important component of treatment for colorectal cancer (CRC) and squamous cell carcinoma of the head and neck (SCCHN). One mechanism of resistance to EGFR inhibition is increased signaling through the PI-3K pathway. PX-866, an irreversible pan-isoform inhibitor of Class 1 PI-3K, is active in models of CRC and direct patient tumor models of SCCHN as a single agent and in combination with EGFR inhibitors. In a Phase 1 study, single agent PX-866 was well tolerated at a maximum tolerated dose (MTD) of 8 mg/day and was associated with anti-tumor activity. Based on these results, a Phase 1/2 study of PX-866 in combination with cetuximab was initiated in patients (pts) with advanced CRC or SCCHN. The phase 1 portion of the study is complete, and is reported here.
Methods: Pts received cetuximab IV once per week at full doses and escalating doses of oral PX-866 once daily on a 21-day cycle using a 3+3 design. Prophylactic treatment for rash was required. Tumor restaging was performed every two cycles. PK assessments included evaluation of cetuximab levels. Archived tissue was collected for biomarker assessment.
Results: 10 pts with CRC and 1 pt with SCCHN enrolled in two dose cohorts of PX-866 (6 mg n=4; 8 mg n=7) with median age 58 yrs (35–82); all ECOG 0/1; and median number of prior systemic treatments 4 (2–8). Seven pts had received prior treatment with an EGFR inhibitor, including 3 and 4 pts each who had received prior cetuximab and panitumumab, respectively, and 1 pt who had received both. There were no DLTs, and the recommended Phase 2 dose included PX-866 at 8 mg/day and full dose weekly cetuximab. The most common adverse events (AEs) included diarrhea, hypomagnesemia, nausea/vomiting, dehydration, fatigue, rash, asthenia, constipation and weight loss, the majority of which were Gr 1/2 in severity. Treatment-related Gr 3/4 AEs were Gr 3 diarrhea (n=1), Gr 3 hyponatremia (n=1) and Gr 3 hypokalemia (n=1). 2 pts had serious AEs of diarrhea considered related to PX-866 alone or the combination with cetuximab. PX-866 had no effect on cetuximab PK compared to historical data. Eight pts were evaluable for response; best response in these pts was 4 PR (50%), 3 SD (38%) and 1 PD (12%), for a disease control rate of 88%. In 5 response-evaluable pts who had previously received an EGFR inhibitor, best response was 1 PR (20%), 3 SD (60%) and 1 PD (20%). The median number of cycles received was 6 (1 to 11), with PD as the most common reason for discontinuation. Biomarker assessments evaluating the presence of PIK3CA and Kras mutations in tumor samples are ongoing and will be presented.
Conclusions: Treatment with PX-866 and cetuximab was well tolerated, with no increase in toxicity of either drug attributable to the combination. The Phase 2 dose of PX-866 in combination with full dose cetuximab is the same as the single agent MTD. The ORR of 50% is encouraging compared to the historical ORR of 11% for single agent cetuximab. The Phase 2 portion of this study comparing PX-866 + cetuximab vs. cetuximab alone in 2 groups of pts (CRC and SCCHN) is now enrolling.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A174.