Abstract A170: Results from the phase 1 portion of a phase 1/2 study of the irreversible PI-3K inhibitor PX-866 and docetaxel.
Authors: Jimeno Antonio , Senzer Neil , Ma Wen Wee , Rudin Charles , Bowles Daniel , Vo Alex , Peterson Scott , Hausman Diana 
Published: June 2012

Abstract
Background: PX-866, an irreversible, pan-isoform inhibitor of Class 1 PI-3K, is active in a number of tumor models as a single agent and in combination with chemotherapy including docetaxel. PX-866 and docetaxel have additive effects in xenograft models of non-small cell lung cancer (NSCLC), and synergistic effects in direct patient tumor models of squamous cell carcinoma of the head and neck (SCCHN). In a Phase 1 study, single agent PX-866 was well tolerated at a maximum tolerated dose (MTD) of 8 mg/day without hematologic toxicity and was associated with anti-tumor activity. Based on these results, a phase 1/2 study of PX-866 with docetaxel was initiated. The phase 1 portion of the study is complete, and is reported here.
Methods: Patients (pts) with advanced solid tumors for which docetaxel is considered standard of care received docetaxel 75 mg/m2 IV on Day 1 and escalating doses of oral PX-866 once daily on a 21 day cycle. PX-866 treatment was initiated on Day 8 of Cycle 1. Dose escalation of PX-866 was performed in cohorts of at least 6 pts treated for two cycles, with enrollment of an expanded cohort at the MTD/recommended Phase 2 dose. Tumor restaging was performed every two cycles. Pharmacokinetics (PK) of PX-866 and docetaxel were characterized. Prophylactic use of growth factors and dose reduction of docetaxel and PX-866 were allowed. Archived tissue was collected for biomarker assessment.
Results: 40 pts have been treated in 3 dose cohorts of PX-866 (4 mg n=10; 6 mg n=10; 8 mg n=20), with median age 59 yrs (25–80); all ECOG 0/1; and mean number of prior treatments 3 (1–11). There were no DLTs, and the presumptive Phase 2 dose is 8 mg. The most common adverse events (AEs) were diarrhea, fatigue, nausea, vomiting, neutropenia, edema, anemia, constipation, cough and anorexia, most of which were Gr 1/2. Treatment-related Gr 3/4 AEs other than neutropenia include diarrhea (n=1), mucositis (n=1) and hypokalemia (n=1). Grade 3/4 neutropenia was reported in 12 pts and was considered related to docetaxel alone. Treatment-related serious AEs were reported in 3 pts including one event of diarrhea related to PX-866, and one event each of febrile neutropenia with pneumonia and nausea/vomiting, both related to docetaxel alone. Combination treatment had no effect on the PK of either docetaxel or PX-866. 19 pts have been evaluable for response; best response was SD in 12 (63%) and PD in 7 (37%). 17 pts have not yet been assessed for response. The mean number of cycles received is 3 (1 to 13); the most common reason for discontinuation is PD. 9 pts have received 7 or more cycles. Results from biomarker assessments of PIK3CA and Kras mutations are available for 11 pts. 5 pts had no mutation (PI3K-wt), 5 pts had a PIK3CA mutation (PI3K-mut), and 1 pt had a Kras mutation. The mean number of cycles received for PI3K-wt pts and PI3K-mut pts is 3 (1–7) and 7 (2–9), respectively. Full clinical, PK and biomarker results will be presented.
Conclusions: Treatment with PX-866 and docetaxel has been well tolerated, with no increase in toxicity of either drug attributable to the combination. Combination treatment had no impact on the PK profile of either drug. The disease control rate of 63% is encouraging in this heavily pretreated population, with a trend to longer time on study in pts with a PIK3CA mutation. The Phase 2 portion of this study will evaluate PX-866 + docetaxel vs docetaxel alone in pts with NSCLC and SCCHN.
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 A170.