A multicenter phase 1 study of PX-866 in combination with docetaxel in patients with advanced solid tumours

Abstract

Background:

This phase I, dose-finding study determined the safety, maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), pharmacokinetics, and antitumour activity of PX-866, a phosphatidylinositol 3-kinase inhibitor, combined with docetaxel in patients with incurable solid tumours.

Methods:

PX-866 was administered at escalating doses (4–8 mg daily) with docetaxel 75 mg m ⁻² intravenously every 21 days. Archived tumour tissue was assessed for potential predictive biomarkers.

Results:

Forty-three patients were enrolled. Most adverse events (AEs) were grade 1 or 2. The most frequent study drug-related AE was diarrhoea (76.7%), with gastrointestinal disorders occurring in 79.1% (docetaxel-related) and 83.7% (PX-866-related). No dose-limiting toxicities were observed. The RP2D was 8 mg, the same as the single-agent MTD. Co-administration of PX-866 and docetaxel did not affect either drug's PKs. Best responses in 35 evaluable patients were: 2 partial responses (6%), 22 stable disease (63%), and 11 disease progression (31%). Eleven patients remained on study for >180 days, including 8 who maintained disease control on single-agent PX-866. Overall median progression-free survival (PFS) was 73.5 days (range: 1–569). A non-significant association between longer PFS for PIK3CA-MUT/ KRAS-WT vs PIK3CA-WT/ KRAS-WT was observed.

Conclusion:

Treatment with PX-866 and docetaxel was well tolerated, without evidence of overlapping/cumulative toxicity. Further investigation with this combination is justified.