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


CONCLUSIONS
Treatment with PX-866 and docetaxel was well tolerated, without evidence of overlapping/cumulative toxicity. Further investigation with this combination is justified.
Division of Medical Oncology, School of Medicine, Universitiy of Colorado, 12801 E. 17th Avenue, MS 8117, Aurora, CO 80045, USA.
D W
DW
Bowles
W W
WW
Ma
N
N
Senzer
J R
JR
Brahmer
A A
AA
Adjei
M
M
Davies
A J
AJ
Lazar
A
A
Vo
S
S
Peterson
L
L
Walker
D
D
Hausman
C M
CM
Rudin
A
A
Jimeno
D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D006067:Gonanes / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D043823:Taxoids / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D006067:Gonanes; C496788:PX-866; D000081082:Phosphoinositide-3 Kinase Inhibitors; D043823:Taxoids; D000077143:Docetaxel