Phase I study of oral rigosertib (ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies.
OBJECTIVE
To determine the pharmacokinetics (PK), maximum tolerated dose (MTD), safety, and antitumor activity of an oral formulation of rigosertib, a dual phosphoinositide 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathway inhibitor, in patients with advanced solid malignancies.


METHODS
Patients with advanced solid malignancies received rigosertib twice daily continuously in 21-day cycles. Doses were escalated until intolerable grade ≥2 toxicities, at which point the previous dose level was expanded to define the MTD. All patients were assessed for safety, PK, and response. Urinary PK were performed at the MTD. Archival tumors were assessed for potential molecular biomarkers with multiplex mutation testing. A subset of squamous cell carcinomas (SCC) underwent exome sequencing.


RESULTS
Forty-eight patients received a median of 2 cycles of therapy at 5 dose levels. Rigosertib exposure increased with escalating doses. Dose-limiting toxicities were hematuria and dysuria. The most common grade ≥2 drug-related toxicities involved urothelial irritation. The MTD is 560 mg twice daily. Activity was seen in head and neck SCCs (1 complete response, 1 partial response) and stable disease for ≥12 weeks was observed in 8 additional patients. Tumors experiencing ≥partial response had PI3K pathway activation, inactivated p53, and unique variants in ROBO3 and FAT1, two genes interacting with the Wnt/β-catenin pathway.


CONCLUSIONS
The recommended phase II dose of oral rigosertib is 560 mg twice daily given continuously. Urinary toxicity is the dose-limiting and most common toxicity. Alterations in PI3K, p53, and Wnt/β-catenin pathway signaling should be investigated as potential biomarkers of response in future trials.
Authors' Affiliations: Department of Medicine, Division of Medical Oncology; Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado; and Onconova Therapeutics Inc, Newtown, Pennsylvania.
Daniel W
DW
Bowles
Jennifer R
JR
Diamond
Elaine T
ET
Lam
Colin D
CD
Weekes
David P
DP
Astling
Ryan T
RT
Anderson
Stephen
S
Leong
Lia
L
Gore
Marileila
M
Varella-Garcia
Brian W
BW
Vogler
Stephen B
SB
Keysar
Elizabeth
E
Freas
Dara L
DL
Aisner
Chen
C
Ren
Aik-Chook
AC
Tan
Francois
F
Wilhelm
Manoj
M
Maniar
S Gail
SG
Eckhardt
Wells A
WA
Messersmith
Antonio
A
Jimeno
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D005998:Glycine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D055815:Young Adult; D000097869:Polo-Like Kinase 1
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D005998:Glycine; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D013450:Sulfones; D000097869:Polo-Like Kinase 1; C507134:ON 01910