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

Abstract

Purpose: 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.

Experimental design: 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.

©2014 AACR.

Figures

Figure 1

A, the median time on study was 6 weeks (95% CI, 1–101+ weeks). Forty-three (89.5%) patients came off study because of progression of disease, 2 patients because of toxicity, and 1 patient died. One patient withdrew consent. One patient remained on study at the time of analysis. B, waterfall plot of tumor responses of the 43 patients for whom serial imaging studies were available. One patient achieved a CR, 1 patient a prolonged PR, and 8 patients achieved stable disease for12 or more weeks (range, 12–36 weeks).

Figure 2

Objective responses to oral rigosertib in 2 patients with HNSCC. A, serial CT scan images of a patient with metastatic HNSCC, who achieved a CR. B, initial tumor growth then reduction in a patient with metastatic HNSCC who achieved a prolonged PR.