Background: Rigosertib (ON 01910.Na) is a novel inhibitor of several kinases, including polo-like kinase 1 and PI-3 kinase, in advanced trials for myelodysplastic syndrome and pancreatic cancer as an IV agent. An oral formulation with good bioavailability was developed and tested in a phase I clinical evaluation in patients with advanced solid tumors. The goals of this study were to determine the dose limiting toxicities, recommended phase II dose, pharmacokinetic (PK) profiles, to document any antitumor activity, and to conduct exome sequencing in selected cohorts.

Methods: Patients (pts) with histologically confirmed solid tumors refractory to standard therapy were given escalating doses of rigosertib (70, 140, 280, 560, 700 mg) twice daily continuously. Doses were escalated until intolerable grade 2 or grade 3/4 toxicities were achieved, at which point the previous dose level was expanded to define the MTD. All pts were assessed for safety, PK, PD and response. At the MTD. Urinary PK assessments were performed at the MTD.

Results: Forty eight pts were treated at 5 dose levels: (70mg n=3; 140mg n=2; 280mg n=3; 560mg n=33; 700mg n=7). The dose limiting toxicity (DLT) was dysuria at 700 mg and led to expansion at 560mg bid. The drug was well tolerated, the primary toxicity being urinary. Grade 2/3 urinary toxicities related to rigosertib at the 560mg recommended phase II dose included dysuria (12/2), cystitis (3/0), hematuria (0/1), urinary frequency/urgency (1/0), urinary hesitancy (1/0), bladder irritation (1/0). Improvements in dysuria were seen with oral hydration and sodium bicarbonate. Two metastatic head and neck squamous cell carcinoma patients refractory to platinum-based therapy had confirmed CR (disappearance of mediastinal and lung disease) and PR (53% decrease of liver metastasis), and have been 98+ and 48+ weeks on study. These patients had pre-treatment PIK3CA copy gain and PTEN loss, respectively. In addition, SD was observed in 2 pts with ovarian cancer (56 weeks, 28 weeks), and 1 pt each with pancreatic neuroendocrine (40 weeks), carcinoid (32 weeks), nasopharyngeal (24 weeks) and renal cell (37 weeks) tumors. A patient with SCC of the cervix developed hemoperitoneum suspected to be related to tumor necrosis, and also had PIK3CA copy gain. Exome sequencing of the entire cohort of HNSCC and SCC has been conducted. Preliminary PK data reveals plasma rigosertib levels above the predicted pharmacodynamically active levels.

Conclusions: Here we present final results of the phase I study or daily rigosertib given orally BID, and molecular correlates in a cohort reflective of the efficacy signal. Based on these dramatic responses to rigosertib in two patients with metastatic HNSCC refractory to platinum-based therapy, a phase II trial is underway in this patient population. Whole exome sequencing analyses from archival tissue will be presented at the meeting.

Citation Format: Antonio Jimeno, Daniel Bowles, Dara Aisner, Jennifer Diamond, Elaine Lam, Colin Weekes, Stephen Leong, Lia Gore, Elizabeth Freas, Gail Eckhardt, Wells Messersmith, Marileila Garcia-Varella, Francois Wilhelm. Phase I and molecular correlates study of oral rigosertib in patients with refractory metastatic head and neck cancer and advanced solid tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-198. doi:10.1158/1538-7445.AM2013-LB-198