Background: Rigosertib (ON 01910.Na) is a new multi-targeted inhibitor of several kinases, including polo-like kinase 1 and PI-3 kinase, and is in advanced trials for myelodysplastic syndrome and pancreatic cancer as an IV agent. An oral formulation with good oral bioavailability has entered phase 1 in patients (pts) with advanced solid tumors to determine the dose limiting toxicities (DLT), recommended phase II dose, pharmacokinetic (PK) profiles, and to document any antitumor activity of this compound. Methods: 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, at which point the previous dose level was expanded to define the MTD. All pts were assessed for safety, PK, PD and response. Urinary PK assessments were also performed at the MTD. Results: 25 pts (median age= 59; median ECOG PS= 1) received a median of 6 weeks of therapy at 5 dose levels: (70 mg n=3; 140 mg n=2 ; 280 mg n=3; 560 mg n=10; 700 mg n=7). The DLT was dysuria at 700 mg and led to expansion at 560 mg bid. There were no DLTs in the expansion cohort. Grade 2/3 toxicities related to rigosertib included dysuria (5/1), cystitis (4/0), urinary frequency (3/0), hematuria (2/1), abdominal pain (2/0), pelvic pain (1/1), nausea (1/0), distention/bloating (1/0) and hyponatremia (0/1). Improvements in dysuria were seen with oral hydration and sodium bicarbonate. A confirmed PR occurred in 1 pt (HN squamous cell ca, 42+ weeks), and 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 (32+ weeks) tumors. Preliminary PK data reveal plasma rigosertib levels above the predicted pharmacodynamically active levels. Conclusions: The MTD of oral rigosertib administered twice daily continuously is 560mg. Dysuria is the dose limiting and most common toxicity and can be managed with oral hydration and sodium bicarbonate. Antitumor activity has been observed. Final safety and efficacy results, plasma and urinary PK relationships, and mutational analyses from archival tissue will be presented.