Phase1/2 Single Arm Study of Rigosertib (ON 01910.Na) in Patients (Pts) with Relapsed or Refractory Acute Leukemia or Transformed Myeloproliferative Neoplasms

Rigosertib (ON01910.Na) is a non-ATP competitive multi-kinase inhibitor which differentially arrests tumor cells in G2-M stages and inhibits polo-like kinase and PI-3 kinase pathways with decreases of Cyclin-D1 and Akt phosphorylation. Earlier clinical studies in advanced solid tumors as well as in myelodysplastic syndrome (MDS) and acute leukemia reported a favorable toxicity profile and showed early evidence of clinical activity. Therefore, we initiated a study in acute myeloid leukemia (AML) investigating alternative schedules to determine the optimal dose and anti-leukemia efficacy.

This phase 1/2 study enrolled pts > 18 years (yrs) of age with relapsed or refractory AML or transformed myeloproliferative neoplasms (MPN). Pts were given rigosertib by continuous IV infusions over 24 hours (hrs) with a fixed dose of 2400mg/day either for 72 hrs or 120 hrs every other week using a standard dose escalation scheme. A blood sample was withdrawn at 6 hrs after the start of infusion during cycle 1 and cycle 2 to assess the plasma concentration of rigosertib. The study was subsequently amended and, after 2 cycles of IV rigosertib (each cycle being 2 weeks) pts could receive rigosertib orally, 560mg twice a day continuously for 20 weeks. The objectives of phase 1 study were to define maximum tolerated dose (MTD), dose limiting toxicities (DLT), identify all toxicities and anti-leukemia activity. Phase 2 primary objective was to determine the clinical efficacy; secondary objectives were to assess time to response or progression, duration of response and overall survival at 6 months.

26 pts have been enrolled in study since September 2010; median age was 66 yrs (range: 32–83 yrs) and 15 of them were males. Twenty pts were on 72 hrs dose schedule. One of the 6 pts in the 120 hrs dose schedule eventually did not participate. The average plasma levels of rigosertib in pts on week 1 and 3 were 9.20 ± 5.05 and 9.81 ± 6.70 μM, respectively. Eight pts were enrolled in phase 2. Diagnosis included: 10 (38%) de novo AML, 11 (42%) MDS related AML, 3 (12%) treatment related AML and 2 (8%) transformed MPN. Pts had received a median of 3 prior therapies (range: 1 to 7). There are 7 (27%) pts with primary refractory AML and 19 (73 %) with relapsed AML. Seven of 26 (27%) pts had a prior allogeneic stem cell transplant and 50% had a complex karyotype. Pts received a median of 2 cycles (range, 1 to 4). Serious adverse events (SAE) seen were: altered mental status, confusion, delirium (8), febrile neutropenia (4), acute respiratory distress (4), leukocytosis (4), sepsis (3), pneumonia (2), urinary tract infection (2),multi organ failure (2), cardiomyopathy (2), fever (1), hypotension (1), hypertension (1), hypokalemia (1), elevated alanine amino transferase (1), pericarditis (1), intracranial hemorrhage (1) and pneumothorax (1). SAE incidence was not related to the duration of infusions (3 or 5 days) and occurred mainly during the first 28 days of treatment. The most common grade1 or 2 adverse events (AE) observed were: hypokalemia (4), thromboembolic events (3), hypotension (2), insomnia (2) and hemorrhoids (2). All the SAEs except altered mental status (AMS) were considered unlikely or not related to the drug. The MTD was determined to be 2400mg over 24 hrs for 3 days. DLT at 2400mg over 24 hrs for 5 days was grade 3 transient AMS (including confusion or delirium). Five pts on 120 hrs schedule developed AMS, 2(40%) of them were thought to be related to rigosertib. Three of 20 pts on 72 hrs schedule had transient AMS and 2 (10%) of them were considered to be possibly related to rigosertib. In terms of efficacy, after 2 cycles best response noted is stabilization of disease with > 50% absolute reduction of peripheral blasts in 2/25 (8%) pts, while in 4(16%) other pts peripheral blasts were maintained at +/−10% of pretreatment level. There was also transient hematologic response with improvement of platelets in another 4 (16%) pts. The most common reasons for treatment discontinuation were disease progression or death from disease related complications. For pts taken off study, the median days on study were 29 (range: 5–92 days). The median survival for all pts was 5 weeks. Phase 2 of the study has 6 active pts.

Interim analysis of phase 1/2 study of rigosertib shows that it has an acceptable toxicity profile with the main AE being transient AMS. Rigosertib therapy results in stable disease in some pts. Study accrual continues.

Off Label Use: Rigosertib is being used for relapsed or refractory AML in phase 1 clinical trial. Maniar:Onconova Therapeutics Inc: Employment, full employee of Onconova with stock options Other. Wilhelm:Onconova Therapeutics Inc: Employment, full employee of Onconova with stock options Other. Cortes:University of Texas, MD Anderson cancer center: Research Funding.