Oral Rigosertib Demonstrates Early Signs of Efficacy in MDS/AML


The investigational small molecule RAS mimetic rigosertib in combination with azacitidine elicited encouraging efficacy and a tolerable safety profile in patients with higher-risk myelodysplastic syndromes, acute myeloid leukemia, or chronic myelomonocytic leukemia.

Lewis R. Silverman, MD

The investigational small molecule RAS mimetic rigosertib in combination with azacitidine elicited encouraging efficacy and a tolerable safety profile in patients with higher-risk myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), or chronic myelomonocytic leukemia (CMML) who were naïve or relapsed/refractory to hypomethylating agents (HMAs), according to findings from the dose-escalation portion of a phase 1/2 clinical trial (NCT01926587) that were recently published in Leukemia Research.1

Among 16 evaluable patients, sequential administration of oral rigosertib and azacitidine led to an overall response rate (ORR) of 56%. Responses were observed in 78% of patients with MDS/CMML and 29% of patients with AML. The median duration of response with the combination was 5.8 months (range, 1.0-32.6).

To determine the maximum-tolerated dose and recommended phase 2 dose (RP2D) of rigosertib, investigators evaluated patients across 3 target dose levels.

Oral rigosertib was administered under fasting conditions at doses of 140 mg twice daily, 280 mg twice daily, and 840 mg daily where patients received 560 mg in the morning and 280 mg in the evening for 3 weeks of a 4-week cycle.

Preclinical findings suggested that rigosertib has synergy with azacitidine when administered as a lead in to concurrent administration. As such, patients were started on rigosertib 8 days prior to receiving azacitidine subcutaneously or intravenously at a standard dose of 75 mg/m2 daily for 7 days of the 4-week cycle.

Eligible patients had to have an ECOG performance status of 2 or lower, baseline serum creatinine of less than or equal to 2 mg/dL, and total bilirubin of less than 2 mg/dL. Patients whose bilirubin was higher due to hemolysis or ineffective erythropoiesis were eligible for enrollment.

In the MDS cohort (MDS, n = 9; CMML, n = 1), patients had to have intermediate-1, intermediate-2, or high-risk disease as defined by the International Prognostic Scoring System. Patients in the AML cohort (n = 8) had to have 20% to 30% bone marrow blasts, have had no more than 1 prior line of salvage therapy, and have a white blood cell count of less than or equal to 25,000 x 109/L that was stable for at least 4 weeks without therapeutic intervention.

All patients treated had a median age of 70.5 years and 61% were male. Twenty-two percent of patients had an ECOG performance status of 0, 67% had a status of 1, and 11% had a status of 2.

The majority of patients (83%) had received prior therapy, including supportive care (17%), intensive chemotherapy (39%), immunotherapy (6%), HMAs (44%), azacitidine (28%), and decitabine (17%). Additionally, 67% of patients had received red blood cell transfusions and 39% had received platelet transfusions within 8 weeks of study entry.

Baseline laboratory testing revealed that the median values for bone marrow blasts, hematocrit, hemoglobin, platelets, leukocytes, neutrophils, bilirubin, and creatinine were 13.5%, 29.8%, 9.7 g/dL, 52.5 x 109/L, 3 x 109/L, 0.91 x 109/L, 0.55 mg/dL, and 1.01 mg/dL, respectively.

Of the 18 total patients treated, 56% experienced a decrease in bone marrow blast percentage of at least 50% compared with baseline. Five patients achieved transfusion independence, of which all remained independent for a median of 69 days (range, 58-162). Three of these patients also remained platelet transfusion independent for a median of 133 days (range, 121-162).

Of the 78% of patients with MDS/CMML who derived a response to the combination, 2 patients experienced complete remission (CR) and 5 patients experienced a CR in their bone marrow. Moreover, 5 of these responses were observed in patients who were HMA naïve.

One patient with AML experienced a morphologic leukemia-free state and 1 experienced a morphologic CR. Both patients were HMA naïve and had received prior therapy.

The median treatment duration was 6.4 months (range, 1.1-41.0), and the median relative dose intensity was 80% with rigosertib and azacitidine (range, 43%-96%).

Regarding safety, no dose-limiting toxicities were observed across dose levels. As such, the RP2D was determined to be 840 mg of rigosertib daily plus the standard dose of azacitidine.

All patients treated experienced at least 1 adverse effect (AE) with the combination. The most frequent AEs included diarrhea (50%), constipation, fatigue, nausea (each 44%), pneumonia, and back pain (each 33%).

Grade 3 or higher AEs were observed in 89% of patients, the most common of which included pneumonia (33%), neutropenia (28%), and thrombocytopenia (22%).

Serious AEs were reported in 72% of patients. Though, some patients experienced more than 1 serious AE. Four patients discontinued treatment as a result of serious AEs, including 2 cases of grade 4 treatment-related thrombocytopenia, 1 case of grade 1 dysphagia and delirium, and 1 case of grade 3 fungal pneumonia.

Additionally, 7 patients died from serious AEs; however, none of these deaths were found to be related to treatment. These serious AEs that led to patient death included pneumonia, worsening AML, cardiac arrest, intracranial hemorrhage, sepsis, and subdural hematoma.

“These results coupled with preliminary data from the phase 2 studies, support further clinical development of this novel combination with a manageable safety profile and efficacy in patients with MDS, both those hypomethylating agent–naïve and after hypomethylating agent failure,” said study principal investigator, Lewis R. Silverman, MD, of the Icahn School of Medicine at Mount Sinai, in a press release.2 “The oral administration of rigosertib is not just more convenient for patients, but may improve treatment compliance, leading to improved clinical outcomes.”

The positive findings from the phase 1 portion of this study support further evaluation of the combination in the ongoing phase 2 portion of the trial.


  1. Navada SC, Garcia-Manero G, OdchimarReissig R, et al. Rigosertib in combination with azacitidine in patients with myelodysplastic syndromes or acute myeloid leukemia: results of a phase 1 study. Leukemia Research. 2020;94(2020):106369. doi:10.1016/j.leukres.2020.106369
  2. Onconova Therapeutics announces publication of phase 1 results in leukemia research exploring oral rigosertib in combination with azacitidine in higher-risk MDS. News release. Onconova Therapeutics, Inc; July 7, 2020. Accessed July 7, 2020.
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