Difficult But Not Impossible: A New Approach to Treatment of Myelodysplastic Syndromes/Chronic Myelomonocytic Leukemia

ONTIME (ON 01910.Na Trial In Myelodysplastic SyndromE): Randomized Study of ON 01910.Na in Refractory Myelodysplastic Syndrome Patients With Excess Blasts

Onconova Therapeutics, Inc.

The Leukemia & Lymphoma Society

NCT01241500

77 study sites in the United States and Europe (Belgium, France, Germany, Italy, and Spain)

270 patients

Eligible patients are ≥ 18 years of age; have a Zubrod performance status of 0-2; have at least one cytopenia; have been diagnosed with MDS or CMML by French, American, British, or World Health Organization criteria (MDS patients must have 5-30% marrow blasts and white blood cell [WBC] count < 25 x 109/L; those with CMML must have 10-20% marrow blasts and a WBC count < 13 x 109/L); are ineligible for, have refused, or have relapsed after stem cell transplant; and have received at least six cycles of azacitidine or four cycles of decitabine within the last two years, and either did not respond to this therapy or responded and then relapsed. Eligible patients need to have had a stable WBC for four weeks prior to enrollment, have adequate renal and hepatic function (creatinine < 2.0 mg/dL, total bilirubin < 1.5 mg/dL, and transaminases < 2.5 times the upper limit of normal), should not receive other therapies for MDS except stable doses of filgrastim or an erythropoiesisstimulating agent, and have had the MDS/CMML diagnosis re-confirmed within six weeks of study entry.

Enrolled patients are randomized in 2:1 ratio to receive either open-label rigosertib (n=180) at a fixed dose of 1800 mg/24 hours, administered as a 72-hour continuous intravenous infusion every two weeks until week 16 and every four weeks thereafter, or best supportive care (BSC) (n=90). Although no cross-over is allowed in this study, patients randomized to BSC are permitted to receive low-dose cytarabine (LDAC) 20 mg/m² subcutaneously once daily for the first consecutive 14 days of each 28-day cycle, for up to four cycles, at the discretion of the treating investigator.

The primary objective of this study is to compare overall survival from the time of randomization to rigosertib or BSC/LDAC until death due to any cause. Interim analyses are planned, and final analysis will occur once there have been 223 deaths. Secondary outcome measures include comparisons of overall response rate (ORR) using 2006 Clinical Trials Corner International Working Group (IWG 2006) standardized response criteria for MDS, time to acute myeloid leukemia (AML) progression using a study-specific definition of progression, quality of life assessed using the EORTC QLQC30 measure, adverse event profiles including infections and bleeding events, and changes in chromosomal aneuploidy.

Patients with MDS or CMML for whom hypomethylating agents (HMAs) have failed have a poor prognosis, and there is currently no standard second-line therapeutic approach for this group. An analysis of 435 patients with MDS for whom azacitidine had failed indicated a median survival of only 5.6 months, with a two-year life expectancy of just 15 percent (Prébet T et al. J Clin Oncol. 2011;29:3322-7). While a select group of patients who were candidates for allogeneic stem cell transplant or a clinical trial lived longer than one year, patients receiving BSC/palliative care alone had a survival of only three months in the azacitidine failure study. Similarly poor outcomes are seen after failure of decitabine, with a median survival of 4.3 months in an MD Anderson series of 87 post-decitabine patients (Jabbour E et al. Cancer. 2010; 116:3830-4).

Rigosertib is a styryl sulfone multi-kinase inhibitor with  inhibitory effects against the phosphatidylinositol 3 kinase (PI3K) and the ability to induce oxidative stress (Chapman CM et al. Clin Cancer Res. 2012;18:1979-91). Rigosertib also induces arrest of mitosis at the G2-M phase that may be mediated through inhibition of Polo-like kinase 1, possibly indirectly (Chun AW et al. Cancer Chemother Pharmacol. 2009;65:177-86). Although only small numbers of patients with MDS were treated with rigosertib before embarking on the randomized trial, in some treated patients, the  proportion of both blasts and hematopoietic cells with chromosomal aneuploidy was reduced (Olnes MJ et al. Leuk Res. 2012;36:982-9). In a series of 60 patients with MDS enrolled in four phase I/II rigosertib trials, of whom 38 had previously received an HMA, eight patients (13%) experienced hematologic improvement, while among 51 patients with excess blasts, 16 (31%) had reduction in blast proportion by ≥ 50 percent and 20 (39%) experienced stability in the blast proportion for at least four to eight weeks (Raza A et al. Blood. ASH Annual Meeting Abstracts. 2011;118:3822). Fatigue and gastrointestinal upset (nausea, cramping, diarrhea) are the most commonly reported adverse events in rigosertib-treated patients.

New drugs for MDS are greatly needed, especially for higher-risk patients for whom HMAs have failed and stem cell transplant is not an option. Rigosertib appears to suppress MDS clones in some cases and may delay disease progression, including AML evolution, though true disease remission appears uncommon. Nonetheless, hematopoietic improvement is an important goal in MDS, as the most common causes of death include infection and hemorrhage.

Almost all patients with MDS will either fail to respond to an HMA or will eventually progress during HMA therapy. If rigosertib is shown to improve survival compared with BSC/LDAC in these patients for whom an HMA has failed, it is likely to become an established second-line therapy for higher-risk MDS in transplant-ineligible patients. While the frequent continuous intravenous administration that is necessary due to the short half-life of the current compound is inconvenient for patients, an oral formulation of rigosertib is in development (Raza A et al. J Clin Oncol. ASCO Meeting Abstracts. 2012;suppl;abstr:3081).

The clinical value of stable disease in MDS is currently unclear, but it has been hypothesized that a survival benefit could be achieved even in patients who do not experience blast reduction during active therapy, via a delay in clonal evolution and disease progression. This hypothesis remains unproven, and the rigosertib randomized trial will help test this assertion.