Hematological Oncology Hematol Oncol (2014) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hon.2137

Original Research Article

Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy Lewis R. Silverman1, Peter Greenberg2, Azra Raza3, Matthew J. Olnes4, James F. Holland1, Premkumar Reddy1, Manoj Maniar5 and Francois Wilhelm5* 1

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA Dept. of Medicine (Hematology), Stanford University Cancer Center, Stanford, CA, USA 3 Columbia University Medical Center, New York, NY, USA 4 Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA 5 Onconova Therapeutics Inc, Newtown, PA, USA 2

*Correspondence to: Francois Wilhelm, MD, PhD, Onconova Therapeutics Inc., 73 Route 31 North, Suite B, Pennington, NJ 08534. E-mail: [email protected]

Received 6 December 2013 Accepted 25 January 2014

Abstract Rigosertib (ON 01910.Na) is an inhibitor of the phosphoinositide 3-kinase and polo-like kinase pathways that induces mitotic arrest and apoptosis in neoplastic cells, while sparing normal cells. Our purpose is to summarize the clinical activity and safety of intravenous (IV) rigosertib delivered by an external ambulatory infusion pump in patients with refractory anemia with excess blasts-1, -2, or, -t myelodysplastic syndromes (MDS) following prior treatment with DNA methyltransferase (DNMT) inhibitors. A total of 39 patients with MDS who fulfilled these criteria were enrolled in four phase 1-2 clinical trials of IV rigosertib. Thirty five (88%) had higher risk disease according to the Revised International Prognostic Scoring System. Median overall survival for this group of 39 patients was 35 weeks. Of 30 evaluable patients with follow-up bone marrow biopsies, 12 (40%) achieved complete (n = 5) or partial (n = 7) bone marrow blast responses. In addition, 15 patients achieved stabilization of bone marrow blasts. One patient with a complete bone marrow response also achieved a complete cytogenetic response. A second patient with stable bone marrow blasts achieved a partial cytogenetic response. Two of the responding patients and three patients with stable disease had hematological improvements. Rigosertib-induced bone marrow blast decreases and stability appeared to be predictive of prolonged survival. IV rigosertib had a favorable safety profile without significant myelosuppression. Most common drug-related toxicities included fatigue, diarrhea, nausea, dysuria, and hematuria. In summary, IV rigosertib is well tolerated and has clinical activity in patients with higher risk MDS following DNMT inhibitor treatment. A multinational pivotal phase 3 randomized clinical trial of rigosertib versus best supportive care for patients with MDS with excess blasts following prior treatment with DNMT inhibitors (ONTIME: ON 01910.Na Trial In Myelodysplastic SyndromE) has recently completed enrollment. © 2014 The Authors. Hematological Oncology published by John Wiley & Sons, Ltd. Keywords: myelodysplastic syndromes; polo-like kinase; phosphatidylinositol 3-kinase; ON 01910.Na; rigosertib; DNA methyl transferase inhibitors

Introduction The myelodysplastic syndromes (MDS) are a heterogeneous group of myeloid neoplasms characterized by ineffective hematopoiesis and a propensity to transform to acute myeloid leukemia (AML) [1]. The main clinical manifestations of MDS include peripheral blood cytopenias, usually in the presence of a normo-cellular or hypercellular bone marrow with dysplastic cellular features [1–3]. Anemia often leads to transfusion dependence and

its attendant complications. Thrombocytopenia and neutropenia contribute to hemorrhagic events and increase infection risk [1], respectively. On the basis of the (Revised) International Prognostic Scoring System (IPSS-R), patients are stratified into risk categories with regard to their potential for progression to AML and survival [4–6]. A small minority of patients with higher risk MDS is considered for disease-modifying therapies such as allogeneic hematopoietic stem cell transplantation (HSCT) [7]. However, for the majority of patients

© 2014 The Authors. Hematological Oncology published by John Wiley & Sons, Ltd. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

L R Silverman et al.

who lack a suitable donor or who are not candidates for HSCT because of their age or comorbidities, treatment with DNA methyltransferase (DNMT) inhibitors, such as 5-azacitidine or decitabine, has become the standard of care [8,9]. DNMT inhibitors are beneficial for a subset of MDS patients, but others fail to respond. Moreover, the vast majority of patients relapse, even after an initial response. For patients who have not responded to, or have progressed after an initial response to DNMT inhibitors, and who are not candidates for HSCT, therapeutic options are limited. Most such patients receive only supportive care, including antibiotics, blood cell products, and erythropoiesis-stimulating agents [10]. These patients are at high risk for leukemic transformation and have a short median survival of less than 6 months [11,12]. Rigosertib (ON 01910.Na) is the sodium salt of (E)-2,4,6trimethoxystyryl-3-carboxymethylamino-4-methoxybenzyl sulfone, a member of a broader class of unsaturated sulfone kinase inhibitors developed by Onconova Therapeutics, Inc. [13]. These compounds allosterically inhibit substrate binding, a property that distinguishes them from adenosine triphosphate-competitive kinase inhibitors used as anticancer drugs. Treatment of malignant cells with rigosertib induces profound mitotic spindle abnormalities and abnormal centrosome localization, G2-M cell cycle phase arrest and mitotic catastrophe, culminating in apoptosis [14,15]. In terms of mechanism of action, rigosertib interferes with the phosphoinositide 3-kinase (PI-3K)/Akt, reactive oxygen species and Ras/Raf/polo-like kinase (PLK) signaling pathways. A unique feature of this compound is that, although it is broadly cytotoxic against malignant cells, it is remarkably non-toxic for non-neoplastic cells [13,14,16]. For this reason, this is a particularly attractive compound to test against neoplastic diseases of the bone marrow such as MDS and acute leukemia. Four phase 1-2 clinical trials of intravenous (IV) rigosertib delivered via external ambulatory infusion pump (EAIP) for patients with MDS and/or AML have been completed. Results of two of these studies have been published [17,18]. Because of their poor prognosis, there is particular interest in the efficacy of rigosertib for patients with higher risk MDS previously treated with DNMT inhibitors. A pooled analysis of the outcomes of such patients enrolled on the four trials is presented here.

Methods Clinical trials Four phase 1-2 clinical trials were conducted to evaluate the safety and efficacy of IV rigosertib delivered by EAIP to patients with MDS or refractory AML. Studies 07-H0225, 04-05, and 04-15 were standard open-label, single-

center, phase 1 dose escalation trials. Study 04-05 included a phase 2 expansion cohort at the recommended phase 2 dose. Study 04-17 was an open-label, single center, single-arm phase 2 trial. All four clinical trials were conducted in accordance with the ethical standards of the responsible institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 1983.

Eligibility criteria Each of the four trials had overlapping subject eligibility criteria, and treatment doses and schedules. Study 07-H0225 included adult patients who had a World Health Organization classification of refractory anemia with excess blasts (RAEB)-1 or -2 or IPSS intermediate-to-high risk MDS, or trisomy 8 AML. Study 04-05 included adult patients with refractory myeloid leukemia (including chronic myelomonocytic leukemia), with MDS unresponsive to DNMT inhibitors or with IPSS intermediate-2 or high risk MDS, who had relapsed after DNMT inhibitor treatment. Study 04-15 included adult patients with AML or MDS. Study 04-17 included adult patients with trisomy 8 MDS or those classified as having IPSS intermediate or high risk MDS who had failed or were intolerant of DNMT inhibitors. In all four studies, patients had to have failed to respond to, relapsed following, or opted out of bone marrow transplantation. All patients were required to have transfusion-dependent anemia and a baseline Eastern Cooperative Oncology Group performance status of ≤2. All patients had to have reviewed and signed informed consent according to the guidelines of their respective Institutional Review Boards prior to study entry.

Treatment plans Each of the four studies used slightly different dosing and escalation schedules. Study 07-H-0225 was a standard phase 1 dose escalation trial with three cohorts receiving rigosertib by EAIP with increases in drug exposure (either by dose or infusion duration) with each successive cohort. Infusions of rigosertib by EAIP were administered over 3–5 days every 2 weeks. Study 04-05 was a phase 1 dose escalation study of rigosertib administered every 2 weeks with increasing duration of an initial 3-day EAIP infusion to a maximum of six consecutive days. Studies 04-15 and 04-17 were phase 1-2 and phase 2 single-arm studies, respectively, to assess the safety and efficacy of 2-day dosing of rigosertib by EAIP administered once a week for 3 weeks on a 4-week cycle. After 16 patients on study 04-15 had been treated according to this schedule, the rigosertib dosing was amended to a 2400 mg/24 h by 3-

© 2014 The Authors. Hematological Oncology published by John Wiley & Sons, Ltd.

Hematol Oncol (2014) DOI: 10.1002/hon

Rigosertib treatment of refractory higher risk MDS

day EAIP infusion every 2 weeks and then further amended to 1800 mg/24 h. Similarly, on study 04-17, after the first three patients had been treated, the rigosertib dosing was amended to a schedule of 1800 mg/24 h by 3-day EAIP infusions every 2 weeks.

Results Patient population Because of their limited treatment options and poor prognosis, we focused on the effects of rigosertib on subjects with RAEB MDS who had previously received DNMT inhibitors. A total of 39 evaluable patients fulfilling these criteria were enrolled onto the four rigosertib trials (Table 1). The majority (69%) of these patients were men, and the median age was 75 years (range 59–87). All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 at baseline. Approximately, one-third each of patients had RAEB-1, RAEB-2, or RAEB-t. In almost all cases, the disease was in the revised IPSS high or very high risk (89%) prognostic categories. Two-thirds (67%) of patients had previously received azacitidine, 20% had received decitabine, and 13% had been treated with both agents. The time intervals between DNMT inhibitor treatment and the start of rigosertib treatment ranged from 8 to 124 weeks (median: 23 weeks). The majority of patients (n = 33, 85%) received either 3-day EAIP infusions of rigosertib every 2 weeks or weekly 2-day EAIP infusions for 3 out of 4 weeks of a 4-week cycle. The remaining six (15%) patients received either 4-day or 5-day EAIP infusions.

Efficacy of intravenous rigosertib following DNA methyltransferase inhibitor treatment in higher risk myelodysplastic syndromes All 39 patients were evaluable for hematological improvement. Thirty (77%) patients had at least one follow-up bone marrow examination (4 to 8 weeks after initiation of therapy), thereby allowing early assessment of bone marrow blast responses. Nine (23%) patients were evaluable for cytogenetic responses. Clinical activity was observed in nine patients with RAEB-1, 11 patients with RAEB-2, and seven patients with RAEB-t. Five of 30 (17%) evaluable subjects achieved a bone marrow complete response (Table 2, Figures 1 and 2A). One of these patients also achieved a complete cytogenetic response and a hematological improvement in platelet count (Table 2). Seven (23%) additional subjects achieved a partial bone marrow response (bone marrow blasts decreased to ≤50% of the pretreatment value but still >5%) (Figure 2A). One of

Table 1. Patient demographics Category

Number (%)

Gender Male Female Age (years) 8 weeks) was seen in 15 (50%) patients (Figure 2A). One patient with trisomy 8 MDS, whose bone marrow blasts remained stable, achieved a partial cytogenetic response. Finally, two additional patients with stable bone marrow blasts achieved hematological improvements, one of both erythrocyte and neutrophil counts, and one of the platelet count (Table 2). Only three (10%) patients progressed; that

© 2014 The Authors. Hematological Oncology published by John Wiley & Sons, Ltd.

Hematol Oncol (2014) DOI: 10.1002/hon

L R Silverman et al.

Table 2. Clinical responses to intravenous rigosertib WHO/FAB class

RAEB-2 RAEB-2 RAEB-1 RAEB-1 RAEB-t RAEB-t RAEB-2 RAEB-t RAEB-1 RAEB-1 RAEB-2 RAEB-2 RAEB-t RAEB-2 RAEB-2 RAEB-1 RAEB-t RAEB-2 RAEB-t RAEB-2 RAEB-t RAEB-1 RAEB-2 RAEB-2 RAEB-1 RAEB-1 RAEB-1

2

IPSS-R

Rigosertib dose (mg/(m )/d)

BM

HI

Cytogenetic response

Survival (weeks)

Very high Very high High High Intermediate Very high Very high High Intermediate High Very high Very high Very high Very high Very high High High Very high High High High Intermediate Very high High High Very high Very high

1050* × 4 1050* × 3 1800+ × 3 1800+ × 3 1800+ × 3 1375* × 3 1375* × 3 2400+ × 3 800* × 2 1800+ × 3 1800+ × 3 800* × 3 800* × 2 1500* × 2 1500* × 2 2400+ × 3 800* × 2 800* × 2 1800+ × 3 1800+ × 3 1800+ × 3 1800+ × 3 800* × 5 800* × 5 1000* × 5 1000* × 5 1000* × 5

mCR mCR mCR mCR mCR mPR mPR mPR mPR mPR mPR mPR SD SD SD SD SD SD SD SD SD SD SD SD SD SD SD

P

Complete No change NA NA NA No change No change NA NA NA NA 40% NA NA NA NA NA NA NA NA NA NA NA NA Partial No change NA

68 71 36 142+ 37 20 58 21 44 103 19 17 40 13 28 22 74 49 53 65 15 36 35 146 114 47 31

N/P N

E/N P

Details of the 27 of 39 (69%) patients who appeared to derive clinical benefit from treatment with intravenous rigosertib. Five patients achieved mCR (bone marrow complete response; ≤5% bone marrow blasts). One of these patients also achieved a cytogenetic complete response and a hematological improvement in platelet count as defined by the International Working Group [28]. Of the seven patients who achieved a partial bone marrow response (mPR; bone marrow blasts decreased to ≤50% of the pretreatment value but still >5%), one also experienced hematological improvement (neutrophils and platelets) and a 40% reduction in abnormal metaphases. Fifteen patients achieved stable disease (SD; failure to achieve at least mPR, but no evidence of progression for >8 weeks). Three of these patients also achieved hematological improvements, and one patient achieved a partial cytogenetic response. *: mg/m2/24 h; +: mg/24 h. WHO, World Health Organization; FAB, French–American–British; IPSS-R, Revised International Prognostic Scoring System; BM, bone marrow; HI, hematological improvements; P, platelet count; E, erythrocyte count; N, neutrophil count; RAEB, refractory anemia with excess blasts; NA: not assessed.

is, their bone marrow blasts increased >50%. In summary, rigosertib treatment was associated with clinical activity, including bone marrow blast control, hematological improvement, and/or cytogenetic responses in 27 of 39 (69%) patients on an intent-to-treat (ITT) basis. Overall, a greater proportion of patients receiving 3-day EAIP infusions of rigosertib every 2 weeks achieved bone marrow blast responses and hematological improvements than patients receiving weekly 2-day infusions for 3 weeks on a 4-week cycle (Table 3). Extending the duration of administration beyond 3 days (either by increasing the duration from 3 to 5 days within patients or between patient cohorts) was not associated with further improvements of bone marrow blast responses (data not shown). The rigosertib dosing schedule of 1800 mg/24 hr × 3 days every 2 weeks was associated with clinical activity in 9 of 12 (75%) patients, and this group included three of the five patients who achieved a bone marrow complete response and

two of the five patients who achieved hematological improvement (Table 3, Figure 2B). On the basis of these results, this dosing schedule was chosen for the subsequent pivotal randomized phase 3 trial of rigosertib for patients with MDS with excess blasts following prior treatment with DNMT inhibitors.

Survival analysis The median overall survival of the 39 patients with RAEB1, -2, and -t previously treated with DNMT inhibitors was 35 weeks on an ITT basis. One long-term survivor was still alive at 142 weeks at the time of analysis. Moreover, a bone marrow blast response or stabilization at 4–8 weeks was associated with a fourfold prolongation in median survival (40 versus 10 weeks, HR = 0.32; logrank p = 0.0003) compared with patients who progressed or were not

© 2014 The Authors. Hematological Oncology published by John Wiley & Sons, Ltd.

Hematol Oncol (2014) DOI: 10.1002/hon

Rigosertib treatment of refractory higher risk MDS

Figure 1. Bone marrow blast responses for the five patients who achieved a bone marrow complete response. The time course of bone marrow blast responses of the five patients who achieved a bone marrow complete response are shown.

assessed. A landmark survival analysis conducted at 8 weeks was statistically significant (HR = 0.40; p = 0.017). These data suggest that early bone marrow response is a biomarker of rigosertib activity predicting survival (Figure 3A). Figure 3B also illustrates the relationship between best bone marrow blast responses or stability and overall survival.

Safety profile of intravenous rigosertib in myelodysplastic syndromes and acute myeloid leukemia A total of 71 patients enrolled on the four clinical trials were evaluable for safety. Toxicity was scored according to the National Cancer Institute Common Terminology

Criteria for Adverse Events (version 3.0) [19]. Adverse events (AEs) that were considered possibly, probably, or definitely attributable to rigosertib and that were reported in at least 5% of patients are summarized in Figure 4. The most frequent drug-related AEs included fatigue, gastrointestinal, and urinary symptoms. Grade 3-4 drug-related AEs reported in three or more patients included urinary symptoms and thrombocytopenia. Serious AEs that were deemed possibly, probably, or definitely related to rigosertib and were observed in two or more patients included hematuria, pollakiuria, and dyspnea. It is important to note that AEs related to myelosuppression were relatively uncommon (Figure 4). Similarly, serial bone marrow biopsies during the period of treatment with rigosertib revealed that overall bone marrow

© 2014 The Authors. Hematological Oncology published by John Wiley & Sons, Ltd.

Hematol Oncol (2014) DOI: 10.1002/hon

L R Silverman et al.

Figure 2. Best bone marrow blast responses in RAEB-1, -2, and -t patients previously treated with DNA methyltransferase inhibitors. (A) Among the patients with refractory anemia with excess blasts (RAEB)-1, -2, or -t previously treated with DNA methyltransferase inhibitors, stabilization or a ≥50% decrease in bone marrow blasts was seen in 27 (69%) patients across all three myelodysplastic syndrome categories. Blue: RAEB-1; red: RAEB-2; yellow: RAEB-t. (B) Best bone marrow blast decreases in the subset of 10 evaluable patients who were treated with the rigosertib dosing schedule used in the pivotal phase III trial.

cellularity did not significantly change (data not shown). The lack of myelosuppression by rigosertib might represent a distinct advantage given the compromised bone marrow function of patients with MDS following DNMT therapy.

Discussion Rigosertib, a dual PI-3K and PLK pathway inhibitor, has promising clinical activity as a single agent for patients with higher risk MDS who have been previously treated with DNMT inhibitors. Drug activity was demonstrated in over two-thirds of patients, as evidenced by bone

marrow blast decreases or stabilization, cytogenetic responses, and/or hematological improvements (Table 2). Median survival of the entire group of 39 patients on an ITT basis was 35 weeks. The rigosertib dosing schedule of 1800 mg/24 hr × 3 days given via EAIP every other week was associated with clinical activity in 9 of 12 patients (Table 3). This dose and schedule of rigosertib were selected for the subsequent pivotal randomized phase 3 trial [ON 01910.Na Trial In Myelodysplastic Syndrome (ONTIME)] (Figure 5). An early decrease in bone marrow blast count or blast count stabilization was associated with improved survival of patients who had been previously treated with DNMT inhibitors (Figure 3) and would qualify as a predictive

© 2014 The Authors. Hematological Oncology published by John Wiley & Sons, Ltd.

Hematol Oncol (2014) DOI: 10.1002/hon

Rigosertib treatment of refractory higher risk MDS

Table 3. Responses to intravenous rigosertib as a function of dose and schedule

All patients All 2-day infusions weekly 3 out of 4 weeks All 3-day infusions every 2 weeks 1800 mg/24 hr × 3 days every 2 weeks

n

mCR

mPR

SD

HI

39 11 22 12

5 0 4 3

9 1 6 2

11 5 5 4

5 1 3 2

Overall clinical benefit rate

27 6 15 9

(69%) (55%) (68%) (75%)

Overall, patients receiving 3-day infusions of rigosertib every 2 weeks achieved the best bone marrow blast responses and hematological improvements. A dosing schedule of 1800 mg/24 hr × 3 days every 2 weeks was selected for the subsequent pivotal phase 3 randomized trial (Figure 5). mCR, bone marrow complete response; mPR, partial bone marrow response; SD, stable disease, HI, hematological improvements.

Figure 3. Survival and relationship with bone marrow blast status. (A) Median overall survival of patients with refractory anemia with excess blasts-1, -2, -t and previously treated with DNA methyltransferase inhibitors was 35 weeks. Maturity index (number of deaths/total number of patients): 38/39 (97%). Median survival of non-progressing subjects (bone marrow complete response, partial bone marrow response, stable disease) 4 to 8 weeks after starting rigosertib treatment was four times as long as survival of patients with progressive disease (PD) or no assessment (NA) of bone marrow response (40 versus 10 weeks; HR = 0.32; Logrank p = 0.0003). (B) Overall survival (weeks) of the 38 refractory anemia with excess blasts-1, -2, and -t patients treated with intravenous rigosertib following DNA methyltransferase inhibitor therapy who had died at the time of this analysis as a function of bone marrow best response.

biomarker of rigosertib efficacy. Early blast clearance is a recognized predictor of survival of patients with AML [20]. Several recent studies illustrate the predictive power

Figure 4. Safety of intravenous rigosertib. Summary of drug-related adverse events (AEs) of any grade reported in ≥5% of 71 safety-evaluable patients (blue), all drug-related grade 3-4 AEs (red), and all drug-related serious AEs (green). Fatigue, nausea, diarrhea, dysuria, and hematuria were the only drug-related AEs that occurred in over 10% of patients.

of bone marrow blast responses in MDS [21–23]. In the largest of these studies, Gore et al. [22] reported that bone marrow responses as well as stable disease correlated with improved survival. Bone marrow blast response is one of the secondary endpoints that is being evaluated in the phase 3 ONTIME pivotal trial of IV rigosertib for patients with MDS with excess blasts previously treated with DNMT inhibitors (Figure 5). Intravenous rigosertib was well tolerated and, most importantly, was not associated with significant myelosuppression, a benefit that is particularly important in the

© 2014 The Authors. Hematological Oncology published by John Wiley & Sons, Ltd.

Hematol Oncol (2014) DOI: 10.1002/hon

L R Silverman et al.

Figure 5. Schema of the pivotal phase 3 trial of rigosertib in myelodysplastic syndromes (ONTIME: ON 01910.Na Trial In Myelodysplastic SyndromE). Onconova has conducted a pivotal randomized phase 3 trial of intravenous rigosertib for patients with de novo or secondary myelodysplastic syndromes (refractory anemia with excess blasts or chronic myelomonocytic leukemia) who had failed to respond to, became intolerant of, or progressed after treatment with azacitidine and/or decitabine. The primary endpoint is overall survival. Secondary endpoints include the overall clinical response (complete remission, partial remission), bone marrow blast responses, hematological improvements and cytogenetic responses as defined by the International Working Group, transition to leukemia, quality of life and the incidence of infections and bleeding episodes.

MDS patient population with limited functional bone marrow reserve. Grade 3-4 drug-related toxicity was uncommon. Only fatigue, gastrointestinal, and urinary symptoms of any grade attributable to rigosertib occurred in more that 10% of subjects. Grade ≥2 urinary toxicity could be mitigated by holding rigosertib until toxicity returned to grade 1 or less and treatment with vigorous hydration (~2 L water/day) and bicarbonate tablets as needed. One of the objectives of the dose escalation trials was to determine whether extended exposure to biologically effective levels of rigosertib was achievable in MDS patients. Pharmacodynamic effects of rigosertib have been investigated in preclinical model systems including single-cell analysis of leukemic cell lines [24] as well as patient bone marrow cells treated with rigosertib ex vivo [17]. These studies evaluated markers relevant to G2/M arrest (cyclin B accumulation, histone H3, and cyclin-dependent kinase 1 phosphorylation). These markers were maximally inhibited at doses of rigosertib in the 0.3- to 1-μM range. In cytotoxicity studies conducted in myeloid neoplastic cell lines, the IC50 of rigosertib ranged from 0.1 to 0.3 μM [25,26]. Another marker particularly relevant to MDS, cyclin D1 level, was also explored in both preclinical and clinical studies [17]. Cyclin D1 messenger RNA levels were reduced in neoplastic bone marrow cells treated

ex vivo with sub-micromolar concentrations of rigosertib. Collectively, these studies suggest that targets relevant to the activity of rigosertib can be effectively inhibited in the high nanomolar to low micromolar range. In fact, pharmacokinetic studies performed on patients receiving 800 mg/m2 rigosertib by EAIP for 3 or 5 days demonstrated that steady-state plasma levels of rigosertib were maintained at approximately 6 μM during the course of the infusion [17]. The rigosertib clinical trial 07-H-0225 enrolled patients with trisomy 8 MDS, which is associated with elevated levels of cyclin D1, c-myc, and survivin in the malignant CD34+ cells. Proof of concept for pharmacodynamic activity of rigosertib was obtained from the first patients enrolled on this study [17]. Cyclin D1 levels in peripheral blood CD34+ cells were monitored in real time in three patients who achieved a hematological response [17]. Treatment with rigosertib decreased the fraction of CD34+ cells expressing cyclin D1 in all three of these patients up to 128 hours after the end of the rigosertib infusion. In contrast, cyclin D1 expression did not change in patients who did not achieve a clinical response. In trial 04-17, Seetharam et al. [18] used a nano-fluidic proteomic immunoassay to analyze intracellular phosphorylation of Akt2 and its isoforms in CD34+ bone marrow cells from five

© 2014 The Authors. Hematological Oncology published by John Wiley & Sons, Ltd.

Hematol Oncol (2014) DOI: 10.1002/hon

Rigosertib treatment of refractory higher risk MDS

patients. In three clinical responders, Akt2 phosphorylation decreased following cycle 1 of rigosertib. In contrast, in two patients who progressed on treatment, Akt2 phosphorylation did not decrease at all or increased post therapy [18]. In aggregate, these preliminary results suggest that treatment with rigosertib may be associated with rapid reductions in cyclin D1 and phospho-Akt2 levels in the malignant cell population. Thus, these parameters could potentially be used as pharmacodynamic markers of rigosertib action. On the basis of the encouraging results of these four studies of IV rigosertib for patients with MDS, Onconova Therapeutics, Inc. has completed accrual to a pivotal multi-center randomized phase 3 trial of IV rigosertib (ONTIME) for patients with de novo or secondary MDS who had failed to respond to, were intolerant of, or progressed after treatment with azacitidine and/or decitabine (Figure 5). Patients with a diagnosis of RAEB-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukemia were eligible. The study excluded RAEB-t patients with proliferative AML. The goal was to accrue 270 patients randomized 1:2 to best supportive care (BSC) only with or without low-dose cytosine arabinoside at the investigator’s discretion, versus BSC plus IV rigosertib administered until disease progression or death. Patients were stratified by the percentage of bone marrow blasts. Growth factors, transfusions, and hydroxyurea (short term to treat blast crisis) were allowed in both groups if clinically justified. The primary endpoint is overall survival. Secondary endpoints include the overall clinical response rate (complete remission, partial remission), bone marrow blast responses, hematological improvements and cytogenetic responses, transition to leukemia, quality of life, and the incidence of infections and bleeding episodes. Results of this trial will be available in 2014.

Conclusion In summary, rigosertib, a dual PI-3K and PLK inhibitor, induces mitotic arrest followed by apoptosis in malignant (pre)leukemic cells while largely sparing normal bone marrow cells. In humans, IV rigosertib has a favorable safety profile and is clinically active against higher risk MDS previously treated with DNMT inhibitors, inducing early bone marrow blast responses or stabilization that appears to be predictive of prolonged survival. Thus, rigosertib appears to be active and well tolerated in a setting in which therapeutic options are limited. These studies also helped define the optimal dose and schedule that provided pharmacodynamic levels of single-agent rigosertib for further exploration. These encouraging results led to the initiation of a pivotal phase 3 international multicenter randomized clinical trial of IV rigosertib for patients with de novo or secondary MDS following prior treatment with DNMT inhibitors.

Conf lict of interest Onconova Therapeutics, Inc., the manufacturer of rigosertib, funded the four clinical trials discussed in this report. In addition, this work was supported in part by the Intramural Program of the Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health. The clinical investigators and the study sponsor, Onconova Therapeutics, Inc., played a key role in study design, in the collection, analysis and interpretation of data, in the writing of the report and in the decision to submit the report for publication. Dr. J. F Holland has served as consultant to Onconova Therapeutics, Inc. Dr. P. Reddy is the scientific founder of Onconova Therapeutics, Inc. Drs. M. Maniar and F. Wilhelm are employees of Onconova Therapeutics, Inc. Clinical investigators disclosed their potential conflicts to study participants.

Acknowledgements We wish to dedicate this paper to the memory of Dr. Elaine Sloand, who was a pioneer in studying apoptotic barriers in MDS and who initiated the first clinical study of rigosertib in MDS. In addition, we wish to acknowledge the contribution of Dr. Isabelle Darnis-Wilhelm who analyzed overall rigosertib safety data. Most importantly, we acknowledge the patients who volunteered to participate in these clinical trials and the physicians and nurses who cared for these patients.

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© 2014 The Authors. Hematological Oncology published by John Wiley & Sons, Ltd.

Hematol Oncol (2014) DOI: 10.1002/hon

L R Silverman et al.

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Hematol Oncol (2014) DOI: 10.1002/hon

Clinical activity and safety of the dual pathway inhibitor rigosertib for higher risk myelodysplastic syndromes following DNA methyltransferase inhibitor therapy.

Rigosertib (ON 01910.Na) is an inhibitor of the phosphoinositide 3-kinase and polo-like kinase pathways that induces mitotic arrest and apoptosis in n...
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