The safety and efficacy of rigosertib in the treatment of myelodysplastic syndromes

Shyamala C. Navada & Lewis R. Silverman

To cite this article: Shyamala C. Navada & Lewis R. Silverman (2016): The safety and efficacy of rigosertib in the treatment of myelodysplastic syndromes, Expert Review of Anticancer Therapy, DOI: 10.1080/14737140.2016.1209413
To link to this article: http://dx.doi.org/10.1080/14737140.2016.1209413

Accepted author version posted online: 11 Jul 2016.
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EXPERT REVIEW OF ANTICANCER THERAPY, 2016

http://dx.doi.org/10.1080/14737140.2016.1209413

DRUG PROFILE
The safety and efficacy of rigosertib in the treatment of myelodysplastic syndromes
Shyamala C. Navada and Lewis R. Silverman
Tisch Cancer Institute, Division of Hematology/Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

ABSTRACT
Introduction: Hypomethylating agents (HMAs) are the standard of care for patients with higher-risk myelodysplastic syndromes (MDS), but patients who relapse or are refractory have a poor prognosis with an estimated survival of 4–6 months. Rigosertib, a Ras mimetic that inhibits the phophoinositide 3- kinase and polo-like kinase pathways, has been tested in patients with higher-risk MDS following treatment with HMAs, where there are no approved second-line therapies.
Areas covered: This review will provide an overview of rigosertib, including safety and efficacy demonstrated in clinical trials.
Expert commentary: There is an urgent need for new treatment options for patients who have failed or progressed on HMAs. Rigosertib is currently undergoing testing as a single agent in certain subsets of higher-risk MDS patients as well as in combination with azacitidine, where preliminary data show efficacy in patients with de novo MDS as well as HMA failures.
ARTICLE HISTORY
Received 18 April 2016
Accepted 1 July 2016 Published online
15 July 2016
KEYWORDS
Myelodysplastic syndromes; rigosertib; polo-like kinase; phosphatidylinositol
3-kinase; ON 0910.Na; hypomethylating agents; DNA methyltransferase inhibitors; Ras-binding domain

⦁ Introduction
The myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow disorders characterized by ineffective hematopoiesis and risk of transformation to acute myeloid leukemia (AML) [1,2]. MDS is predominantly a disease of older patients with a median age of 65 years, and the inci- dence in this patient population is between 75 and 162 per 100,000 and growing. It is estimated that the prevalence of MDS in the United States is somewhere between 60,000 and 170,000 and projected to rise as the population ages [3].
The majority of patients with higher-risk MDS (classified by the International Prognostic Scoring System [IPSS] [4] or Revised IPSS [IPSS-R] [5]) die from progressive bone marrow failure within 1 to 2 years due to infection or hemorrhage. The IPSS-R stratifies patients into risk groups according to five prognostic variables: bone marrow blasts, cytogenetics, hemo- globin, platelets, and neutrophils; this in turn predicts progres- sion to AML and survival.
Allogeneic stem cell transplant is the only curative approach for patients with MDS. However, the majority of patients either lack a suitable donor or are not candidates due to age or comorbidities [6].
Hypomethylating agents (HMAs; i.e., azacitidine and deci- tabine) are the standard of care for patients with higher-risk MDS [7–9]. However, only azacitidine has been shown to extend survival in a randomized trial compared to best sup- portive care (BSC) [10–13]. Patients who have relapsed or are refractory to HMAs have a poor prognosis with a median survival of 4–6 months [14,15]. There are no approved sec- ond-line therapies for this patient population.
Rigosertib (ON 01910.Na) is a small molecule inhibitor of protein and acts as a Ras-mimetic binding to the Ras-binding domain of multiple Ras effector proteins (including the phos- phoinositide-3-kinase (PI3K) and polo-like kinase (PLK) path- ways) that induces mitotic arrest and apoptosis in neoplastic cells while sparing normal cells. It is well tolerated and demon- strated activity in phase I/II trials in higher-risk MDS patients failing HMA therapy [16]. It is the first drug that was tested in a multicenter, randomized, phase III study in patients with higher-risk MDS whose disease had progressed, failed, or relapsed on azacitidine or decitabine [17]. This review dis- cusses the mechanism of action of rigosertib, safety profile, results of prior clinical trials, and the future of drug development.

⦁ Overview of market
Outcomes after HMA failure remain poor and represent an unmet need in the treatment of MDS. Treatment failure can be divided into primary HMA failure, characterized by no response or progression during initial treatment, versus sec- ondary failure, defined as relapse after response [14]. Stable disease is controversial, defined as no increase in myeloblasts combined with the absence of hematologic improvement or progression by International Working Group (IWG) criteria [18]. Since there are no standard therapies after HMA failure, investigational therapy is often recommended. In the absence of clinical trials, limited options are available with low success rates. One such approach is HMA crossover, i.e., sequential treatment with another azanuceloside. In one study, 14 patients with MDS post-azacitidine failure/intolerance were treated with decitabine with an overall response rate of 28%

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CONTACT Shyamala C. Navada [email protected] Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, Box 1079, New York, NY, USA
© 2016 Informa UK Limited, trading as Taylor & Francis Group

Table 1. Summary of drugs in development for myelodysplastic syndrome (MDS) patients after hypomethylating agent (HMA) failure.

Class Agent

Nucleoside analogues Clofarabine and sapacitabine
Topoisomerase II inhibitors Vosaroxin
Kinase inhibitors Rigosertib, erlotinib, and dasatinib Next-generation hypomethylating agents SGI-110 and oral azacitidine Hedgehog inhibitor PF-04449913
PDL-1 inhibitor MEDI 4736
Aminopeptidase inhibitor Tosedostat
Thrombopoietin mimetic Eltrombopag PDL-1: programmed death-ligand 1.

[19]. Another study demonstrated that 19% of patients responded to decitabine after azacitidine failure (n = 21), and 40% responded to azacitidine after decitabine failure (n = 10) [20]. However, these studies were retrospective with limited numbers of patients and included patients who were intoler- ant to treatment. An alternative strategy is to administer lower doses of chemotherapy agents, such as cytarabine, melphalan, etoposide, and topotecan, although the response rates have been low with these agents [21].
Several agents have been tested in MDS patients after HMA failure and are in clinical development. These are summarized in Table 1.

⦁ Rigosertib (introduction to drug: chemistry/ pharmacodynamics/pharmacokinetics)
Rigosertib is the sodium salt of (E)-2,4,6-trimethoxystyryl-3- carboxymethylamino-4-methoxybenzyl sulfone, an unsatu- rated sulfone kinase inhibitor developed by Onconova Therapeutics, Inc., Newtown, PA, USA [22] (Figure 1). Rigosertib is a Ras-mimetic that inhibits the PI3K and PLK cellular signaling pathways by binding directly to the Ras-

Figure 1. Chemical structure of rigosertib.

binding domain found in Ras effector proteins [23] (Figure 2). It induces mitotic spindle abnormalities and abnor- mal centrosome localization, G2-M cell cycle phase arrest, and mitotic catastrophe, resulting in apoptosis [24,25].
Early studies suggest that treatment with rigosertib down- regulates translation of cyclin D and cMyc proteins [26]. Excess cyclin D was associated with the antiapoptotic state in MDS patients who had trisomy 8. Therefore, rigosertib was tested on ex vivo cultures of bone marrow from MDS patients with trisomy 8, and significant decreases in the number and proportion of aneuploid cells with the abnormality were detected [27].
Pharmacodynamic effects of rigosertib have also been stu- died in preclinical models, including single-cell analysis of leukemic cell lines as well as patient bone marrow cells treated with rigosertib. These studies evaluated markers associated with G2/M arrest, including cyclin B accumulation, histone H3, and cyclin-dependent kinase 1 phosphorylation. These markers were maximally inhibited at doses of rigosertib in the 0.3–1-µM range. In cytotoxic studies done in malignant

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Figure 2. Rigosertib mechanism of action. Reprinted from [19] with permission from Elsevier. RTK = receptor tyrosine kinase.

myeloid cell lines, the half maximal inhibitory concentration (IC50) of rigosertib ranged from 0.1 to 0.3 µM. These studies

Table 2. Responses to intravenous rigosertib in phase I/II studies.

% Response

suggested that rigosertib could effectively inhibit its targets in
n mCR mPR SD HI
(%)

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the high nanomolar to low micromolar range [27].
Preclinical pharmacokinetic studies indicated that rigosertib is rapidly cleared from the plasma following intravenous (IV) administration with a short elimination half-life. Biliary excre- tion was the predominant route of elimination. However, rigo- sertib did not appear to be extensively metabolized in vivo. Given the short half-life and rapid clearance of the drug, it was decided to initiate phase I trials using administration by con- tinuous IV (CIV) infusion [28]. Pharmacokinetic studies on patients showed that plasma levels of rigosertib plateaued rapidly when the drug was administered by CIV infusion and remained at steady state throughout the infusion. In patients receiving 800 mg/m2 of CIV infusion rigosertib for 3 or 5 days, steady-state plasma levels were maintained at approximately 6 µM during the course of infusion [27].
Rigosertib has also been tested in the oral formulation in MDS patients, although in fewer patients than the IV formula- tion. Drug exposure increased with escalating oral doses. Oral rigosertib was rapidly absorbed following a single fasting dose (Tmax ~1 h). Systemic exposure increased in a linear and dose- proportional manner over the range of 70–700 mg. Elimination half-life from plasma (2.79 ± 1.23 h) was similar to IV dosing (3.25 ± 0.97 h). Mean absolute oral bioavailability ranged from 13.9% (fed) to 34.8% (fasting) in patients treated with the recommended dose of 560 mg. The rate and extent of rigosertib absorption decreased with food intake [29].

⦁ Clinical efficacy
IV rigosertib was tested in four phase I to II clinical trials in patients with MDS or refractory AML [16]. Three of the studies (07-H-0225, 04-05, and 04-15) were open-label, single-center, phase I, dose-escalation trials. Study 04-05 included a phase II expansion cohort. Study 04-17 was an open-label, single-cen- ter phase II trial. Each of the trials had overlapping eligibility criteria with slightly different dosing and escalation schedules [16,26,30].
These four studies included 39 MDS patients who had previously received HMA therapy. Thirty-five (88%) of these patients had higher-risk disease according to the IPSS-R [5]. Median age was 75 years, and 69% of patients were male. Sixty-seven percent of patients received prior azacitidine, 20% received prior decitabine, and 13% had been treated with both HMAs. Eighty-five percent of patients received either a 3-day CIV infusion of rigosertib every 2 weeks or weekly 2-day CIV infusions for 3 out of 4 weeks. The remaining 15% received either 4- or 5-day CIV infusions.
Of 30 evaluable patients, 12 (40%) achieved a bone marrow blast response. Five patients achieved a marrow complete response (mCR) per IWG criteria. Seven patients had a marrow partial response (mPR), defined as a reduction in bone marrow blasts to ≤50% of the pretreatment value but still >5%. Fifteen patients (50%) achieved stabilization of bone marrow blasts, i.e., failure of marrow response but no evidence of progression for >8 weeks. Five patients achieved hematological improve- ment, two who had also achieved a marrow response, and
All patients 39 5 9 11 5 27 (69)
3-day CIV infusion Q 2 weeks 22 4 6 5 3 15 (68)
2-day CIV weekly 3 out of 4 weeks 11 0 1 5 1 6 (55)

mCR: marrow complete response; mPR: partial bone marrow response; SD: stable disease; HI: hematologic improvement; CIV: continuous intravenous.

three with stable bone marrow blasts (Table 2). One patient with an mCR also had a complete cytogenetic response, and a second patient with stable bone marrow blasts had a partial cytogenetic response [16].
A greater number of responders received 3-day CIV infu- sions of rigosertib every 2 weeks compared to weekly 2-day infusions for 3 weeks of a 4-week cycle. Extending the dura- tion beyond 3 days was not associated with further improve- ment of bone marrow blast responses. The dosing schedule of 1800 mg/24 h × 3 days every 2 weeks produced clinical activity in 9 of 12 (75%) patients; given the higher percentage of responders in this group, this was the dose chosen for the randomized phase III trial.
Median overall survival for these 39 patients was 35 weeks on an intent-to-treat basis. A bone marrow blast response or stabilization at 4–8 weeks was associated with an improve- ment in overall survival (40 versus 10 weeks, p = .0003) com- pared with those who progressed or did not have a follow-up bone marrow assessment.
Rigosertib has also been tested in the oral formulation with phase I results demonstrating clinical activity. Overall, 37 patients were treated with a median age of 74 years. Seventy-three percent of patients had received prior HMA therapy. Median duration of treatment was 15 weeks. Two patients with refractory anemia with excess blasts had mCR. Four patients each achieved transfusion independence and hematological improvements [29].
Oral rigosertib was also tested in a randomized, two-arm study in lower-risk transfusion-dependent MDS patients requiring at least 4 units of red cells over 8 weeks. Patients received the recommended phase II dose of 560 mg twice daily. This was modified to 560 mg in the morning and 280 mg in the afternoon to mitigate urinary toxicity. Of 33 patients on intermittent dosing (2 out of 3 weeks) treated for at least 8 consecutive weeks, 15 (45%) achieved transfusion indepen- dence lasting a median of 17 weeks. Intent-to-treat analysis revealed 17/48 (35%) of patients achieved transfusion inde- pendence [31]. Final results of this study have not been con- firmed or published to date.
Given encouraging results from the above studies, a phase III, multicenter randomized trial of IV rigosertib versus BSC (which could include low-dose cytarabine) was completed in patients with de novo or secondary MDS with excess blasts who had failed to respond, were intolerant of, or progressed after treatment with HMA therapy [17]. The primary end point of the study was overall survival. The trial was conducted in 74 centers in Europe and the United States. Two-thirds of patients were randomized to receive rigosertib 1800 mg/24 h via 72-h CIV infusion administered every other week; after eight 2-week cycles, the treatment was extended to every 4 weeks. In the

Table 3. Summary of phase III trial results. Table 4. Most common grade ≥3 adverse events in phase III rigosertib study.

Complete response 0 0
Partial response 0 0
Marrow CR 39 (20) 14 (14)
Marrow PRa 14 (7) 3 (3)
Stable disease 69 (35) 15 (15)
Failure 13 (7) 5 (5)
Progressive disease 48 (24) 16 (16)
Not evaluable 16 (8) 47 (47)
Platelet response 5 (3) 5 (5)
Neutrophil response 9 (5) 6 (6)
Erythroid response 4 (2) 3 (3)

Response per IWG criteria
Rigosertib group
(n = 199) (%) BSC group (n = 100)

Adverse event
Rigosertib group (n = 184) (%)
Best supportive care group (n = 91) (%)

Anemia 34 (18) 7 (8)
Thrombocytopenia 35 (19) 6 (7)
Neutropenia 31 (17) 7 (8)
Febrile neutropenia 22(12) 10 (11)
Pneumonia 22 (12) 10 (11)

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IWG: International Working Group; BSC: best supportive care; CR: complete response; PR: partial response.
aNot part of IWG criteria.

BSC group, 37% of patients received low-dose cytarabine. The two groups were similar with regard to baseline characteristics.
Median overall survival was 8.2 months in the rigosertib group compared to 5.9 months in the BSC group (p = .33). No patients had an overall complete or partial response, but 53 of 199 (27%) of patients in the rigosertib group and 17 of 100 (17%) in the BSC group had an mCR or mPR (Table 3). Although not part of the IWG, marrow PR was noted because a reduction in blasts in the marrow was associated with an improvement in survival in previous studies using rigosertib. Patients received rigosertib for a median of five cycles with median duration on study of 10.2 weeks.
In post hoc analyses, there appeared to be a survival benefit in several subgroups receiving rigosertib [17]. Those sub- groups included patients who had primary HMA failure, i.e., no response or progression during treatment as opposed to secondary HMA failure (relapse after response); patients with monosomy 7 or trisomy 8; those aged younger than 75 years; those who had received less than 9 months of previous HMA therapy; and patients with very high-risk disease by IPSS-R.

⦁ Safety and tolerability
In the four phase I/II studies of IV rigosertib, a total of 71 patients were evaluable for safety. The most frequent drug-related adverse events (AEs) included fatigue, gastrointestinal, and urin- ary symptoms. Grade 3 to 4 drug-related toxicity was uncom- mon. Grade ≥2 urinary toxicity often improved with holding rigosertib until toxicity returned to grade 1 or less along with vigorous hydration and bicarbonate tablets. The mechanism by which rigosertib causes urinary toxicity is unknown but is cur- rently under investigation. Serious AEs observed in two or more patients included hematuria, pollakiuria, and dyspnea. Drug- related myelosuppression was relatively uncommon [16].
In phase I/II studies of oral rigosertib, the drug was gener- ally well tolerated. On the phase I study, dose-limiting toxicity, consisting of grade 3 dysuria and shortness of breath, occurred at the 700-mg twice-daily dose. The incidence of grade 2 or 3 drug-related non-hematologic toxicity was dose dependent, occurring in 46% of patients overall. Most com- mon drug toxicities included urinary symptoms, abdominal pain, diarrhea, fatigue, hypotension/syncope, and anorexia.
Five patients experienced grade 3 non-hematological toxicity. In the phase II component, 12% of patients experienced rever- sible grade 3 urinary toxicity, including dysuria, hematuria, cystitis, and urinary urgency, while 35% experienced grade 2 urinary toxicity [29,31].
In the phase III randomized study, the most common grade 3 or higher AEs were anemia, thrombocytopenia, neutropenia, febrile neutropenia, and pneumonia (Table 4). Rigosertib was discontinued because of treatment-related AEs in 8 of 184 patients. Forty-one of 184 patients (22%) in the rigosertib arm and 30 of 91 patients (33%) in the BSC arm died due to AEs. Investigators attributed three deaths to rigosertib treat- ment, two from renal failure and one from septic shock [17].

⦁ Regulatory affairs
Rigosertib is not currently approved by the US FDA for the treatment of MDS. A randomized phase III trial is underway to assess the effect of rigosertib on survival and safety in selected subgroups that appeared to have a benefit from treatment in the prior study. Rigosertib is also being tested in combination with azacitidine in both de novo MDS patients and HMA failures.

⦁ Conclusion
HMAs are standard therapy for patients with higher-risk MDS; however, all patients ultimately relapse or fail to respond, and these patients have a poor prognosis. There is no approved second-line therapy for this patient population. Rigosertib, a Ras- mimetic that inhibits the PI3K and PLK pathways, was safe and well tolerated and demonstrated clinical activity in phase I/II studies in MDS patients who had received prior HMA therapy. However, in a randomized, phase III multicenter study, rigosertib did not meet its primary end point of survival benefit compared to BSC in this patient population. Certain subgroups appeared to benefit from treatment, including patients who did not respond or progressed during initial HMA treatment, patients with monos- omy 7 or trisomy 8, those aged younger than 75 years, those who had received less than 9 months of previous HMA therapy, and patients with very high-risk disease by IPSS-R. An ongoing phase III study is testing the drug’s effect on survival and safety in these subgroups.

⦁ Expert commentary
Given the lack of approved therapies for MDS patients who have failed or progressed on HMAs and the poor prognosis of this patient population, there is an urgent unmet need for new treatment options. IV rigosertib alone did not provide a

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survival benefit in HMA failures; however, it might be bene- ficial in certain subsets of patients, which is being tested in an ongoing phase III trial. Perhaps more compelling is the com- bination of azacitidine and oral rigosertib, which was tested in a phase I/II study in de novo MDS patients as well as HMA failures. Sequential exposure with rigosertib followed by aza- citidine achieved maximum synergy in vitro and was therefore the schema used in the clinical trial [32]. Preliminary data of the combination demonstrated an overall response rate of 77% in MDS patients. Sixty-four percent of patients who had previously received an HMA and either did not respond or relapsed responded to the combination, and this represents a novel and important observation [33]. The combination was well tolerated and could be safely administered in repetitive cycles for 2+ years without evidence of cumulative toxicity. The phase II component is ongoing. Further studies of this combination deserve investigation both in the de novo and in the HMA failure populations.

⦁ Five-year view
Only three drugs are currently approved by the FDA for the treatment of MDS (azacitidine, decitabine, and lenalidomide), and no new therapies have been approved in the United States since 2006. Allogeneic stem cell transplant is the only curative option, but the majority of patients are not candi- dates due to age, poor performance status, or lack of an adequate donor. Therefore, there is a significant unmet need for this patient population, particularly for those who fail HMAs and carry a poor prognosis. Several drugs are under investigation, including oral azacitidine for transfusion-depen- dent lower-risk MDS, rigosertib (alone and in combination with azacitidine) for HMA-refractory higher-risk MDS, vorino- stat in combination with azacitidine for higher-risk MDS, oral sapacitabine for HMA-refractory higher-risk MDS, and eltrom- bopag for patients with significant thrombocytopenia. Improving overall survival, without sacrificing quality of life, is a key therapeutic goal for higher-risk MDS patients. Further studies are necessary to determine which newer therapies, including optimal doses and schedules, could provide a survi- val benefit.

Key issues
⦁ Rigosertib is a Ras-mimetic that inhibits the PI3K and PLK cellular signaling pathways and causes G2/M cell cycle phase arrest.
⦁ Intravenous rigosertib has been tested in MDS patients whose disease has failed or progressed on hypomethylating agents, azacitidine or decitabine.
⦁ Oral rigosertib has been tested in lower-risk red cell trans- fusion dependent MDS patients. It has also been studied in combination with azacitidine in de novo MDS patients as well as the HMA failure population.
⦁ Rigosertib is safe and well-tolerated. Drug-related myelo- suppression is relatively uncommon in a heavily pre-treated population. Urinary toxicity has been seen with both the IV

and oral formulations and can be mitigated with hydration and sodium bicarbonate tablets.
⦁ Rigosertib did not demonstrate an overall survival benefit compared to best supportive care in a randomized phase III trial; however, certain subgroups appeared to benefit, including patients who did not respond or progressed dur- ing initial HMA treatment, patients with monosomy 7 or trisomy 8, age younger than 75 years, those who had received less than 9 months of previous HMA therapy, and patients with very high-risk disease by IPSS-R.
⦁ An ongoing phase III study is testing rigosertib’s effect on survival and safety in the above subgroups.

Funding
This paper was not funded.

Declaration of interest
LR Silverman and SC Navada receive research funding from Onconova Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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