Oral Rigosertib Research Articles

613 Oral rigosertib demonstrates preliminary efficacy in the treatment of recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma

613 Oral rigosertib demonstrates preliminary efficacy in the treatment of recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma

Rigosertib Oral in Transfusion Dependent Lower Risk Myelodysplastic Syndromes (LR-MDS): Optimization of Dose and Rate of Transfusion Independence (TI) or Transfusion Reduction (TR) in a Single-Arm Phase 2 Study

Background:LR-MDS patients have limited treatment options and a large number are transfusion dependent (Raza A, Expert Opinion 2016, 4:9). Erythropoiesis stimulating agents (ESA) are the first line of therapy for LR-MDS patients, but the overall response rate remains low. Thus, novel strategies with the goal of red blood cell (RBC) transfusion reduction (TR) and independence (TI) are required. Rigosertib, a small molecule inhibitor of RAS effector pathways (Athuluri-Divakar SK, Cell 2016;165:643) is under investigation in MDS. The absolute bioavailability of oral rigosertib is about 35% (Komrokji, BJH 2013; 162:517). Here we expand an earlier report (Raza A, ASH 2013 #2745) on rigosertib oral in LR-MDS with updates on dose optimization on the frequency of TI or TR.Methods:Rigosertib oral was tested in this phase 2 study in LR (intermediate-1 or low risk per IPSS classification) transfusion-dependent MDS patients. Fifty-four (65.9%) patients had received ESA. Rigosertib was administered to RBC transfusion-dependent patients; defined as requiring a minimum of 4 packed red blood cell (PRBC) units over 8 weeks, in the cohorts shown in see Table below. Patients were eligible for efficacy analysis if they received a minimum of 8 weeks of rigosertib in their assigned dosing cohort. Erythrocyte stimulating agents (ESAs) were allowed on study. TI is defined as no PRBC transfusions over a period of 8 sequential weeks; TR a reduction in 4 or more RBC units over a period of 8 sequential weeks.Results:Eighty-two patients with a median age of 70 years (range 54-90) were enrolled between May 2012 and February 2015, at 5clinical sites, and received a median of 5.4 months (range 0.1-28.8) of oral rigosertib. Of the 82 enrolled patients, 9 patients were treated with 560 mg BID continuously, 7 patients treated with 560 mg in the AM and 280 mg in the PM continuously, 35 patients treated with 560mg BID intermittently, 31 patients treated with 560mg in the AM and 280mg in the PM intermittently. Sixty patients were treated with ESA and oral rigosertib while on study. An unusual adverse event (AE) (urinary events) was identified as related to dosing. Continuous rigosertib dosing cohorts were closed early due to higher urinary adverse events (AEs) or less efficacy with the lower dose of rigosertib.EfficacyOf the 82 patients, 66 patients received intermittent dosing for at least 8 consecutive weeks; and 20 of 62 evaluable patients (32%) achieved TI lasting 8 to 85+ weeks; with a median of 18 weeks. The highest rate of TI (44%) was observed in the 560 mg BID intermittent cohort: 15 of 34 eligible patients achieved TI lasting 8 to 85+ weeks; with a median of 18 weeks (TABLE). Ninty-three percent (93%) of these 15 patients received rigosertib with continued ESA.SafetyDue to urinary AEs continuous 560 mg BID dosing is no longer being studied. For all intermittent patients (n=66); the most frequent treatment emergent adverse events observed were urinary with pollakiuria (42.4%), fatigue and micturition urgency (33.3%), urinary tract pain (28.8%), hematuria and dysuria (24.2%).In the 560 mg BID intermittent group, 71.4% of all patients experienced urinary AE, the most frequent being pollakiuria (51.4%), micturition urgency (37.1%), and dysuria, hematuria, and urinary tract pain (34.3%); and fatigue (42.9%). Grade 3 or greater hematuria was observed in 11.4% of these patients and dysuria and urinary tract pain in 5.7%. Several strategies were investigated to ameliorate or manage the urinary AEs.Notably, no significant treatment emergent myelosuppression, or other notable AEs were evident in these patients.Conclusions:Oral rigosertib treatment resulted in TR & TI. Patients administered rigosertib for 2 out of 3 weeks at a dose of 560 mg BID (1120 mg over 24 hrs) achieved an impressive TI rate of 44% (15/34). Based on the rate of TI, and the observed urinary AEs, the risk benefit profile of oral intermittent dosing is favorable. Oral rigosertib at a total dose of 1120 mg over 24 hrs administered intermittently in HR-MDS pts in combination with azacitidine is now being studied; with novel strategies employed to continue to minimize the unusual urinary AEs. [Display omitted] DisclosuresRaza:Kura Oncology: Research Funding; Celgene Inc.: Research Funding; Syros Pharmaceuticals: Research Funding; Janssen R&D: Research Funding; Novartis: Speakers Bureau; Genoptix: Speakers Bureau; Onconova Therapeutics: Research Funding, Speakers Bureau. Lee:Alexion Pharmaceuticals: Consultancy; Amgen: Consultancy; Clinipace: Consultancy; Baxalta: Consultancy. Ali:Kura Oncology: Consultancy; Onconova Therapeutics: Consultancy. Fruchtman:Onconova Therapeutics, Inc.: Employment. Petrone:Onconova Therapeutics, Inc.: Employment. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Heaney:Novartis: Consultancy; Onconova Therapeutics: Research Funding.

Rigosertib in combination with azacitidine in patients with myelodysplastic syndromes or acute myeloid leukemia: Results of a phase 1 study

Phase 1 results from a Phase 1/2 study comprise 18 patients with myelodysplastic syndromes (MDS; n = 9), acute myeloid leukemia (AML; n = 8), and chronic myelomonocytic leukemia (CMML; n = 1) who were either hypomethylating agent naïve (n = 10) or relapsed/refractory following prior hypomethylating agent therapy (n = 8) (NCT01926587). Patients received oral rigosertib, an inhibitor of Ras-effector pathways, in 3 successive cohorts (140 mg twice daily, 280 mg twice daily, or 840 mg/day [560 mg morning/280 mg evening]) for 3 weeks of a 4-week cycle. Patients received parenteral azacitidine (75 mg/m2/day × 7 days) during the second week; the cycle repeated every 4 weeks. The combination was well tolerated for a median of 4 (range 1–41) cycles, with 72% of patients experiencing ≥1 serious adverse events. No dose-limiting toxicities were observed. Thus, no maximum tolerated dose was reached. The most frequently reported adverse events were diarrhea (50%), constipation, fatigue, and nausea (each 44%), and pneumonia and back pain (each 33%). Sequential administration demonstrated an overall response rate of 56% in evaluable patients, with responses observed in 7/9 MDS/CMML patients (78%) and 2/7 AML patients (29%). Further clinical studies are warranted to investigate this doublet therapy in patients with myeloid malignancies.

Phase II Study of Oral Rigosertib Combined with Azacitidine (AZA) As First Line Therapy in Patients (Pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS)

Phase II Study of Oral Rigosertib Combined with Azacitidine (AZA) As First Line Therapy in Patients (Pts) with Higher-Risk Myelodysplastic Syndromes (HR-MDS)

Phase 3, Multi-Center, International, Randomized, Double-Blind, Placebo Controlled Study of Oral Rigosertib + Injectable Azacitidine (AZA) Versus Injectable Azacitidine in Treatment-Naive Patients with Higher-Risk Myelodysplastic Syndrome (HR-MDS)

Background The only approved medications for treatment of first line HR-MDS are HMAs (AZA & decitabine (DEC) in US, AZA only in EU). It is estimated that progression to Acute Myeloid Leukemia (AML) as well as median OS for these pts is <1-3 yrs (Greenberg 2012). Although AZA monotherapy demonstrated improvement in OS in HR-MDS, clinically meaningful & durable responses continue to be limited to a subset of pts (Silverman 2006). One obvious strategy is to identify a novel drug that can be administered effectively in combo with AZA & has minimal overlapping toxicity with AZA. Based on this current approach & favorable results of the Ph2 study (Navada EHA 2019) the 1st pivotal Ph3 randomized study of oral rigosertib in combo with AZA has been developed as part of an effort to increase overall responses as well as reduce risk of transformation to AML for pts with treatment-naive HR-MDS. Studies have demonstrated that rigosertib binds directly to the Ras-Binding Domains (RBD) found in Ras effector proteins, such as the Raf kinases & PI3K & inhibits the RAS-RAF-MEK & the PI3Ks pathways (Athuluri-Divakar 2016 Cell 2016). In vitro, the combo of rigosertib with AZA synergistically inhibits growth & induces apoptosis of leukemic cells in a sequence-dependent fashion. Sequential exposure with rigosertib followed by AZA achieved maximum synergy with clinically achievable concentrations (Skiddan AACR 2006, Silverman EHA 2019). In a ph2 study (09-08) oral rigosertib at doses ≥ 840 mg/d administered in combo with AZA demonstrated efficacy in HMA-naive MDS pts with an ORR of 90% & a CR rate of 34%. The combo administered in repetitive cycles for more than 2 yrs was well tolerated & the observed GU toxicity was mitigated using specific management guidelines. Based on the efficacy data & favorable safety profile, the pivotal Ph3 trial presented here in treatment-naive HR-MDS population has been developed. (Navada EHA 2019). Study Design & Methods Ph3, multi-center, international, randomized, double-blind, placebo-controlled study to be conducted in treatment-naive pts with HR-MDS who will receive oral rigosertib 1120mg/d (560 mg morning & 560 mg afternoon) or placebo in combo with AZA 75mg/m2 daily (SC or IV). Pts will take rigosertib/placebo on days 1-21 of a 28-day cycle & starting on Day 8, AZA will be administered by SC injection or IV infusion at a 75 mg/m2 daily dose for 7 days of a 28-day cycle according to the approved label. 400 pts are anticipated for enrollment. Major inclusion criteria are shown in Figure 1. Major exclusion criteria are prior treatment with rigosertib or HMA; chronic myelomonocytic leukemia; & prior BMT. Treatment will continue until disease progression as defined by IWG 2006, or unacceptable toxicity. Treatment will continue until PD as defined by IWG 2006 or unacceptable toxicity, after which pts will be followed for survival every 2 mos until death or 3 yrs, whichever occurs first. The primary analysis of all efficacy endpoints will be in the intention-to-treat population. The safety population will include all pts classified according to the protocol treatment they received, regardless of random assignment. Randomized pts who receive no treatment will be excluded. Management guidelines for treatment emergent adverse events requiring dose adjustments, either dose delay or dose modification at time of AE, is provided in protocol. The final analysis of response rate will be conducted using IWG 2006. Endpoints All endpoints for the study are provided in Table 1. Conclusion This pivotal Phase 3 trial in treatment-naive HR-MDS population has been developed based on efficacy data & favorable safety profile from 09-08. The Intergroup randomized ph2 combo study in pts with HR-MDS treated with AZA + lenalidomide (ORR 49%), or AZA + vorinostat (ORR 27%) had a similar ORR to pts treated with AZA monotherapy (ORR 38%) (Sekeres 2017). In contrast, the ph2 study of oral rigosertib in combo with AZA had an ORR of 90% & a CR rate of 34% (Navada EHA 2019). This proposed study is the 1st ph3 combo study of oral rigosertib with AZA & may provide a potential new treatment for first line in a pt population with poor prognosis & limited therapeutic options. Disclosures Garcia-Manero: Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Navada:Onconova Therapeutics Inc: Research Funding. Fenaux:Astex: Honoraria, Research Funding; Aprea: Research Funding; Jazz: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Adesanya:Onconova Therapeutics, Inc.: Employment. Azarnia:Onconova Therapeutics, Inc.: Employment. Fruchtman:Onconova Therapeutics, Inc.: Employment. Silverman:Medimmune: Research Funding; Celgene: Research Funding; Onconova Therapeutics Inc: Patents & Royalties, Research Funding.

S839 PHASE II STUDY OF ORAL RIGOSERTIB COMBINED WITH AZACITIDINE IN PATIENTS WITH HIGHER‐RISK MYELODYSPLASTIC SYNDROMES (MDS)

Background:Azacitidine based combination trials have not demonstrated improved response or outcome over single agent azacitidine (Sekeres JCO 2017; Ades ASH 2018). Results of a Phase I/II study in MDS patients demonstrated oral rigosertib and standard‐dose azacitidine to be well‐tolerated with efficacy in HMA‐naive and HMA‐failure patients: at 560 mg qAM/280 mg qPM rigosertib dosing, overall response rate (ORR) was 77%; 88% for HMA‐naive group, 60% for HMA‐failure group. An increase in genitourinary (GU) adverse events was noted with the combination. Rigosertib at higher doses (1120 mg/day) yielded maximum ORR in lower‐risk MDS and was thus investigated in additional cohorts (Raza ASH 2017). Risk‐mitigation strategies were employed to reduce GU AEs (Navada ASH 2018).Aims:‐Methods:Oral rigosertib was administered on Day 1–21 of a 28‐day cycle (840 mg or 1120 mg total); parenteral (SC or IV) azacitidine 75 mg/m2/day was given for 7 days starting on Day 8 in patients with MDS including both HMA naive and HMA failures.Results:Of those patients receiving ≥840 mg rigosertib, 55 were evaluable for response. 26 were treated with 840 mg rigosertib and 29 were treated with 1120 mg.Median duration of response was 12.2 months (range, 0.1–24.2+) and 10.8 months (range, 0.1–11.8+) for HMA naive and HMA‐failure pts, respectively. Median number of cycles to initial/best response was 1/4 and 2/5, respectively.Responses per IWG 2006 occurred in all IPSS‐R subgroups. In low/intermediate (N = 17), CR occurred in 4 (24%), PR was 0, mCR was 5 (29%), stable disease was 2 (12%), progression was 0, not evaluable was 3 (18%), HI in 9 (53%). In high risk (N = 23), CR occurred in 2 (9%), PR in 1 (4%), mCR was 8 (35%), stable disease was 6 (26%), progression was 1 (4%), not evaluable was 4 (17%), and HI in 7 (30%). In very high risk (N = 33), CR occurred in 5 (15%), PR was 0, mCR was 10 (30%), stable disease was 2 (6%), progression was 4 (12%), not evaluable was 11 (33%), and HI in 11 (33%).The following Safety‐optimization strategies were employed to minimize genitourinary toxicities of hematuria and dysuria: Second rigosertib dose must be taken at 3 PM (±1 hour) at least 2 hours after lunch to avoid a nocturnal bladder dwell time (Maniar M, et al. ASCO 2018 Sub for Pub) Oral hydration of at least two liters of fluid per day is encouraged Mandatory bladder emptying prior to bedtime Urine pH approx. 2 hours after AM dose. Sodium bicarbonate suggested 650 TID if pH < 7.5 Summary/Conclusion:Oral rigosertib with azacitidine demonstrated efficacy in HMA‐naive patients. The combination markedly improved hematopoiesis and reduced blasts in HMA‐failure patients. The combination was well‐tolerated in repetitive cycles for 25+ months. Risk mitigation strategies reduced urinary AEs in the expansion cohort. A pivotal Phase 3 trial is planned in an HMA‐naive patient population.image

Phase 2 Expansion Study of Oral Rigosertib Combined with Azacitidine (AZA) in Patients (Pts) with Higher-Risk (HR) Myelodysplastic Syndromes (MDS): Efficacy and Safety Results in HMA Treatment Naïve & Relapsed (Rel)/Refractory (Ref) Patients

Phase 2 Expansion Study of Oral Rigosertib Combined with Azacitidine (AZA) in Patients (Pts) with Higher-Risk (HR) Myelodysplastic Syndromes (MDS): Efficacy and Safety Results in HMA Treatment Naïve & Relapsed (Rel)/Refractory (Ref) Patients

Evaluation of Underlying Cause of Genitourinary (GU) Adverse Events (AEs) in Patients with Myelodysplastic Syndromes upon Oral Administration of Rigosertib: Safety and Pharmacokinetic Analysis of Rigosertib across Three Clinical Trials

Introduction: Oncogenic mutations of Ras genes have been implicated in number of human cancers whereby the cells grow uncontrollably, and evade death signals (Ledford, Nature, 520, 278, 2015). Rigosertib is a small molecule that inhibits cellular signaling in cancer cells by acting as a Ras mimetic (Athuluri-Divakar SK, Cell 2016). Rigosertib, as a single agent, was evaluated in a Phase III clinical trial in refractory MDS patients where the drug was administered as a 3 day continuous IV infusion every other week (NCT01241500). Rigosertib has also been evaluated in Phase I/II trials via oral route of administration in patients with solid malignancies (NCT01168011); and with myelodysplastic syndromes (NCT01926587). We performed pharmacokinetic and safety analysis of 253 patients across three different trials. The pharmacokinetics and safety profile of orally administered Rigosertib was evaluated in patients with MDS and solid malignancies. The results were compared to data obtained from high risk MDS patients receiving intravenous rigosertib therapy. In this investigation, we present evidence that differential GU toxicity of Rigosertib is probably related to the route of administration and dosing regimen; and independent of the underlying disease state.Methods: Data was analyzed from three clinical studies. Study NCT01241500 was conducted with MDS patients (n = 184) who were administered Rigosertib by continuous IV infusion (1800 mg/day for 72 hours) every 2 weeks. Blood samples were collected at 6, 24, 30, 48, 56 and 72 hours after infusion initiation. In Study NCT01168011, patients with advanced solid tumors (n=33) received oral Rigosertib (560 mg) Q12 hours of a 28-day cycle (3 weeks on, 1 week off). Study NCT01926587, conducted in MDS patients (n=36) with oral administration Rigosertib in combination with parenteral Azacitidine, evaluated the same AM dose but a lower 280 mg PM dose. In both studies, pharmacokinetic assessment was conducted after administration of the AM dose (560 mg) on day 1 of cycle 1. Blood samples were collected predose and 0.5, 1, 1.5, 2, 4, 6 and 8 hours after administration. For Study NCT01168011, urine was collected for 24 hours (0-4, 4-8 and 8-24 hrs) to determine the percent of dose excreted in urine. Rigosertib concentrations in plasma and urine were determined by a validated LC/MS-MS method. Rigosertib pharmacokinetic parameters were estimated using non-compartmental analysis. Treatment emergent adverse events were recorded throughout each study.Results: There was no difference in Rigosertib pharmacokinetic parameters between the two patient populations (Table 1) upon oral administration, and the plasma concentration-time profiles were super imposable (Figure 1). Approximately 2% of the orally administered dose was recovered in the urine. In both studies, the most common AEs observed were GU AEs (dysuria, hematuria). The incidence of grade ≥2 GU toxicity observed with oral dosing was 17 of 33 (52%) and 17 of 36 (47%) in Study NCT01168011 and NCT01926587, respectively. The incidence of GU AEs in both the studies was comparable even though the PM dose was lower (560 mg vs 280mg) in study NCT01926587. Peak plasma concentration and AUC0-∞ were similar in patients with or without urinary symptoms. Compared to oral dosing, the incidences of GU AEs were dramatically lower (10%) following IV infusion despite 8-fold higher and more prolonged systemic exposure (Table 2).Conclusions: This study demonstrates that the urinary adverse events and systemic exposure are similar in patients with either solid malignancies or MDS treated with orally administered rigosertib. The incidence of GU AEs is relatively high in spite of the very low amount (2%) of the administered dose eliminated through the renal route. In contrast, the GU AEs are significantly lower when Rigosertib is administered by IV infusion despite of 8 fold higher exposure. This is probably due to the short half-life of drug and dosing holiday of 12 days between two doses within the cycle. The higher incidence of GU AE upon oral administration is likely related to the dwell time of high concentration of drug in the bladder at night in patients treated daily for 3/4 weeks. This was successfully addressed in the clinical trial, NCT01926587 expansion with risk mitigation strategies, by deploying a novel dosing regimen derived through pharmacokinetic modeling and simulation (Taft, et al; ASH 2018 Abstract Submitted). [Display omitted] DisclosuresManiar:Onconova Therapeutics, Inc: Employment, Equity Ownership. Ren:Onconova Therapeutics, Inc: Employment, Equity Ownership. Zbyszewski:Onconova Therapeutics, Inc: Employment, Equity Ownership. Petrone:Onconova Terapeutics Inc.: Employment, Equity Ownership. Fruchtman:Onconova Therapeutic Inc: Employment, Equity Ownership. Taft:Onconova Therapeutics, Inc: Research Funding.

Amelioration of Rigosertib Treatment Related Genitourinary (GU) Adverse Events (AEs) in Patients with Myelodysplastic Syndromes: Implementation of Novel Dosing Regimen Derived through Pharmacokinetic Modeling in Phase 2 Study of Oral Rigosertib in Combination with Azacitidine

Introduction: Rigosertib is a small molecule inhibitor of cellular signaling pathways in cancer cells by acting as a Ras mimetic. The inhibitory effect is mediated by Rigosertib binding to the Ras-binding domain found in many Ras effector proteins (Athuluri-Divakar SK, Cell 2016). Oral administration of Rigosertib was initially evaluated in lower risk MDS patients. The drug, administered as 560 mg BID (q12hr; 2/3 wks), was associated with high rates of transfusion independence but with significant GU AEs (Raza, et al, Blood 2017 130:1689). Subsequently, a reduction in the PM dose to 280 mg led to a decrease in GU AEs, suggesting a causal relationship with nocturnal bladder drug concentration. When oral administration of Rigosertib was tested with standard dose of parenteral Azacitidine in a Phase I/II trial (NCT01926587) at a dose of 560/280 mg (Q12hrs, 3/4 weeks), the ORR was 77%; with 60% for the HMA relapsed/refractory group for the high risk MDS patients. The impressive response rate, in the combination treatment, was also associated with significant GU AEs. Hence, it is important to understand the underlying cause and devise ways to maximize response rates with minimization of GU AEs.Previously, it was established that GU AEs were unlikely to be related to the higher systemic exposure of the drug (Maniar, et al ASH 2018, Abstract submitted) but attributed to the nocturnal dwell time of high drug concentration in the bladder of patients treated with continuous oral administration (3/4 weeks). In this investigation, we developed a pharmacokinetic model to simulate the systemic and bladder exposure of Rigosertib after repeated oral dosing. The overall aim was to identify and implement an oral dosing regimen for Rigosertib that would maximize the systemic exposure with minimization of nocturnal bladder concentration, thereby potentially mitigating or eliminating the GU AE's.Methods: A 2-compartment model with 1st order absorption and elimination (Figure 1) was fitted to data collected from patients with solid malignancies at a 560 mg dose (n=25). Model parameter estimates were then used to generate a virtual population of 100 patients. Each virtual patient was randomly assigned parameter values based on the 95% confidence interval for each parameter estimate obtained through the modeling analysis. Model simulations were then performed to evaluate the steady state systemic and urinary exposure of Rigosertib in the virtual population after treatment with different dosing schedules (Figure 2). Besides plasma exposure (Cmax, AUC), the predicted rigosertib bladder concentration during the sleep-cycle was also assessed. From this analysis, optimal dosing regimens were selected for evaluation in a Phase 2 study in HR-MDS patients in combination with Azacitidine. The model was validated by comparing the predicted systemic exposure with observed data using these optimal dosing regimens, and by comparing Grade 3 GU AE's events from the pre- and post-optimization of dosing regimen (NCT01926587).Results: The model-predicted steady state plasma concentration-time profile of Rigosertib for different dosing regimens is shown in Figure 3. The duration of exposure of drug above minimum effective concentration (MEC, 0.175 ug/ml) was not changed by varying the dosing regimen. Importantly, model simulations demonstrated that BID dosing, with the dosing interval of 8 hours, would reduce the bladder concentration of Rigosertib by as much as 70% during sleep without compromising systemic drug exposure (Table 1). As illustrated in Table 2, model simulated Rigosertib exposure (Cmax, AUC) compared favorably with data from patients treated with the novel twice daily dosing regimens (560mg/560mg and 840 mg/280mg, dosing interval of 8 hours), thereby validating the model. Preliminary safety data from the on-going trial demonstrates that the Grade 3 GU AEs were significantly reduced (12%) with the optimized dosing regimen compared to the pre-optimized dosing regimen (29%) despite using a higher total dose of drug (1120 mg vs 840 mg).Conclusions: This study demonstrates the utility of pharmacokinetic modeling for designing a dosing regimen directed at reducing the incidence of toxicity. The identified dosing regimen, along with mitigation strategies, successfully reduced the risk of Grade 3 GU AEs of rigosertib without compromising the duration of systemic exposure of Rigosertib above MEC in HR MDS patients. [Display omitted] DisclosuresTaft:Onconova Therapeutics, Inc: Research Funding. Ren:Onconova Therapeutics, Inc: Employment, Equity Ownership. Zbyszewski:Onconova Therapeutics, Inc: Employment, Equity Ownership. Morgan:Onconova Therapeutics, Inc: Consultancy. Petrone:Onconova Terapeutics Inc.: Employment, Equity Ownership. Fruchtman:Onconova Therapeutic Inc: Employment, Equity Ownership. Maniar:Onconova Therapeutics, Inc: Employment, Equity Ownership.

43 - Combination of Oral Rigosertib and Injectable Azacitidine in Patients with Myelodysplastic Syndromes (MDS)

43 - Combination of Oral Rigosertib and Injectable Azacitidine in Patients with Myelodysplastic Syndromes (MDS)

Comprehensive Analysis of Safety: Rigosertib in 557 Patients with Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML)

▪Background: Rigosertib (RIG) is a RAS-mimetic interacting with the RAS-binding domains of RAF kinases, preventing their binding to RAS and inhibiting the RAS-RAF-MEK pathway. Rigosertib also binds to the RAS-binding domains of Ral-GDS and PI3Ks (Athuluri-Divakar, et al, Cell 165:643, 2016). Mutations of RAS are involved in proliferative processes important in neoplastic transformation (Gil-Bazo, et.al, Cancer Biology and Therapy 17:719, 2016).As of May 2016, 557 patients with MDS or AML received IV (N=335) or oral (N=222) rigosertib. All IV rigosertib was administered as monotherapy. Oral rigosertib was administered as monotherapy (N=168) or in combination with injectable azacitidine (AZA; N=54). Safety results across this rigosertib development program have not been presented.Methods: We reviewed all treatment-emergent adverse events (TEAEs) among patients with MDS/AML treated with rigosertib IV monotherapy, rigosertib oral monotherapy, or in combination therapy, overall and by grade of severity, and serious TEAEs and TEAEs leading to discontinuation. Due to the unexpected observation of urinary AEs, including occasional gross hematuria, we analyzed urinary AEs in greater detail.Results: Rigosertib IV monotherapy: The most common TEAEs were fatigue (33%), nausea (33%), diarrhea (27%), constipation (25%), anaemia (24%) and pyrexia (24%). The most common ≥Grade 3 AEs were anaemia (21%), febrile neutropenia (13%), pneumonia (12%) and thrombocytopenia (11%). The most common serious AEs were febrile neutropenia (10%), pneumonia (9%), and sepsis (7%). The most common AEs leading to discontinuation of IV rigosertib were sepsis and pneumonia (3% each) (Table 1).Rigosertib oral monotherapy: The most common TEAEs were pollakiuria (increased urinary frequency) (35-%), fatigue (32%), diarrhoea (26%), dysuria (29%) and haematuria (24%). The most common ≥Grade 3 AEs were anaemia (17%), thrombocytopenia (5%), haematuria (4%) and urinary tract infection (4%). The most common serious AE was pneumonia (6%). The most common AEs leading to discontinuation of patients receiving oral rigosertib as monotherapy were (dysuria [8%], urinary tract pain [7%], haematuria [5%] and urinary frequency [5%] (Table 2).Rigosertib oral in combination with azacitidine (AZA): The most common TEAEs were nausea (41%), fatigue (39%), diarrhea (37%), constipation (37%) and dysuria (28%). The most common serious AEs were pneumonia (11%) and febrile neutropenia (7%). The most common AEs leading to discontinuation were AML (4%) and pneumonia (4%) (Table 3).In patients fully evaluable for gross hematuria the cause of bleeding was bladder inflammation. Urinary and plasma concentration of RIG were examined to assess dose relationship.According to the azacitidine package insert, the incidence of gross hematuria of any grade with single agent azacitidine is 6.3 % and Grade 3-4 of 2.3%.Evaluations performed of hematuria among 5 studies of oral rigosertib (4 monotherapy and 1 in combination with AZA) in patients with MDS/AML (Table 4).Conclusions: Rigosertib IV or oral formulations were generally well tolerated in clinical trials in over 500 patients with MDS/AML. Gastrointestinal AEs were most frequently reported with IV rigosertib and genitourinary AEs were seen more often with oral than IV dosing. The greater rate of urinary AEs in the oral than in the IV studies indicates a need for close monitoring of these patients and proactive risk management, such as adequate hydration, timing of administration of the second dose, and bladder emptying prior to sleep. Studies are being designed to optimize dosing and schedule to maximize efficacy and minimize hematuria of single agent oral rigosertib. A randomized trial of oral rigosertib/azacitidine versus azacitidine will be required to optimize the clinical benefit and safety in the management of higher-risk patients with MDS. [Display omitted] [Display omitted] [Display omitted] DisclosuresFenaux:Celgene: Honoraria, Research Funding; Janssen: Research Funding; Novartis: Honoraria, Research Funding; Astex: Research Funding; Teva: Honoraria, Research Funding. Al-Kali:Celgene: Research Funding; Onconova Therapeutics, Inc.: Research Funding. Navada:Onconova Therapeutics, Inc.: Research Funding. Roboz:Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy; Cellectis: Research Funding. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Onconova: Consultancy; Amgen: Consultancy; Astex: Consultancy. Platzbecker:Onconova, Teva, Celgene, Janssen, Novartis, Amgen: Honoraria, Research Funding. Petrone:Onconova Therapeutics, Inc.: Employment. Brownstein:Onconova Therapeutics, Inc.: Consultancy. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Maniar:Onconova Therapeutics, Inc.: Employment. Silverman:Onconova Therapeutics, Inc.: Patents & Royalties: Co-Patent holder for the combination of azacitidine and rigosertib, Research Funding.

Multicenter, Open-Label Phase I Clinical Study of Oral Rigosertib in Japanese Patients with Recurrent/Relapsed or Refractory Myelodysplastic Syndromes: Tolerability, Efficacy, and Pharmacokinetic Profiles

Background:Rigosertib is a novel phosphoinositide 3 kinase pathway inhibitor that induces G2/M arrest leading to the apoptosis of cancer cells and myeloblasts and causes minimal damage to normal cells. A Phase I study in the U.S. showed the safety and good tolerability of oral rigosertib in patients (pts) with low, intermediate-1, intermediate-2, or high risk myelodysplastic syndromes (MDS).Methods:A multicenter, open-label Phase I clinical study was conducted to examine the tolerability of oral rigosertib in Japanese pts with recurrent/relapsed or refractory MDS, and to determine the recommended dose for a Phase II clinical study. The key eligibility criteria were as follows: patients with recurrent/relapsed or refractory MDS, aged 20 years or older, ECOG PS of 0 to 2, and no major organ dysfunctions. Rigosertib (280 and 560 mg BID) was administered orally in one 21-day cycle that consisted of the 14-day, twice-daily, oral administration term, followed by the 7-day monitoring term. In principle, oral rigosertib was administered in up to cycle 6. The primary endpoint was the dose-limiting toxicity (DLT) in each dose group. The secondary endpoints were as follows: 1) safety as assessed with adverse events (AEs) and laboratory results; 2) efficacy as assessed according to the International Working Group 2006 criteria; and 3) pharmacokinetics.Results: Between March 2013 and November 2014, 10 patients were enrolled at 7 medical institutions in Japan. However, 1 of them did not receive rigosertib because of a tendency for PS deterioration. Six pts were male, the median age was 70 years (range 52 to 80 years), and ECOG PS was 0 in 7 pts and was 1 in 2 pts. Consequently, 3 and 6 pts were eventually assigned to the 280 and 560 mg dose groups, respectively. According to the FAB classification, 4, 2, 2, and 1 pts were categorized to RAEB, RARS, RA, and RAEB-t, respectively. The prognostic factor according to IPSS was Int-1 risk in 4 pts (1 and 3 pts in the 280 and 560 mg dose groups, respectively) and was Int-2 in 5 pts (2 and 3 pts in the 280 and 560 mg dose groups, respectively). In the 280 mg dose group, 2 of 3 pts completed cycle 6, and the median relative dose intensity (RDI) was 86% (77 to 92%). In the 560 mg dose group, the maximum number of cycles delivered was 4, and the median RDI was 85% (68 to 93%). A total of 57 AEs developed. In the 280 mg dose group, grade 3 or higher nonhematologic toxicities, grade 3 type 2 diabetes mellitus, and grade 4 delirium (1/3, 33.3%) developed. In the 560 mg dose group, grade 3 AEs: cholecystitis, periodontitis, pneumonia, soft tissue infection, increased alanine aminotransferase, increased aspartate aminotransferase, and prolonged QT interval, as well as grade 5 urinary tract infection (1/6, 16.7%) developed. DLTs (all of which were grade 3 or higher nonhematologic toxicities) were observed with 1 of 3 pts in the 280 mg dose group (type 2 diabetes mellitus and delirium) and with 2 of 6 pts in the 560 mg dose group (urinary tract infection and prolonged QT interval). Serious AEs were 2 events in 1 of 3 pts in the 280 mg dose group (type 2 diabetes mellitus and delirium) and were 6 events in 3 of 6 pts in the 560 mg dose group (soft tissue infection, periodontitis, cholecystitis, and pneumonia in 1 pt, hematuria in 1 pt, and urinary tract infection in 1 pt). One pt in the 560 mg dose group died of septic shock that had been caused by a urinary tract infection during the study period. The hematological remission rate was 11.1% (1 marrow CR; 1/9 pts), and the hematological improvement rate was 11.1% (1 HI-P; 1/9 pts); however, cytogenetic response was not found. Plasma concentrations of rigosertib increased rapidly after each oral administration. Among the PK parameters, intersubject variability was observed in the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC). However, changes suggesting the accumulation of rigosertib during repeated oral administration (e.g., consistent increases in the Cmax and AUC) were not found. The urinary excretion rates of rigosertib on day 1 were 1.6 ± 1.0% and 11.0 ± 6.6% (mean ± SD) in the 280 and 560 mg dose groups, respectively.Conclusions: The present chemotherapy regimen of oral rigosertib was well tolerated. Our study indicates that the recommended dose for a Phase II clinical study is 560 mg BID in Japanese patients with recurrent/relapsed or refractory MDS. DisclosuresIshizawa:SymBio Pharmaceuticals: Research Funding. Usuki:Nippon Shinyaku: Honoraria; Sumitomo Dainippon Pharma: Honoraria; MSD: Honoraria; Kyouwa-Kirin: Honoraria; Novartis: Honoraria; Bristol-Myer-Squibb: Honoraria; SymBio Pharmaceuticals: Research Funding. Ando:SymBio Pharmaceuticals: Research Funding. Ueda:SymBio Pharmaceuticals: Research Funding. Uike:SymBio Pharmaceuticals: Research Funding. Onishi:SymBio Pharmaceuticals: Research Funding. Iida:SymBio Pharmaceuticals: Research Funding.

Combination of Oral Rigosertib and Injectable Azacitidine in Patients with Myelodysplastic Syndromes (MDS): Results from a Phase II Study

Combination of Oral Rigosertib and Injectable Azacitidine in Patients with Myelodysplastic Syndromes (MDS): Results from a Phase II Study

Rigosertib in myelodysplastic syndromes (MDS)

ABSTRACTIntroduction: Therapeutic options for myelodysplastic syndromes (MDS) are limited to hypomethylating agents (HMA) and lenalidomide. Rigosertib, a small molecule which blocks RAS-mediated activation of proteins containing a common RAS binding domain, appears to be a promising novel drug.Areas covered: Discovery, mechanism of action of rigosertib, and results of clinical trials are described. More than 500 patients have been treated and the safety, pharmacokinetics, and efficacy of rigosertib are summarized. These studies are placed in the context of the history of therapeutic development in MDS and the promise of new, tailored treatments based on emerging knowledge of the heterogeneity and molecular biology of the disease.Expert opinion: In summary, the Phase III study failed to meet the primary endpoint but clearly showed significant improvement in survival in a subset of very high risk MDS patients who were primary HMA failures. A new Phase III trial designed to validate these findings is now ongoing. Oral rigosertib, in a Phase II trial, produced transfusion independence in ~35% patients with lower risk MDS with or without recombinant erythropoietin. A methylation based signature appears to distinguish between the two groups. Validation of these early encouraging observations through future clinical trials is eagerly anticipated.

A Phase II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndromes (MDS)

A Phase II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndromes (MDS)

Abstract 2425: An in vitro platform to dissect drug responsiveness in refractory anemia with ringed sideroblasts (RARS)

Abstract Background: The pathophysiology of low-risk myelodysplastic syndrome (LR-MDS) remains unknown and therapeutic options are limited. In a phase-II trial, with oral rigosertib, a small molecule inhibitor of PI3K and PLK pathways, was shown to have a 39% response rate, in patients with LR-MDS. Rigosertib caused an increase in hemoglobin, a decrease in transfusion requirements, and, in some patients who were previously refractory, “re-sensitization” to erythropoietin (EPO) therapy. Thus far, the mechanism of this responsiveness remains unknown. Whole exome sequencing revealed broad spectrum mutations in these patients, including mutations in SF3B1, SRSF2 and TET2. However, there was no correlation between mutational spectrum and responsiveness. Methods: CD34+ cells were isolated from bone marrow (BM) mono nuclear cells derived from BM aspirates. Bone marrow stromal cells (BMSC) were isolated from bone biopsies of patients with MDS. Normal CD34+ cells and BMSC were obtained commercially. CD34+ cells were co-cultured with stromal cells plated a day before and stimulated with concentrations of EPO and rigosertib. Differentiation was assessed by staining cells with various markers of erythroid differentiation and analyzed by FACS. We show that co-culture of CD34+ stem cells from the bone marrow of patients with their own BMSC recapitulates key features of the MDS phenotype and rigosertib responsiveness. Results: Normal (non-MDS) CD34+ cells co-cultured with normal BMSC showed striking responsiveness to EPO stimulation, as evidenced by the increased production of CD45- low/GPA+/ band 3+/Integrin-Alpha4+ erythroid cells (2.47 fold increase compared to no EPO). In contrast, RARS CD34+ cells co-cultured with MDS stromal cells showed no erythroid differentiation with EPO stimulation (1.09 fold change compared to EPO). Notably, LR-MDS co-cultures showed increased erythroid differentiation with the addition of 20 nm and 100 nm rigosertib in the presence of EPO (1.28 and 1.4 fold increase, respectively, compared to EPO alone). Moreover, co-cultures obtained from 3/3 patients that showed responsiveness in vivo were responsive to combined EPO/rigosertib stimulation in vitro, while 2/2 non-responsive patients were not responsive in vitro. Conclusions: We have created an in vitro platform to dissect the mechanism of rigosertib responsiveness in RARS patients. This is a novel co-culture-based system that recapitulates key features of the RARS phenotype. Without reliable animal models for this disease, this platform may offer a viable method to characterize drug responsiveness, dissect mechanisms, and offer patient-specific drug responsiveness information, since individual CD34+ cells are co-cultured with a patient's own BMSC. We wish to use this in vitro co- culture test to prospectively predict responsiveness to experimental drugs in patients, thereby focusing the drug on only selected patients. Citation Format: Daniela Georgieva, Sheherzad Preisler, Michael Churchill, Abdullah Mahmood Ali, Azra Raza, Siddhartha Mukherjee. An in vitro platform to dissect drug responsiveness in refractory anemia with ringed sideroblasts (RARS). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2425. doi:10.1158/1538-7445.AM2015-2425

A Phase I/II Study of the Combination of Oral Rigosertib and Azacitidine in Patients with Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML)

Background:Rigosertib is a small molecule anti-cancer agent targeting PI3/polo-like kinase pathways that promotes G2/M arrest and has effects on the B-Raf and Ras pathways. It is currently being tested as a single agent with the intravenous (IV) formulation in patients (pts) who have relapsed or are refractory to hypomethylating agents (HMAs) as well as with the oral formulation in lower-risk, red-cell transfusion-dependent MDS patients. Azacitidine (AZA) is first-line therapy for pts with higher-risk MDS. In vitro, the combination of rigosertib with AZA acts synergistically to inhibit growth and induce apoptosis of leukemic cells (Skidan et al 2006). This effect appears to be sequence dependent, requiring exposure to rigosertib first, followed by AZA. These nonclinical results provided the rationale to combine the 2 agents in a phase I/II study in pts with MDS and AML.Methods: Pts with MDS and non-proliferative AML, who were previously untreated or had failed or progressed on an HMA were included in the phase I component of the study. Oral rigosertib was administered twice daily from day 1 through day 21 of a 28-d cycle. AZA 75 mg/m2/d was administered for 7 days starting on day 8 of the 28-d cycle. Pts were entered in 3 escalating-dose cohorts of rigosertib in a classic 3+3 design: [1] 140 mg twice daily; [2] 280 mg twice daily; [3] 560 mg qAM and 280 mg qPM. A CBC was performed weekly and a bone marrow (BM) aspirate and/or biopsy was performed at baseline and every 4-8 weeks afterwards.Results: Eighteen pts have been treated with the combination of oral rigosertib and AZA. Pts had diagnoses of intermediate-1 MDS (3), intermediate-2 MDS (6), high-risk MDS (2), CMML (1), and AML (6); median age was 70.5 years; 61% of pts were male. Pts have received 1-10+ cycles of treatment with the total number of cycles administered thus far being 58. Cytogenetic profiles by IPSS were good (8 pts), poor (8 pts), and intermediate (2 pts). 11of 18 patients were transfusion dependent at baseline [RBC (11), platelet (6)]. One patient became RBC transfusion independent after 3 cycles of treatment. 5 additional patients have had a reduction in their RBC and platelet transfusion requirements. 56% of patients received prior treatment with HMAs: AZA (6 pts), decitabine (4 pts). The most frequent adverse events (AEs) in Cycle 1 included constipation, diarrhea, nausea, fatigue, hypotension, and pneumonia. The AEs did not differ significantly among the 3 cohorts. Elevation in creatinine in 1 pt in cohort 1 was a possibly related grade 3 dose-limiting toxicity that required subsequent expansion of the cohort. Drug-related dysuria/cystitis was not reported in this pt population. Responses according to IWG 2006 criteria were observed in the BM and peripheral blood: Complete Response (CR) (1 pt), Cri (CR with incomplete blood count recovery) (4 pts), stable disease (2), hematologic improvement-erythroid (1). Six pts received fewer than 4 cycles of treatment and are too early to evaluate. Six pts came off study for the following reasons: progression of disease (1), pt request (1), death from pneumonia (2), received stem cell transplant (1), persistent fungal pneumonia (1). Two evaluable pts have responded to the combination after progression or failure on HMA alone.Conclusions: The combination oforalrigosertib at 560/280 mg BID (recommended phase II dose) and standard-dose AZA can be safely administered and appears to be well tolerated in repetitive cycles in pts with MDS and non-proliferative AML. The AE profile does not differ significantly from that of AZA alone. Data from the Phase I component of this study suggest activity in patients with MDS after HMA failure. Additional data are required to evaluate this observation. The Phase II segment of this study is underway to further assess the response of the combination.TablePatient IDDiagnosisPrior HMA% Blasts in BM at Baseline% Blasts in BM after TreatmentIWG Response1MDSNo21CRi2AMLNo400CRi3AMLNo22N/ANE4MDSAzacitidine00NE5AMLNo59N/ANE6MDSNo21<5CRi7MDSNo21CR8MDSNo2.52SD9AMLDecitabine25N/ANE10MDSDecitabine123CRi11CMMLAzacitidine23SD12MDSAzacitidine41HI-E13AMLAzacitidine4740TE14AMLDecitabine77TE15MDSNo95TE16AMLNo256TE17AMLNo1519TE18AMLAzacitidine6445TEIWG = International Working Group CR = Complete Response CRi = Complete Response with incomplete blood count recovery NE = Not Evaluable SD = Stable Disease HI-E = Hematologic Improvement - Erythroid TE = Too Early DisclosuresWilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Demakos:Onconova: Consultancy. Azarnia:Onconova Therapeutics, Inc: Employment. Silverman:Onconova: with Icahn School of Medicine at Mount Sinai Patents & Royalties.

Phase I Study of Oral Rigosertib (ON 01910.Na), a Dual Inhibitor of the PI3K and Plk1 Pathways, in Adult Patients with Advanced Solid Malignancies

To determine the pharmacokinetics (PK), maximum tolerated dose (MTD), safety, and antitumor activity of an oral formulation of rigosertib, a dual phosphoinositide 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathway inhibitor, in patients with advanced solid malignancies. Patients with advanced solid malignancies received rigosertib twice daily continuously in 21-day cycles. Doses were escalated until intolerable grade ≥2 toxicities, at which point the previous dose level was expanded to define the MTD. All patients were assessed for safety, PK, and response. Urinary PK were performed at the MTD. Archival tumors were assessed for potential molecular biomarkers with multiplex mutation testing. A subset of squamous cell carcinomas (SCC) underwent exome sequencing. Forty-eight patients received a median of 2 cycles of therapy at 5 dose levels. Rigosertib exposure increased with escalating doses. Dose-limiting toxicities were hematuria and dysuria. The most common grade ≥2 drug-related toxicities involved urothelial irritation. The MTD is 560 mg twice daily. Activity was seen in head and neck SCCs (1 complete response, 1 partial response) and stable disease for ≥12 weeks was observed in 8 additional patients. Tumors experiencing ≥partial response had PI3K pathway activation, inactivated p53, and unique variants in ROBO3 and FAT1, two genes interacting with the Wnt/β-catenin pathway. The recommended phase II dose of oral rigosertib is 560 mg twice daily given continuously. Urinary toxicity is the dose-limiting and most common toxicity. Alterations in PI3K, p53, and Wnt/β-catenin pathway signaling should be investigated as potential biomarkers of response in future trials.

Oral Rigosertib (ON 01910.Na) Treatment Produces An Encouraging Rate Of Transfusion Independence In Lower Risk Myelodysplastic Syndromes (MDS) Patients; A Genomic Methylation Profile Is Associated With Responses

▪Rigosertib, a novel orally bioavailable small molecule inhibitor of PI3-Kinase and PLK1 pathways, was tested in a phase II study in lower risk (intermediate-1 or low risk per IPSS classification) transfusion-dependent MDS patients. This randomized, two-arm study administered rigosertib (560 mg bid) either intermittently (2 out of 3 weeks) or continuously to transfusion-dependent patients (4 units RBC transfusions over 8 weeks). Erythrocyte stimulating agents (ESAs) were allowed on study. Forty eight patients have been enrolled as of August 2nd, 2013 and another 12 patients will be enrolled. Continuous dosing was stopped after 9 patients due to a higher urinary toxicity resulting in 39 patients receiving intermittent dosing. Overall the drug was well tolerated, except for reversible grade 3 urinary toxicity (dysuria, hematuria, cystitis, and urinary urgency) in 6/48 (12%) patients while 17/48 (35%) experienced grade 2 urinary toxicity. Notably, no significant treatment emergent myelosuppression was evident in these patients. Dosing has been modified to a total daily dose of 840 mg (560 mg am/280 mg afternoon) to improve urinary tolerability. Other measures to manage urinary symptoms include hydration, sodium bicarbonate and dose reduction or interruption. Of 33 patients (3 with del5q) on intermittent dosing treated for at least 8 consecutive weeks, 15 (45%) achieved transfusion independence (TI or no RBC transfusion for at least 8 consecutive weeks) lasting 8 to 53+ weeks (median=17 weeks). Intent-to-treat analysis showed 17/48 (35%) patients achieved TI. Twelve of 15 responding patients were refractory to prior treatment with ESAs. Fourteen of 15 responding patients (11 out of 12 ESA refractory) received concomitant ESAs, suggesting an effect of rigosertib on ESA resistance or potential synergy with ESA. These effects are being explored in additional trials now in planning.There was no obvious correlation of response to karyotype or other classifications. We hypothesized that DNA methylation profiles could help explain the differences between responders and non-responders. Pre-therapy bone marrow mononuclear cells from 32 patients (including 4 from the prior Phase I study previously reported in ASH 2011) were analyzed using the Illumina 450K methylation array platform. Seven had complete response or CR (TI + increase in Hb >2Gm/dL), 10 had partial response or PR (TI without Hb increase) and 15 had no response or NR. Supervised hierarchical clustering by methylation intensity demonstrated a distinct profile associated with complete responders. Bisulfite sequencing (which allows quantification of multiple consecutive CpGs in an amplicon) of several differentially methylated loci confirmed the Illumina 450K data. In general, hypermethylation of a group of genes was associated with responders. Functional annotation of the hypo and hypermethylated genes which best distinguished CRs from NRs showed that the genes most affected by methylation were related to regulation of transcription followed by genes involved in cell-cell adhesion, inflammatory response, apoptosis and proliferation. Additional patient samples are being analyzed to confirm these results. In this interim analysis the observed correlation of hematological response to genomic methylation status suggests the possibility of preselecting patients likely to benefit from treatment with rigosertib. ConclusionsIntermittent dosing of oral rigosertib is well tolerated and active in producing transfusion independence in lower risk MDS patients. A genomic methylation signature, once confirmed in prospective studies, may allow pre-selection of responders. Disclosures:Raza:Onconova Therapeutics: Research Funding. Al-Kali:Onconova Therapeutics: Research Funding. Tibes:Onconova Therapeutics: Research Funding. Spitzer:Onconova Therapeutics: Research Funding. Wilhelm:Onconova Therapeutics: Employment, Equity Ownership. Mukherjee:Onconova Therapeutics: Research Funding.

Phase II study of orally administered rigosertib (ON 01910.Na) in transfusion-dependent lower-risk myelodysplastic syndrome (MDS) patients.

7031 Background: Rigosertib, a novel small molecule inhibitor of PI3-Kinase and PLK pathways is currently evaluated (IV infusions) in a phase III trial in higher risk MDS patients who have failed hypomethylating agents. A previous phase I study found good bioavailability and activity of orally administered rigosertib in transfusion-dependent MDS patients (ASH 2011). Here we report preliminary results from an ongoing phase II study. Methods: This is a randomized, two-arm study of oral rigosertib (560 mg bid) administered either intermittently (2 out of 3 weeks) or continuously. Transfusion-dependent patients must have received at least 4 units RBC transfusions over 8 weeks before randomization, and can receive transfusions and erythrocyte stimulating agents (ESAs) while on study. Results: Twenty nine MDS patients (25 intermediate-1 and 4 low risk per IPSS classification) have been randomized as of December 17, 2012. Overall oral rigosertib was well tolerated except for a high incidence (5 of 9 patients) of grade 2+ urinary side effects (dysuria, hematuria, cystitis, and urinary urgency), in the continuous dosing arm. Accordingly, the protocol was amended to allow all patients to be treated with intermittent dosing, with option of dose interruption/reduction resulting in a much lower frequency of urinary side effects (4/20 patients with urinary grade 2+ toxicity). Fifteen patients (none of them with del5q cytogenetic) have been treated with intermittent dosing for at least 8 weeks. Seven (47%) patients achieved transfusion independence (no RBC transfusion for at least 8 consecutive weeks), which lasted 8 to 27 + weeks. Six of 7 responding patients were refractory to prior treatment with ESAs and 5 of these 7 patients received concomitant ESAs, suggesting an effect of rigosertib on ESA resistance. Conclusions: Preliminary results of this phase II study indicate that intermittent dosing of rigosertib administered orally is well tolerated and active in producing transfusion independence in approximately 50% transfusion dependent, lower risk MDS patients. The contributing role of rigosertib and ESAs in these transfusion responses is being investigated. Clinical trial information: NCT01584531.