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In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 15_suppl ( 2016-05-20), p. 7020-7020

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2016.34.15_suppl.7020

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2016

detail.hit.zdb_id: 2005181-5

In: Journal of Clinical Investigation, American Society for Clinical Investigation, Vol. 124, No. 1 ( 2014-1-2), p. 40-46

Type of Medium: Online Resource

ISSN: 0021-9738

URL: Article

DOI: 10.1172/JCI69739

Language: English

Publisher: American Society for Clinical Investigation

Publication Date: 2014

detail.hit.zdb_id: 2018375-6

In: Seminars in Oncology, Elsevier BV, Vol. 41, No. 6 ( 2014-12), p. e51-e59

Type of Medium: Online Resource

ISSN: 0093-7754

URL: Article

DOI: 10.1053/j.seminoncol.2014.09.023

Language: English

Publisher: Elsevier BV

Publication Date: 2014

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3259-3259

Abstract: Background: Patients (pts) withHR-MDS have a median OS of 4 to 6 months (mo) after HMA failure (Prebet et al, J Clin Oncol 2011) and no approved salvage therapy. Development of new therapeutics for this population will benefit from the availability of surrogate endpoints and markers that can predict survival. Gore et al established response to azacitidine (Vidaza®) in first-line therapy for HR-MDS as a reasonable surrogate to predict survival (Gore et al, Haematologica 2013). Rigosertib, a novel dual PI3K/PLK pathway inhibitor, has been shown to reduce bone marrow blasts (BMBL) in these pts (Seetharam et al, Leuk Res 2012). Silverman et al described complete or partial bone marrow (BM) response, or stabilization after 4-8 weeks (wks) of treatment with rigosertib as a potential surrogate for predicting survival in pts with HR-MDS after failure of primary HMA therapy (Silverman et al, Hematol Oncol 2014). We tested this hypothesis in the context of a randomized Phase III trial. Methods:Pts with HR-MDS were randomly assigned 2:1 to rigosertib or best supportive care (BSC) after progressing on, failing to respond to, or relapsing after HMA treatment. BM aspirates were assessed pretreatment, at 4 weeks and at 8-week intervals thereafter. Central slide review was undertaken in a representative population of samples. The BMBL response at each time point was assessed using the following definitions: bone marrow complete response (mCR) = BMBL ≤ 5% and decrease of ≥ 50% from baseline; bone marrow partial response (mPR) = BMBL decrease from baseline of ≥ 50%, but BMBL still 〉 5%; stable disease (SD) = BMBL decrease or increase from baseline of 〈 50%; progressive disease (PD) = BMBL increase from baseline of ≥ 50% by an absolute minimum of 5%; Not evaluable (NE). Results:Bone marrow assessment was carried out in 156 patients (pts) on the rigosertib arm and 24 pts on the BSC arm at 4 wks after enrollment, and in 86 and 20 pts, respectively, at 12 wks. The invasive BM procedure was optional on the BSC arm, which accounts for the low number of assessments in this group. BM responses at the 2 time points are presented in Table 1. Since no difference in overall survival was noted between pts who had objective BM response and those who did not progress (ie, stable disease), a landmark analysis was conducted that separated pts who were alive at the 4-wk landmark time into two 4-wk response categories: BM response + SD vs. PD. Results of this analysis in rigosertib-treated patients were statistically significant at p = 0.011, with a hazard ratio (HR) of 0.62 and a median OS (from 4 wks onward) of 9.8 months in the mCR + mPR + SD group vs. 4.6 months in the PD group (Figure 1). Another landmark analysis was conducted at 12-wks. Results of this analysis were also significant (p 〈 0.001) in rigosertib-treated patients, with an HR of 0.39 and a median OS (from 12 wks onward) of 10.4 months in the mCR + mPR + SD group vs.7.5 months in the PD group (Figure 2). A time-dependent Cox regression of OS by 4-wk BMBL response reinforced the validity of the 4-wk and 12-wk BM assessments as surrogate biomarkers for survival (Table 2). Conclusions: These data suggest that BMBL response at 4 or 12 weeks was correlated with OS in this population of pts with HR-MDS treated with rigosertib after HMA failure and are consistent with previous observations in Phase II studies. Table 1 4- and 12-week Bone Marrow Blast Response (Intention-to-Treat Population) Number (%) of Patients 4-wk BMBL Response 12-wk BMBL Response Rigosertib N = 199 BSC N = 100 Rigosertib N = 199 BSC N = 100 Pts with BMBL assessment 156 (78) 24 (24)* 86 (43) 20 (20)* BM complete response (mCR) 22 4 11 5 BM partial response (mPR) 8 2 9 2 Stable disease (SD) 77 9 32 8 Progressive disease (PD) 49 9 34 5 * Bone marrow assessment was not required on the BSC arm. Figure 1 Figure 1. Figure 2 Figure 2. Table 2 Time-dependent Cox Regression of Overall Survival by Bone Marrow Blast Response Analysis Rigosertib BSC Wald P-value Hazard Ratio (95% Confidence Interval) Wald P-value Hazard Ratio (95% Confidence Interval) By 4-wk BMBL response 0.051 0.72 (0.51 - 1.00) 0.56 0.83 (0.45 - 1.54) By 12-wk BMBL response 0.0005 0.55 (0.39 - 0.77) 0.16 0.68 (0.39 - 1.17) *Stratified by pretreatment BMBL: 5%-19% vs. 20%-30% Disclosures Fenaux: Celgene: Research Funding; Janssen: Research Funding; Novartis: Research Funding. Sekeres:Celgene Corp.: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Wilhelm:Onconova Therapeutics, Inc: Employment, Equity Ownership. Azarnia:Onconova Therapeutics, Inc: Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3259.3259

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 3167-3167

Abstract: Background: Based on a model suggesting leukemia can be driven by combined effect of mutations in an epigenetic gene (DNMT3) and Ras, the combination of a hypomethylating agent (HMA) such as azacitidine (AZA) and a Ras mimetic such as rigosertib (RIG) may have enhanced activity in both MDS and AML. The mechanism of action for RIG (Athuluri-Divakar et al, Cell 2016) documents its interference with the RAS-binding domains of RAF kinases and inhibition of the RAS-RAF-MEK and the PI3Ks pathways. In vitro, the combination of RIG with AZA was found to act synergistically to inhibit growth and to induce apoptosis of leukemic cells in a sequence-dependent manner (exposure to RIG first, followed by AZA) (Skidan et al, AACR 2006). Rigosertib's low bone marrow toxicity in pre-clinical assays, effective inhibition of human hematopoietic tumor cell lines, and its synergy with AZA suggests the potential value of combination treatment for patients (pts) with MDS. Phase I results of the current clinical study in pts with MDS or AML showed the combination of oral RIG and standard-dose AZA to be well-tolerated with evidence of efficacy (Navada et al, Blood 2014). The phase II portion of the study was initiated to further evaluate the combination in pts with MDS. Methods: Phase II results are presented for HMA-treatment-naïve MDS pts and for those with MDS failing to respond to or progressed on a prior HMA. Oral RIG was administered twice daily on Day 1-21 of a 28-day cycle at the recommended Phase II dose (RPTD: 560 mg qAM and 280 mg qPM). AZA 75 mg/m2/d SC or IV was administered for 7 days starting on Day 8. A CBC was performed weekly and a bone marrow aspirate and/or biopsy were performed at baseline, D29, and then every 8 weeks thereafter. Results: The combination of oral RIG and injectable AZA has been administered to a total of 54 pts, of whom 40 were pts with MDS including HMA-treatment-naïve (N=23) and previously HMA treated pts (N=17). Median age was 66 years (range 25-85); 73% of pts were male; and ECOG performance status was 0, 1, and 2 in 23%, 73%, and 5%, respectively. 17 pts received prior HMA therapy: 12 AZA, 4 decitabine, and 1 both. Patients have received 1-36+ cycles of treatment (median, 6 cycles), with a median duration of treatment of 25 weeks (range 4 to 145+ weeks). 8 (20%) and 2 (5%) of pts have been treated for more than 1 and 2 years, respectively. Table 1 shows the response per IWG 2006 criteria (Cheson, Blood 2006) among 33 evaluable patients. The response per IWG 2006 was complete remission (CR) in 8 (24%), concurrent marrow CR and hematologic improvement (HI) in 9 (27%), marrow CR alone in 7 (21%), and HI alone in 1 (3%). When overall response is defined as CR plus PR plus HI - responses with improvement in marrow function and thus either normalization of the peripheral blood count or lineage improvement - defined here as Clinical Benefit Response - 55% of all evaluable pts and 70% of the evaluable HMA-treatment-naïve patients showed responses meeting these criteria. Median time to initial response was 2 cycles (2.2 months), and median time to best response was 3 cycles (3.3 months). Median duration of response was 8 months for CR, 14.3 months for marrow CR, 7.4 months for erythroid response, 8 months for platelet response, and 6.2 months for neutrophil response. Clinical response is classified by IPSS-R risk categories below. The most frequently reported adverse events are nausea (41%), fatigue (39%), diarrhoea (37%), constipation (37%), dysuria (28%), decreased appetite (28%), haematuria (24%, 8% Grade 3), pyrexia (24%), dizziness (22%), thrombocytopenia (20%), back pain (20%), dyspnoea (20%), and cough (20%). Eight deaths were reported on study with most common causes including infection and progression of disease. Conclusions: The combination oforalRIG and standard-dose AZA was well tolerated in repetitive cycles in pts with MDS. Response per IWG 2006 criteria was observed both in HMA-treatment-naïve patients (85%) and in patients after failure of prior HMA therapy (62%); employing Clinical Benefit Response as the criteria, these groups had 70% and 31% response, respectively. These clinical results confirm the preclinical synergistic interaction with the combination of RIG and AZA reported by Skidan et al, and suggest that the combination can overcome clinical resistance to HMAs. Based on these results, a Phase III study of the combination of oral RIG and AZA in patients with MDS is planned. Disclosures Navada: Onconova Therapeutics, Inc.: Research Funding. Daver:Karyopharm: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Ariad: Research Funding; Otsuka: Consultancy, Honoraria; Kiromic: Research Funding; BMS: Research Funding. DiNardo:Agios: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding. Konopleva:Reata Pharmaceuticals: Equity Ownership; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline: Consultancy, Research Funding; Eli Lilly: Research Funding; Cellectis: Research Funding; Calithera: Research Funding. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Petrone:Onconova Therapeutics, Inc.: Employment. Zbyszewski:Onconova Therapeutics, Inc.: Employment. Fruchtman:Onconova: Employment. Silverman:Onconova Therapeutics, Inc.: Patents & Royalties: Co-Patent holder for the combination of azacitidine and rigosertib, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.3167.3167

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1704-1704

Abstract: Background: Myelodysplastic Syndrome (MDS) and Aplastic Anemia (AA) are often associated with clinical immune manifestations. An abnormal profile of the T-cell repertoire can be detected in these patients (pts) and is thought to play a role in bone marrow (BM) insufficiency. The presence of a co-existent large granular lymphocytic (LGL) clone may exacerbate cytopenias independent of the primary disease mechanism and offers another target for therapeutic intervention. Treatment for LGL proliferation is usually immunosuppressive therapy but there is no accepted standard of care. Methods: We explored the role of intravenous immunoglobulin (IVIG) as a treatment for immune-related cytopenias, i.e. Coombs negative (C-) hemolytic anemia, in a series of 12 consecutive pts with an LGL clonal proliferation documented by flow cytometry and TCR clonal rearrangements. Of the 12 cases, 9 had MDS (7 lower-risk), 1 AA with LGL liver involvement, and 1 primary myelofibrosis. One patient (pt) had suspected MDS. Overall response was assessed by MDS IWG criteria 2006. We defined a hemolysis response (HLR) as complete normalization (CR) or, a greater than 50% improvement (PR) in deviation from normal values of LDH, reticulocytes, indirect bilirubin and haptoglobin. Duration of HLR was defined as the time from onset of HLR to the time of resumption of hemolysis and loss of effect of IVIG. Results: All pts were treated with IVIG administered at a dose of 500mg/kg of IVIG once per week, in repeated cycles, with a duration ranging from 1-4 week(s) per cycle. Clinical characteristics (Table 1): M/F ratio 10/2; median age 69. Ten pts had a CD3+ T-LGL and 2 had a CD3-/CD16+/CD56+ NK-LGL circulating clone. Karyotype abnormalities were non-specific; 8 pts had 1-3+ reticulin BM fibrosis; 4 had mutations in RNA-splicing genes: SF3B1 (2); SETBP1 (1); SRSF2 (1). Ten pts were evaluable for response: 8 pts responded (ORR 80%): Hematological improvement (HI-erythroid) 8/8 (100%); a hemolysis CR (HLR-CR) occurred in 7 (87.5%) and hemolysis PR (HLR-PR) in 1 pt (12.5%). Median number of cycles, follow up, and duration of treatment were 16, 21.5 and 9.5 months (mo), respectively. The HLR-CR was durable and prolonged in 3/8 (38%) pts; 2 of these 3 pts (67%) did not require maintenance IVIG. Relapse from HLR occurred in 4, during infection or chemotherapy, but the response returned to the original level by shortening the intervals between administration of IVIG. One pt had relapsed after an initial response and then became refractory to IVIG. In follow up at month 38, 75% of pts were still responding to treatment, and 1 pt was still in remission after 46 mo. In 4 of 6 pts, corticosteroid treatment was discontinued and no longer required for chronic hemolysis, with general improvement of steroid related symptoms. Some patients had been on steroids maintenance for periods ranging from months to years. Response was more durable with continuous rather than sporadic dosing. Adverse events were not specific: 1 pt with self-limited isolated palpitations; 1 pt with hypertension not requiring intervention. Conclusions: Treatment with IVIG of immune cytopenias associated with LGL clones and BMF yields durable responses in 80% of pts. IVIG, especially at high concentrations, may enhance apoptosis, suppress proliferation of T-cells and induce immune-regulation. Given the relative rarity of LGL clones in MDS, further investigational studies will help define the role of IVIG and clarify the mechanism of action in this group of pts with MDS and BMF associated with LGL clones. Table 1. Variable Observed % Symptomatic anemia (fatigue, SOB) 9/12 75 B symptoms (recurrent fever) 2/12 16.6 Infections (bacteremia Campylobacter with migratory arthritis and dermatitis; cellulitis bacteremia S. epidermidis and osteomyelitis) 2/12 16.6 Skin lesions (leg focal ulceration and dermal fibrosis) 1/12 8.3 Splenomegaly 7/12 58.3 Hepatomegaly 2/12 16.6 Adenopathy (mediastinal) 1/12 8.3 Neuropathy 2/12 16.6 Hematologic disorders 11/12 91.6 Myelodysplastic syndrome 9/12 75 Severe aplastic anemia 1/12 8.3 Myeloproliferative neoplasm (PMF) 1/12 8.3 Lymphoproliferative neoplasm (FL+MDS) 1/12 8.3 Hemolytic anemia 11/12 91.6 Solid tumors (anal, squamous cell; breast ca) 2/12 16.6 Autoimmune disorders 7/12 58.3 ITP 3/7 42.8 Ulcerative colitis 1/7 14.3 Pernicious anemia 1/7 14.3 Systemic lupus erythematosus 1/7 14.3 Immune pancreatitis 1/7 14.3 MGUS 4/12 33.3 Disclosures Off Label Use: IVIG.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.1704.1704

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 35-36

Abstract: Background Myelodysplastic Syndrome (MDS) is characterized by ineffective clonal hematopoiesis with peripheral blood cytopenias, leading to death from infection or bleeding. Azacitidine (AZA), a hypomethylating agent (HMA) is the standard of care for treatment of MDS patients (pts) with higher-risk MDS [Silverman LR, The Myelodysplastic Syndrome in Cancer Medicine, Editors: R.J. Bast, et al. 2017]. Responses to AZA occur in 50% of pts with significant effects on hematopoiesis ranging from improvement in a single lineage to complete restoration of blood counts and transfusion independence [Silverman LR, et al. Leukemia, 1993] . AZA treatment is associated with global DNA hypomethylation, including human endogenous retroviruses (HEV) which further activates innate immune signaling [Chiappinelli KB,et al. Cell, 2015]. The exact mechanism by which AZA improves hematopoiesis is unknown. AZA improves overall survival of pts, yet despite this, 100% of pts ultimately fail treatment with worsening cytopenias or transformation to leukemia [Silverman LR, et al. B. J Clin Oncol, 2002; Cancer, 2011] . Thus, understanding the mechanism of resistance and identification of targets which can reverse HMA failure and improve hematopoiesis in MDS pts is critical. Our clinical data demonstrate that AZA combined with Rigosertib (RIGO), a novel Ras mimetic that inhibits Ras/Raf signaling [Athuluri-Divakar SK, et al. Cell, 2016], yields a response rate of 54% of pts who were HMA failures [Navada SC, et al. EHA 2019] . The response was associated with significant improvement in hematopoiesis and represents a critical observation in overcoming the epigenetic clinical resistance phenotype. The precise mechanism that leads to reversal of the resistance phenotype is poorly understood. Methods: We investigated the differential protein expression in response to different treatment (AZA, RIGO alone and sequential combinations RIGO/AZA; AZA/RIGO) in vitro in MDS-L cell line by Reverse phase protein array (RPPA). Further, we also studied the functional role of these treatments on differentiation in the cell line by growing cells on semi-solid media as well as by flow cytometry using various stem cell and differentiation markers (CD34, CD38, CD45, CD123). Results: RPPA analysis indicated a discrete responses to treatment in the MDS-L cell line. The response was prominent with differential expression of 43 proteins specifically in MDS-L cells treated with RIGO/AZA that include PIK3R1, AKT1, mTOR, p38 MAPK, PTEN, RPS6KA1 (Fold change (FC) & lt; -2). All of these proteins are downregulated which suggests inhibition of PI3K and mTOR signaling. Proteins belonging to metabolic pathways, including ACC1 and ACLY, were found to be downregulated, whereas proteins related to mitochondrial function and oxidative phosphorylation (OXPHOS) were upregulated (FC & gt; 1.5/ & lt; -1.5) in cells treated with RIGO/AZA. In addition, we found that MDS-L cells represented both CD34+CD38+ and CD34+CD38- populations by FACS analysis (Fig 1). AZA increases the percentage of CD34+CD38+, indicative of differentiation, whereas RIGO alone increased the percentage of CD34+CD38- cells, representing a primitive stem cell population (Table in Fig 1). Based on the combination of differentiation markers (illustrated in fig 1), we observed that RIGO alone, and sequenced as combination RIGO/AZA, impacts different progenitors such as granulocyte-macrophage progenitor (GMP), megakaryocyte erythroid progenitor (MEP), and multipotent progenitor (MPP). RIGO/AZA treatment showed a decrease in GMP, while the % of MEP was increased, as compared to other treatments. Moreover, we found a remarkable reduction in the number of colony forming units on differentiation media in response to RIGO (83%) and RIGO/AZA (90%). Conclusions: These data demonstrate that in addition to inhibition of the PI3/AKT/mTOR pathway, the RIGO/AZA combination also impacts metabolic and differentiation pathways of MDS-L cells. RIGO alone appears to promote maintenance of a primitive stem cell population, while the RIGO/AZA sequenced combination appears to push the cells toward a cycling stage with increased expression of genes associated with OXPHOS. In comparison, when treated with RIGO, cells remain in a less differentiated stage. Further studies are underway to determine the effect of metabolic changes on differentiation and maintenance of hematopoietic stem cells. Figure Disclosures Navada: Onconova Therapeutics Inc: Research Funding. Reddy:Onconova Therapeutics Inc: Research Funding. Silverman:Celgene: Research Funding; Medimmune: Research Funding; Onconova Therapeutics Inc: Patents & Royalties, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-142908

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 230-230

Abstract: Background: AZA is first line therapy for pts with HR-MDS with an overall response rate (ORR) between 35 and 60% in various publications; with CR/PR rates ranging between 23 and 29% in 3 randomized phase II/III studies (Silverman et al., JCO 2002; Fenaux et al., Lancet Oncol 2009; Sekeres, JCO 2017). AZA also has demonstrated efficacy in older pts with AML (Dombret et al., Blood 2015; Fenaux et al., JCO 2010). Rigosertib interferes with the RAS-binding domains of RAF kinases and inhibits the RAS-RAF-MEK and the PI3Ks pathways (Athuluri-Divakar, Cell 2016). RAS and other genes in this pathway are frequently mutated in HR MDS and putatively drive the malignant clone (Sperling et al., Nat Rev CA 2017). In vitro, the combination of rigosertib with AZA synergistically inhibits growth and induces apoptosis of leukemic cells in a sequence-dependent fashion (Skidan et al; AACR 2006 Abstract 1310). In a trial in lower-risk MDS, oral rigosertib was studied as a single agent at various doses including 560 mg BID for 14-21 days in 28 day cycles and yielded a transfusion independence (TI) rate of 44% - the highest reported TI rate (Raza, ASH Abstract #108660 2017). Based on this observation we expanded the ongoing Phase I/II trial and tested rigosertib at a total of 1120 mg per day with standard dose parenteral AZA (75mg/m2 x 7 days q28 days) in two different schemes as described in methods (NCT01926587). At a dose of 560 mg AM, 280 mg evening the ORR was 77%; 88% for the HMA naïve group and importantly 60% for the HMA Rel/Ref group. Of note, adverse events of interest have been genitourinary (GU) toxicities, particularly hematuria and dysuria. Thus, risk-mitigation strategies (Table 1) were employed to minimize hematuria with higher dose rigosertib at 1120 mg; including the rationale for the lower afternoon (280 mg) dose. We report here the initial results of efficacy and safety. Methods: In the Phase II Expansion cohort, up to 45 pts with HR MDS/RAEB-t/non-proliferative AML were randomized 1:1 into 2 cohorts both to receive 1120 mg of rigosertib over 24 hours: either 560 mg in the morning and 560 mg in the afternoon, or 840 mg in the morning and 280 mg in the afternoon (part of hematuria/dysuria risk mitigation; moving second dose from evening to afternoon to minimize overnight bladder dwell time as permitted by PK analysis (Maniar, ASH Abstract 2018). Each cohort is stratified among HMA naïve and HMA Rel/Ref pts. Hematologic response is determined per IWG 2006. Results: As of July 2018 in the rigosertib 1120 mg cohort in combination with AZA, 45 pts were enrolled; 43 treated, 31 evaluable for response; 14 pts continue on treatment, and 31 pts discontinued (includes 2 enrolled but not treated). To be evaluable for response, a minimum of 12 weeks of the doublet was required. Of the 31 pts evaluable for response, 17 pts are prior Rel/Ref, 14 pts are HMA naïve. The # of prior HMA cycles is 2-15; 13 failed AZA; 1 failed DAC; 2 failed both; and 1 failed other (experimental). The median duration of treatment at this time point for the overall population is 5 months (1-14+). The ORR (Table 2) for the all patients is 68%; 59% for the prior Rel/Ref cohort and 79% for the HMA naïve cohort. For responding patients, responses are seen in both 1120 mg cohorts as shown. Safety: In 43 patients treated with oral rigosertib at 1120 mg and AZA, with risk-mitigating strategies to minimize hematuria, Grade 1 & 2 hematuria = 16%; ≥3 Grade Hematuria = 5% have been seen to date (Table 3). This compares to an incidence of 12 % Gr 3 hematuria at a lower dose of rigosertib (840 mg); and prior to risk mitigation strategies. Incidence of hematuria of any grade with single agent AZA is 6.3 % & Grade ≥3 2.3% (VIDAZA, package insert 2004). Conclusion: The combination of oral rigosertib and AZA in HMA naïve patients with HR-MDS is encouraging compared to single agent AZA. The combination also has activity and reverses the HMA clinical resistance in a substantial number of patients after Rel/Ref, a finding with potentially significant clinical implications. Dose exploration with a higher dose of oral rigosertib (1120mg) administered in different dosing schemes in combination with standard dose AZA continues to be studied to optimize safety and efficacy. By employing risk mitigation strategies, the incidence of GU AEs, including hematuria, has been substantially reduced. We will update the safety and efficacy data at the time of presentation. Based on this data a pivotal trial is planned. Disclosures Navada: Onconova: Research Funding. Atallah:Pfizer: Consultancy; Abbvie: Consultancy; Jazz: Consultancy; BMS: Consultancy; Novartis: Consultancy. Shammo:Incyte: Consultancy, Honoraria, Research Funding; Onconova: Other: research support; Alexion: Honoraria, Other: research support; Novartis: Consultancy, Honoraria; Celgene: Other: research support. Griffiths:Novartis, Inc.: Research Funding; Celgene, Inc: Honoraria, Research Funding; Astex/Otsuka Pharmaceuticals: Honoraria, Research Funding; Pfizer, Inc.: Research Funding; Alexion Inc.: Honoraria, Research Funding. Khaled:Juno: Other: Travel Funding; Alexion: Consultancy, Speakers Bureau; Daiichi: Consultancy. Pemmaraju:abbvie: Research Funding; stemline: Consultancy, Honoraria, Research Funding; celgene: Consultancy, Honoraria; Affymetrix: Research Funding; samus: Research Funding; SagerStrong Foundation: Research Funding; cellectis: Research Funding; daiichi sankyo: Research Funding; novartis: Research Funding; plexxikon: Research Funding. Zbyszewski:Onconova Therapeutics, Inc: Employment, Equity Ownership. Maniar:Onconova Therapeutics, Inc: Employment, Equity Ownership. Petrone:Onconova Terapeutics Inc.: Employment, Equity Ownership. Fruchtman:Onconova Therapeutic Inc: Employment, Equity Ownership. Silverman:Johnson and Johnson: Research Funding; Onconova Therapeutics Inc.: Patents & Royalties, Research Funding; Bayer: Research Funding; Celgene: Research Funding; Medimmune: Research Funding; Mount Sinai School of Medicine: Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-119259

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 33, No. 15_suppl ( 2015-05-20), p. 7017-7017

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2015.33.15_suppl.7017

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2015

detail.hit.zdb_id: 2005181-5

In: Blood Research, The Korean Society of Hematology, Vol. 57, No. 2 ( 2022-06-30), p. 135-143

Type of Medium: Online Resource

ISSN: 2287-979X , 2288-0011

URL: Article

DOI: 10.5045/br.2022.2021163

Language: English

Publisher: The Korean Society of Hematology

Publication Date: 2022

detail.hit.zdb_id: 2711910-5