Santini, Valeria

Abstract 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. Disclosures Fenaux: 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.

Abstract Introduction: Patients with RR-AML, particularly older adults, have dismal outcomes and limited therapy options. Given low response rates and high toxicity with salvage intensive chemotherapy, and frequent ineligibility for allogeneic stem cell transplantation (alloSCT), many patients are treated with HMAs. Robust data regarding use of HMAs in AML predominates in the frontline setting, while their use in RR-AML has limited supportive data. Here wesought to analyze theoutcomes and their predictors in patients with RR-AML treated with HMAs. Methods:We collected data, spanning a period from 2006 to 2016, from 7 centers in the United States and 4 centers in Europe regarding patients treated with HMAs for RR-AML. Responses were defined by International Working Group criteria. Kaplan-Meier methods estimated overall survival (OS) from initiation of HMAs to death or end of follow-up. Multivariable logistic regression models estimated odds for response, and multivariable Cox Proportional Hazard (CPH) models estimated hazards ratios (HR) for OS. Covariates considered included HMA received, age at diagnosis (in years), AML classification at diagnosis (AML with myelodysplasia-related changes [AML-MRC], therapy-related [t]-AML), disease status (relapsed vs. refractory), number of therapy lines prior to HMA (1 vs. 2 vs. >=3), duration of first complete remission (CR1), white blood cell count, peripheral blood blast percentage, bone marrow (BM) cellularity (<=20% vs. > 20%), BM blast percentage (<=20% vs. >20%), cytogenetic risk group, and the presence of complex or chromosome 7 abnormalities. Results: Of 514 patients, 217 patients (42.2%) had refractory and 297 (58%) had relapsed AML. By end of study, 415 patients (88.5%) had died. Median follow-up for living patients was 11.6 months.Median age at diagnosis was 64 years (range [R], 16-92). AML-MRC was diagnosed in 29.0% while 8.2% had t-AML. Median number of prior therapies was 2 (R, 1-7), with 48.3% receiving 1 prior line, 30.2% receiving 2 prior lines, and 21.5% receiving >=3 prior lines. Prior alloSCT was performed in 21.2%. Only 1.9% had good risk (core binding factor) karyotype, while 56.2% had intermediate risk karyotype, and 41.9% had poor risk karyotype. Azacitidine was used in 45.8% and decitabine in 54.2%; median number of azacitidine cycles was 4 (Interquartile range [IQR], 2-6) compared to 2 for decitabine (IQR, 1-4, p <0.001). Best response to HMAs was CR in 11.7% (95%CI, 9%-14%), CRi in 6.4% (95%CI, 4.3%-8.8%), hematologic improvement (HI) in 8% (95%CI, 5.7%-10.5%), stable disease (SD) in 9.8% (95%CI, 7.2%-12.5%), while 64.1% (95%CI, 57.7%-66.2%) had progressive disease (PD). Median OS from HMA initiation for all patients was 6.9 months (IQR, 3.0-13.3). There was a significant difference in OS based on best response achieved [Figure 1]. Unadjusted OS showed an insignificant trend for worsening with increasing number of prior lines of therapy [Figure 2A]. In unadjusted analyses, there was no difference in OS based on HMA received in all patients [Figure 2B] or the subset who received only 1 prior line of therapy (median OS: Azacitidine vs. decitabine 8.4 vs 7.3 months, p=0.88). Following HMA therapy, the median number of subsequent therapies was 0 (R, 0-6), and only 12.8% underwent alloSCT. In multivariate CPH models, HMA used was not significantly associated with OS (HR=0.80, 95%CI, 0.42-1.51, p=0.49), while increasing age, and presence of complex cytogenetics and chromosome 7 abnormalities were significantly associated with risk of death [Table 1]. In multivariable logistic regression models, HMA used was not associated with achieving CR+CRi (Odds ratio=0.56, p=0.32). Conclusions: In this largest reported cohort of patients with RR-AML treated with HMAs, we found that HMAs are often used as alast line of therapy, with a minority of patients receiving subsequent treatment. Nonetheless, the minority of patients who achieve CR (11.7%) with HMA therapy had a median OS of 25.6 months. Therefore, use of HMAs for management of RR-AML is a reasonable intervention in the absence of clinical trial options. There appears to be no difference in OS or probability of achieving CR+CRi based on HMA used. Ongoing analyses in this dataset include further evaluations of predictors, including genetic mutations, and the development of prediction tools for clinical outcomes with HMA therapy. Figure 1. Figure 1. Disclosures Podoltsev: Ariad: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Ritchie:Novartis: Honoraria; Incyte: Speakers Bureau; Arian: Speakers Bureau; Pfizer: Honoraria; Celgene: Speakers Bureau. Sekeres:Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau. Al-Kali:Onconova Therapeutics, Inc.: Research Funding; Celgene: Research Funding. Santini:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Onconova: Consultancy; Amgen: Consultancy; Astex: Consultancy. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Prebet:celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gore:celgene: Consultancy, Honoraria. Zeidan:Ariad: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Background:There are limited treatment options for red blood cell (RBC) transfusion dependent (TD) LR (IPSS Low/Int‐1) MDS patients who are relapsed/refractory to ESAs. Imetelstat is a first‐in‐class telomerase inhibitor that targets cells with short telomeres and active telomerase, characteristics observed in some MDS patients across all disease stages. Preliminary results show that imetelstat is effective treatment in LR‐MDS patients inducing durable TI (Steensma et al ASH 2018 Abstr463).Aims:We report updated efficacy data with a median follow‐up of 12.1 months in 38 LR non‐del(5q) MDS patients, R/R to ESA and LEN/HMA naive from the open‐label, single‐arm Part 1 of IMerge, an ongoing phase 2/3 study (NCT02598661).Methods:Part 1 of the IMerge study included patients with LR MDS, who were heavily transfused (≥4U/8wks), were R/R to ESA or had sEPO >500 mU/mL. Imetelstat 7.5 mg/kg was administered IV every 4 weeks. The primary endpoint was 8‐week TI rate; key secondary endpoints included 24‐week TI rate, safety, duration of TI, and hematologic improvement (HI) rate. Among the initially enrolled patients, higher 8‐week TI rate was observed in the non‐del5q, LEN/HMA naive patients. Therefore, the study was amended to subsequently enroll only these patients. From a total of 57 patients enrolled in Part 1, 38 were non‐del(5q), LEN/HMA naïve patients (13 in the initial and 25 in the expansion cohort). Here we report long‐term efficacy, safety and biomarker data from these 38 patients.Results:Median baseline RBC transfusion burden was 8U/8weeks (range 4–14), 37% of the patients had IPSS Int‐1; 71% had WHO 2001 RARS or RCMD‐RS subtype and 32% with evaluable sEPO levels had baseline level >500 mU/mL.As of 23 January 2019, median follow‐up was 12.1 months for the 38 patients, representing 30.4 and 11.6 months for the initial 13 and additional 25 patients, respectively. The 8‐week TI rate was 45% (17/38) and median TI duration was 8.5 months (range 1.8–32.4). Of the 17 responding patients, 10 (59%) remained transfusion free for over 24 weeks. The 8‐week TI rate did not differ based on the presence of ring sideroblasts or baseline sEPO levels. The 24‐week TI rate was 26% (10/38). Erythroid HI, defined as transfusion reduction by at least 4 units /8 weeks (IWG2006), was achieved in 68% (26/38) of the patients. The most frequently reported adverse events were manageable and reversible grade ≥3 cytopenias. 6/38 patients had IPSS‐R intermediate/poor cytogenetic risk. All 6 patents achieved 8‐week TI; 2/6 patients achieved partial cytogenetic response. Post treatment decrease in telomerase hTERT RNA level was observed in 25/34 (73.5%) patients with available sample. Among 7 patients with pre‐ and post‐treatment mutation analyses, six had SF3B1 mutations at baseline, and a decrease in the mutation VAF was observed in 2 patients that had longest TI duration on study.Summary/Conclusion:In high RBC transfusion burden patients with non‐del(5q) LR‐MDS R/R to ESA and naive to LEN/HMA, single‐agent imetelstat yielded 8‐week TI rate of 45%, with a median duration of 8.5 months (range 1.8–32.4). The 24‐week TI rate was 26%. HI‐E rate was 68%. All patients with IPSS‐R intermediate and poor cytogenetic risk responded. Biomarker analyses of telomerase activity and mutation allele burden indicate an effect on the malignant mutant clone. These data support Part 2 of IMerge, Phase 3 placebo‐controlled, randomized portion of the study, expected to open mid‐2019.

Key Points In the largest study of HMAs in RR-AML to date, 16% of patients achieved CR/CRi and experienced a median OS of 21 months. Low proliferative disease (peripheral blood blasts <5%) was associated with improved response and OS.