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Introduction: Cytarabine is a backbone of intensive acute myeloid leukemia (AML) chemotherapy; yet it is associated with toxicity which precludes its use in older patients and in those with comorbidities. Aspacytarabine (BST-236) is a prodrug of cytarabine, which is inactive in its intact prodrug form until cytarabine is gradually released in the plasma and inside the cells. Due to the pharmacokinetics and metabolism of aspacytarabine, the peak toxic systemic exposure to cytarabine is decreased, resulting in reduced systemic toxicity with relative sparing of normal tissues, thus enabling delivery of high cytarabine doses to AML patients otherwise unfit to receive intensive cytarabine therapy. Presented herein are the data, including final primary endpoint analysis, from a phase 2b study that recently completed enrollment. Aims: To evaluate the efficacy and safety of aspacytarabine as a single agent for induction and consolidation therapy of newly diagnosed AML patients unfit for standard induction chemotherapy. Methods: Aspacytarabine was administered at 6-day courses of 4.5 g/m 2/d (equimolar to 3 g/m 2/d cytarabine) daily 1-hour intravenous infusions, for 1-2 induction and 1-3 consolidation courses, to AML patients age ≥75 years or otherwise unfit for intensive chemotherapy. Patients with secondary or therapy related AML, and patients who received prior hypomethylating agents (HMA) ± venetoclax therapy for a preceding condition were eligible. Primary endpoint is complete remission with complete hematological recovery (CR). Secondary and exploratory endpoints include safety, duration of response (DOR), overall survival (OS), and minimal residual disease (MRD). NCT03435848. Results: Enrollment into the study was completed in May 2021. Sixty-five newly diagnosed AML patients unfit for standard chemotherapy (median age 75 years, range 54-88 years) were treated with aspacytarabine and completed 1-4 courses (median 1 course) at doses of 4.5 g/m 2/d, including 39 patients (60%) with de novo AML and 26 patients (40%) with secondary AML. Eleven patients (17%) were previously treated for MDS/CMML with HMA (median 14 courses), including 1 patient (2%) with HMA + venetoclax. Thirty-two patients (49%) and 15 patients (23%) had adverse or intermediate European LeukemiaNet (ELN) scores, respectively. The baseline median bone marrow blasts was 43%, and 25 patients (38%) had ECOG PS 2 or 3 at enrollment (Table 1). Aspacytarabine was well-tolerated in repeated-course administration. Grade ≥3 drug-related adverse events included hematological events and infections, with, importantly, no severe gastrointestinal or neurological events. The 30-day all-cause mortality rate was 12.5% (95% CI, 5.9-23.7). Of the 65 intention-to-treat AML patients, 24 (37%) achieved a CR following 1 (17 patients) or 2 (7 patients) courses. The median time to complete neutrophil and platelet recovery were 27 days (range 11-39 days) and 26 days (range 18-40), respectively. The CR rates in de novo and secondary AML patients were 44% and 27%, respectively. Twenty-seven percent of the patients with prior HMA therapy achieved a CR, including the 1 patient with prior HMA + venetoclax treatment. The CR rates in patients at the age of ≥75 years and patients with adverse ELN scores were 35% and 34%, respectively. Of the 21 patients in CR evaluable to date for MRD analysis by multiparameter flow cytometry, 11 (52%) became MRD negative following aspacytarabine treatment. Follow up is ongoing, with a current median duration of follow up of 5.2 months. The median DOR has not yet been reached at 12 months, and median OS of responders not reached at 24 months (Figure 1). Conclusions: Aspacytarabine appears to be an effective regimen for AML with a considerable reduction of the attendant toxicities that typically are associated with standard intensive cytotoxic therapies. The results of the phase 2b study are consistent with the previously completed phase 1/2a study, which demonstrated safety and a 36% CR rate in a similar population, suggest that aspacytarabine, given as monotherapy, is generally safe and effective as a first-line therapy for AML patients who are unfit for intensive chemotherapy These data support a role for aspacytarabine as a new treatment option for older patients with AML. Furthermore, this agent may serve as a backbone for combination therapy with targeted or other chemotherapy agents, as well as in younger patients with AML. Figure 1 Figure 1. Disclosures Altman: Boehringer Ingelheim: Research Funding; BMS: Research Funding; Immunogen: Research Funding; Syros: Consultancy; GlycoMimetics: Other: Participation on an advisory board; Daiichi Sankyo: Consultancy; AbbVie: Consultancy, Other: Advisory Board, Research Funding; Fujifilm: Research Funding; Kura Oncology: Consultancy; Kartos: Research Funding; Biosight: Consultancy, Other: Travel fees, Research Funding; Astellas: Consultancy, Other: Advisory Board, Research Funding; ALZ Oncology: Research Funding; Amgen: Research Funding; Aprea: Research Funding; Theradex: Consultancy, Other: Advisory boards; Kura: Research Funding. Koprivnikar: Bristol Myers Squibb: Speakers Bureau. McCloskey: Amgen: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Pfizer: Consultancy; Novartis: Consultancy; Incyte: Speakers Bureau; BMS: Honoraria, Speakers Bureau; COTA: Other: Equity Ownership. Kota: Pfizer: Consultancy; Novartis: Consultancy; Incyte: Research Funding. Emadi: Secura Bio.: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; KinaRx, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Co-founder. Zuckerman: BioSight Ltd: Honoraria; AbbVie: Honoraria; Janssen: Honoraria; Orgenesis Inc.: Honoraria; Cellect Biotechnology: Honoraria; Novartis: Honoraria; Gilead Sciences: Honoraria, Speakers Bureau. Levy: Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Epizyme: Consultancy, Other: Promotional speaker; Dova: Consultancy, Other: Promotional speaker. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Wolach: Novartis: Consultancy; Amgen: Research Funding; Janssen: Consultancy; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy; Neopharm: Consultancy. Percival: AbbVie: Research Funding; Biosight: Research Funding; BMS/Celgene: Research Funding; Cardiff Oncology: Research Funding; Glycomimetics: Research Funding; Nohla therapeutics: Research Funding; Oscotec: Research Funding; Pfizer: Research Funding; Trillium: Research Funding. Roboz: Actinium: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Jazz: Consultancy; MEI Pharma - IDMC Chair: Consultancy; Mesoblast: Consultancy; Glaxo SmithKline: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Janssen: Research Funding; Daiichi Sankyo: Consultancy; Blueprint Medicines: Consultancy; Bristol Myers Squibb: Consultancy; Helsinn: Consultancy; Jasper Therapeutics: Consultancy; Astellas: Consultancy; Astex: Consultancy; Agios: Consultancy; Pfizer: Consultancy; Otsuka: Consultancy; Roche/Genentech: Consultancy. Levi: AbbVie: Consultancy, Research Funding. Flaishon: BioSight Ltd.: Current Employment. Cohen: BioSight Ltd.: Current Employment. Tessler: BioSight Ltd.: Current Employment. Blumberg: BioSight Ltd.: Current Employment. Gengrinovitch: BioSight Ltd.: Current holder of individual stocks in a privately-held company. Ben Yakar: BioSight Ltd.: Current Employment. Rowe: Biosight Inc.: Consultancy.

Introduction: BST-236 (aspacytarabine), a novel pyrimidine antagonist, is a cytarabine prodrug designed to deliver high cytarabine doses with reduced systemic toxicity. BST-236 pharmacokinetics and metabolism reduce peak systemic exposure to free cytarabine and enable intensive treatment to patients otherwise unfit for intensive therapy. An open label phase 2b study, following a completed phase 1/2a dose escalation study, is ongoing. Enrolled are newly-diagnosed acute myeloid leukemia (AML) patients unfit for standard therapy, including patients with treatment-related AML or AML secondary to myelodysplastic syndrome (MDS) with prior exposure to hypomethylating agents (HMA). Aims: To evaluate the efficacy and safety of BST-236 induction and consolidation in AML patients unfit for standard induction therapy. Methods: BST-236, at a dose of 4.5 g/m2/d (containing 3 g/m2/d of cytarabine), is evaluated as a first-line induction and consolidation therapy in newly-diagnosed AML patients unfit for standard chemotherapy. Patients with secondary AML, previously treated with HMA, as well as patients with therapy-related AML, are eligible. Each BST-236 induction and consolidation course consists of 6 daily 1-hour intravenous infusions. Results: To date, in the phase 1/2 and phase 2 studies, 42 AML patients were treated with BST-236, of whom 20 newly-diagnosed AML patients unfit for standard chemotherapy (median age 73 years) completed 1-4 courses of 4.5 g/m2/d BST-236. Of these, 40% had de novo AML and 60% had secondary AML. Thirty percent of patients were previously treated with HMA for MDS (median 10 courses), and 10% received prior chemo- or radiotherapy. The median baseline bone marrow blast percentage was 38 (range 13-94), and 35% and 53% of patients had intermediate or adverse European LeukemiaNet (ELN) score, respectively. BST-236 is safe and well-tolerated in repeated-course administration. Grade >2 adverse events include mainly hematological events and infections, with no other drug-related typical high-dose cytarabine events such as severe mucositis or cerebellar toxicity. Related serious adverse events include only cytopenia and pneumonia. The 30-day mortality rate is 7%. The complete remission (CR) rate in the evaluable patients to date who received 4.5 g/m2/d BST-236 is 50% in the de novo patients, 20% in secondary AML patients, and 20% in patients with prior HMA treatment. Forty-three percent of patients with adverse cytogenetics attained a CR, including 1 of 3 patients with a TP53 mutation. The median number of courses for reaching a CR is 1, and notably, all patients with bone marrow remission achieved complete hematological recovery within 36 days. BST-236 consolidation was well-tolerated and did not result in increased toxicity, enabling full count recovery. While none of the patients have undergone stem cell transplant, considered ineligible by the treating investigator, responses to BST-236 were durable and median overall survival (OS) for responders is not reached at 23 months (Figure 1A). Median OS for secondary AML patients was 6.8 months, and not reached for the de novo AML patients (Figure 1B). Follow up is ongoing with additional patients enrolling on study; updated analysis of response, minimal residual disease (MRD), duration of response, and OS will be presented at the meeting. Conclusions: The cumulative clinical data suggest that BST-236 as a single agent treatment is a safe and efficacious induction and consolidation therapy for patients who are unfit for standard intensive chemotherapy, including patients with adverse cytogenetics and prior exposure to HMA. The data may establish BST-236 as a new intensive therapy backbone of AML and may, for the first time, allow older adults deemed unfit for standard intensive induction and consolidation therapy, to benefit from an intensive treatment. Disclosures Altman: Genentech: Research Funding; Novartis: Consultancy; Syros: Consultancy; Theradex: Other: Advisory Board; Agios: Other: advisory board, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; AbbVie: Other: advisory board, Research Funding; Fujifilm: Research Funding; Kartos: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; ImmunoGen: Research Funding; Amgen: Research Funding; Aprea: Research Funding; Amphivena: Research Funding; Janssen: Consultancy; Immune Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; ASH: Consultancy; Cancer Expert Now: Consultancy; PeerView: Consultancy; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; PrIME Oncology: Consultancy; France Foundation: Consultancy. Luger:Ariad: Research Funding; Biosight: Research Funding; Kura: Research Funding; Onconova: Research Funding; Agios: Honoraria; Acceleron: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Daiichi-Sankyo: Honoraria; Hoffman La Roche: Research Funding; Loxo Oncology: Honoraria. Koprivnikar:Amgen: Speakers Bureau; Novartis: Speakers Bureau; Alexion: Speakers Bureau; BMS: Speakers Bureau. Kota:Novartis: Consultancy, Honoraria; Incyte: Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Honoraria; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical, Company Ltd, Cambridge, MA, USA: Honoraria; Xcenda: Honoraria. Emadi:Jazz Pharmaceuticals: Research Funding; NewLink Genetics: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; KinaRx: Other: co-founder and scientific advisor. Bhatnagar:Novartis: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapuetics: Research Funding; Cell Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bixby:GlycoMimetics: Research Funding. Burch:Janssen: Other: paid speaker. Wolach:Amgen: Other: Fees for lectures and Consultancy; Janssen: Other: Fees for lectures and Consultancy; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Fees for lectures and Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Astellas: Consultancy, Honoraria, Other: Fees for lectures and Consultancy; Pfizer: Consultancy, Honoraria. Levi:Abbvie Inc: Consultancy, Research Funding. Flaishon:BioSight Ltd.: Current Employment. Tessler:BioSight Ltd.: Current Employment. Gengrinovitch:BioSight Ltd.: Current Employment. Ben Yakar:BioSight Ltd.: Current Employment. Rowe:Pluristem ltd: Consultancy.

High-dose cytarabine is the backbone of acute myeloid leukemia (AML) treatment. Nevertheless, its use in older patients is considerably limited due to increased toxicity. BST-236 (INN aspacytarabine) is a novel cytarabine prodrug designed to deliver high-dose cytarabine to target cells with reduced systemic exposure to free cytarabine. This phase 1/2a dose-escalation study was designed to evaluate BST-236 safety, pharmacokinetics, and efficacy in older or unfit-for-intensive-therapy patients with acute leukemia. Twenty-six patients, unfit for standard therapy, who were either relapsed/refractory or newly diagnosed, received BST-236 in 6 dose-escalating cohorts (range 0.3 to 6 g/m(2) per day). BST-236 was administered intravenously once daily over 60 minutes for 6 consecutive days. The median age was 76.5 (26 to 90), with 84.6% of patients ≥70 years. BST-236 was safe and well tolerated. The maximal tolerated dose was 6 g/m(2) per day. Overall response rate was 29.6%. A subgroup analysis of newly diagnosed patients with AML, de novo or secondary to myelodysplastic syndrome, unfit for standard induction (median age 78), demonstrated overall response of 45.5%. The median overall survival was 6.5 months and was not reached in patients achieving complete remission. The findings of this phase 1/2 study suggest that BST-236 safely delivers high and efficacious cytarabine doses to older patients who are unfit for standard induction and lays the foundation for further studies of BST-236 in AML. This trial was registered at www.clinicaltrials.gov as #NCT02544438.

Introduction: Aspacytarabine (BST-236) is a prodrug of cytarabine, a backbone of acute myeloid leukemia (AML) therapy. Due to its unique pharmacokinetics and metabolism, treatment with aspacytarabine evades peak exposure to free cytarabine, which reduces non-hematological toxicity and enables delivery of high-dose cytarabine also to patients unfit for standard therapy. Data from a completed phase 1/2a and an ongoing phase 2b studies in AML patients unfit for standard therapy, including patients with AML secondary to therapy and myelodysplastic syndrome (MDS) with prior exposure to hypomethylating agents (HMA), demonstrate promising single-agent efficacy and safety of aspacytarabine as a potential first-line AML treatment for this challenging population. Aims: To evaluate the efficacy and safety of aspacytarabine in AML patients unfit for standard induction therapy. Methods: A completed phase 1/2a study and an ongoing phase 2b study evaluate the efficacy and safety of aspacytarabine as a single-agent therapeutic for AML. The phase 1/2a, dose-escalation study enrolled newly-diagnosed patients unfit for standard therapy and patients with relapsed/refractory AML. Patients were treated with 0.3-6 g/m2/d aspacytarabine in 6 dose-escalating cohorts. The ongoing multi-center phase 2b study expands the subgroup of newly-diagnosed AML patients unfit for standard therapy, to evaluate the efficacy and safety of aspacytarabine as a first-line therapy for this population. Secondary AML patients, treated with HMA, chemotherapy, or radiotherapy for a prior condition, are allowed. Patients in the phase 2b study are treated with the selected aspacytarabine dose of 4.5 g/m2/d, containing approximately 3 g/m2/d of cytarabine. Each aspacytarabine treatment course (induction and consolidation) consists of 6 1-hour daily intravenous infusions. Results: To date, 34 AML patients, median age 76 years, received at least 1 dose of aspacytarabine, including 30 patients unfit for standard induction therapy due to age or comorbidities. Overall, 25 patients completed 1 course of aspacytarabine, 4 patients completed 2 courses, 1 patient completed 3 courses, and 1 patient completed 4 courses of aspacytarabine. Three patients (in the phase 1/2a study) did not complete the first course. Aspacytarabine was safe and well-tolerated in repeated-course administration, including in older and unfit patients. Adverse events included mainly hematological "on-target" events with no drug-related mucositis or cerebellar toxicity. Twenty-one patients were newly-diagnosed with AML, either de novo or secondary to MDS or therapy. The patient population was characterized by older age (median 76 years, range 67-88 years), and the majority (67%) of patients had secondary AML, including 10 patients (48%) who were previously treated with HMA (median of 10 courses) or radiotherapy. The median baseline bone marrow blast percentage of this population was 75, and 43% and 48% had intermediate or adverse European LeukemiaNet (ELN) cytogenetic score, respectively. Despite these poor-prognostic characteristics, the 30-day mortality rate in the group of patients receiving ≥4.5 g/m2/d aspacytarabine was 7%. The combined complete remission (CR) rate of all doses was 33%, including 1 patient reaching a CR with partial platelet recovery (CRp). The CR rate in patients treated with at least 4.5 g/m2/d aspacytarabine is 36%, with median time for complete hematological recovery of 27 days (range 21-30) following induction and consolidation. Notably, among the 7 patients who reached a CR/CRp (median age 77), 3 secondary AML patients reached a CR, including 2 patients with prior exposure to HMA (5 and 10 courses) and 1 with prior exposure to radiotherapy (Table 1). Duration of response and overall survival follow up is ongoing and will be presented at the meeting. Conclusions: The accumulating clinical data suggest that aspacytarabine is safe and efficacious for the treatment of AML patients who are unfit for standard induction therapy, including patients with prior exposure to HMA, which may establish aspacytarabine as a new therapeutic backbone for AML, either as a single agent or in combination with targeted therapy. Disclosures Altman: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; Novartis: Consultancy; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cancer Expert Now: Consultancy; France Foundation: Speakers Bureau; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Luger:Seattle Genetics: Research Funding; Pfizer: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Cyslacel: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria. Kota:Takeda: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Flaishon:BioSight Ltd.: Employment. Tessler:BioSight Ltd.: Employment. Gengrinovitch:BioSight Ltd.: Employment. Ben Yakar:BioSight Ltd.: Employment. Rowe:BioSight: Consultancy.

Introduction: First line therapy of AML has not changed significantly since the 1970s and still relies on cytarabine as its backbone. Older patients or patients with comorbidities have low tolerability to intensive cytarabine treatment due to increased morbidity and mortality related to its toxicity, such as cerebellar toxicity, bone marrow suppression, gastrointestinal toxicity and infections. Hence, currently available intensive cytarabine treatment is unjustified in this population due to its poor risk/benefit ratio, and therefore, older and unfit AML patients are usually treated with reduced intensity therapy with poor outcomes. BST-236 is a new compound of cytarabine covalently bound to asparagine. It acts as a pro-drug of cytarabine, enabling delivery of high cytarabine doses to leukemia cells with lower systemic exposure to the free drug and relative sparing of normal tissues. As such, BST-236 may serve as an ideal therapy for leukemia, particularly for delivering high doses of cytarabine to medically unfit or older adults. The aim of this Phase I/II study was to evaluate the safety and optimal dose of BST-236 in refractory/relapsed or newly-diagnosed acute leukemia patients unfit for standard induction therapy. Methods: Acute leukemia patients, either relapsed/refractory, or older or unfit newly-diagnosed, were enrolled to a prospective open label single arm study. The study included 6 dose-escalating cohorts of patients treated with 6 daily doses of BST-236 administered as a 1-hour intravenous infusion. Cohorts 1-4 enrolled patients age ≥18 years, dosed with 0.5 g/m2, 1.5 g/m2, 3 g/m2 or 4.5 g/m2, respectively, with a 50% dose reduction in each cohort for patients age >50 years. Cohorts 5 and 6 enrolled patients ≥70 years of age, dosed with 4.5 g/m2 or 6 g/m2, respectively (Table 1). Results: Twenty-six (26) patients received at least 2 daily doses of BST-236, twenty-three (23) of them (14 males and 9 females) completed at least one 6-day treatment course, including 2 patients who received 2 courses. Out of the 23 patients who completed at least one treatment course, median age 77 (range 27-90), 6 had relapsed/refractory AML following standard chemotherapy, median age 64 years (range 27-81), 15 were newly-diagnosed AML patients unfit for standard chemotherapy, median age 78 years (range 70-89), including 11 patients (73%) with AML secondary to myelodysplastic disorder (MDS) or myeloproliferative neoplasms, median age 77 years (range 70-89), and 2 patients with de novo ALL, age 79 and 90. BST-236 treatment was well-tolerated and MTD was not reached in this study. Notably, the maximal dose of 6 g/m2/d BST-236 is the molar equivalent of 4 g/m2/d of cytarabine. Moreover, adverse events were mainly hematological "on-target" events, and no neurological events or >grade 2 events such as mucositis, diarrhea, or alopecia were reported in any of the cohorts during treatment or within 30 days of follow up. Assessment of the outcome of cohort 6 is still ongoing and will be available in the coming weeks. The majority of the newly diagnosed AML patients in cohorts 1-5 responded to BST-236 (Figure 1). The overall response and Complete Remission (CR) rates, of the newly-diagnosed AML patients (de novo and secondary to MDS) was 71% and 43%, respectively. Follow up of the Overall Survival (OS) of these patients is still ongoing, and is currently 6.9 months (active) for all responders, 9.2 months (active) for CR patients, and 0.6 months for the non-responders (Figure 2). Notably, 67% of the responding patients had secondary AML, refractory to hypomethylating agents (HMA). No CR was reached in the 6 patients suffering from relapse or refractory AML, and their median OS was 2.3 months (Figure 2). Conclusions: This Phase I/II study demonstrates that BST-236, a cytarabine pro-drug, is able to safely deliver high-dose cytarabine to older and unfit patients (median age 78) with no significant typical cytarabine toxicities other than "on-target" hematological events. Moreover, the general wellbeing of the patients during and after administration, as noted by the treating physicians, was exceptionally improved compared to intensive therapy. The good safety profile, accompanied by the high response rates and significantly prolonged survival of the older and unfit newly-diagnosed population, most of them refractory to HMA, is highly encouraging. A phase II study is planned to confirm these results. Disclosures Zuckerman: BioSight Ltd.: Consultancy. Gengrinovitch: Biosight: Employment. Flaishon: BioSight: Employment. Ben Yakar: Biosight: Employment.

Glycosylation is the most versatile and one of the most abundant protein modifications. It has a structural role as well as diverse functional roles in many specific biological functions, including cancer development, viral and bacterial infections, and autoimmunity. The diverse roles of glycosylation in biological processes are rapidly growing areas of research, however, Glycobiology research is limited by the lack of a technology for rapid analysis of glycan composition of glycoproteins. Currently used methods for glycoanalysis are complex, typically requiring high levels of expertise and days to provide answers, and are not readily available to all researcher. We have developed a lectin array-based method, Qproteome™ GlycoArray kits, for rapid analysis of glycosylation profiles of glycoproteins. Glycoanalysis is performed on intact glycoproteins, requiring only 4–6 h for most analysis types. The method, demonstrated in this manuscript by several examples, is based on binding of an intact glycoprotein to the arrayed lectins, resulting in a characteristic fingerprint that is highly sensitive to changes in the protein's glycan composition. The large number of lectins, each with its specific recognition pattern, ensures high sensitivity to changes in the glycosylation pattern. A set of proprietary algorithms automatically interpret the fingerprint signals to provide a comprehensive glycan profile output.

e18520 Background: Cytarabine, the first-line treatment for acute myeloid leukemia (AML), is associated with severe toxicity and high treatment-related mortality (TRM), especially in older patients. Hence, while AML incidence increases with age, advanced age and comorbidities limit cytarabine administration. BST-236 is a new cytarabine pro-drug, enabling delivery of high dose cytarabine to leukemia cells with lower systemic exposure to the free drug. The aim of this study was to evaluate the safety and optimal BST-236 dose in acute leukemia patients. Methods: A Phase I/IIa prospective open label study enrolled adult relapsed/refractory or newly-diagnosed acute leukemia patients. Patients are enrolled into 6 BST-236 escalating-dose cohorts (0.3 – 6 g/m2/d). Treatment was administered as 1-hour daily infusion for 6 days. To date, 18 patients, median age 77 (27-90), were treated with up to 4.5 g/m2/day: 6 relapsed/refractory AML patients, median age 64 (27-81), and 12 newly-diagnosed, unfit for standard chemotherapy patients (7 secondary AML; 5 de novo AML/ALL), median age 79 (70-90). Results: BST-236 treatment was well-tolerated. Only 6 SAEs were assessed as possibly/probably related to BST-236, all “on-target” hematological toxicity events or bacterial infections. The 8-weeks TRM (including from disease progression) in the newly-diagnosed population was 16%. No neurological events or > grade 2 typical cytarabine events such as mucositis, diarrhea, or alopecia were reported during treatment or within 30 days of follow up. Response to the treatment was observed in 6 of the 12 newly-diagnosed patients, including 4 complete remissions (CR), with increased overall survival (OS). No response was reached in the relapse/refractory patients. Conclusions: BST-236 is safe and very well tolerated, enabling delivery of high dose cytarabine to old patients, resulting in overall response and CR rates of 50% and 33%, respectively and increased OS. Notably, 67% of the responding patients had secondary AML, refractory to hypomethylating agents. A phase II study is planned to confirm these encouraging results. Clinical trial information: NCT02544438.

Introduction: Therapy of acute myeloid leukemia (AML) has not changed significantly during several decades. High-dose cytarabine, although used as the first-line treatment for AML since 1970s and as a second-line treatment for acute lymphoblastic leukemia (ALL), is associated with severe side effects, such as cerebellar toxicity and bone marrow suppression. Hence, while the incidence of AML increases with age, doses of cytarabine are significantly attenuated or the drug is entirely excluded from the regimen used in older adults due to its potential toxicities, particularly in individuals with hepatic or renal dysfunction. Astarabine is a new composition of cytarabine covalently bound to asparagine. It is designed to target cytarabine to leukemic blasts, thus avoiding extramedullary toxicity. Leukemic cells, which are dependent on an external source of amino acids in general and asparagine in particular, due to their high metabolic rate, have a relatively increased uptake of Astarabine. Inside the blasts, Astarabine is cleaved to cytarabine, enabling targeted killing and relative sparing of normal hematopoiesis. As such, Astarabine may serve as an ideal therapy for leukemia, particularly for delivering high doses of cytarabine to medically unfit or older adults who otherwise can be given supportive therapy only. The aim of this study was to evaluate the safety and optimal dose of Astarabine in refractory/relapsed or medically unfit patients with acute leukemia. Methods: This Phase I/IIa prospective open label study enrolled patients aged ≥18 years with relapsed/refractory or newly-diagnosed acute leukemia unfit for intensive therapy, as judged by the treating physician. The study was approved by the Rambam IRB (approval #0384-11). Patients were enrolled into 6 Astarabine escalating-dose cohorts, each composed of 3-6 patients. Treatment was administered as a 1-hour single daily infusion for 6 days. For cohorts 1-4, Astarabine doses for each infusion were 0.5g/m2, 1.5g/m2, 3g/m2 and 4.5g/m2. The doses were reduced by 50% for patients >50 years. Since dose limiting toxicity (DLT) was not reached in cohorts 1-4, the study was extended to include cohorts 5 and 6 with daily Astarabine doses of 4.5g/m2 and 6g/m2, respectively, with no dose reduction for patients >50 years old. Results: The outcome of 15 patients is reported herein. Six patients with a median age of 64 years (range 27-81) had refractory/relapsed AML, 9 patients with a median age of 80 years (range 70-90) were newly diagnosed (secondary AML - 6, de-novo AML - 2, de-novo ALL - 1) and unfit for intensive therapy. Astarabine treatment was well-tolerated. Two patients died (one from pneumonia and one from sudden death 2 weeks from end of treatment) before completing 30 days post-treatment and hence were excluded from the outcome analysis. Response to the treatment was observed in the bone marrow of 6 of the 7 newly-diagnosed patients for whom bone marrow analysis was available, 3 of whom had a continuous complete remission (CR) for 4 (ongoing), 8, and 10 months post-treatment, and 3 had a continuous partial remission (PR) for 3,7, and 7 (ongoing) months. The median overall survival (OS) of the patients with CR/PR is 7 months to date (table 1). No significant response was observed in the relapsed/refractory patients, with a median OS of 2.5 months. Twelve patients died from disease progression. Conclusions: Astarabine, a new composition of leukemia-targeted cytarabine, is safe and very well tolerated, even in patients over 80 years of age, resulting in response in 6 of 7 newly diagnosed patients with acute leukemia. To the best of our knowledge, this is the first report permitting high-dose of cytarabine, considered a cornerstone of leukemia therapy, to be given to a population of patients that heretofore did not have this option. Further dose escalation studies are currently ongoing at a cytarabine-equivalent dose of 4.5 and 6 g/m2/day. A phase II study is planned to confirm these encouraging results and define the use of Astarabine for patients otherwise unable to receive high doses of cytarabine. Disclosures Zuckerman: BioSight Ltd: Consultancy, Research Funding. Gengrinovitch:BioSight Ltd: Employment, Equity Ownership, Patents & Royalties: Inventor all of the patents. Ben-Yakar:BioSight Ltd: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor of all patents.

Introduction: Therapy of acute leukemia has not changed significantly over the years. Both acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) typically present or have a second peak in older adults, which often precludes intensive therapy due to associated comorbidities. Astarabine, a construct of cytarabine covalently bound to asparagine, is a pro-drug specifically targeting leukemic blasts which are dependent on an external source of asparagine. Within the blasts, Astarabine is cleaved to cytarabine enabling targeted killing and relative sparing of normal hematopoiesis. As such, Astarabine may serve as an ideal therapy for leukemia and, particularly, for medically unfit/older adults otherwise given only supportive therapy. Additionally, targeted killing by Astarabine may be more efficacious and can lead to improved responses in relapsed/refractory patients. The aim of this study was to evaluate the safety and optimal dose of Astarabine in refractory/relapsed or medically unfit patients with acute leukemia. Methods: This prospective open label study enrolled patients >18 years of age with relapsed/refractory acute leukemia or those unfit for intensive therapy, as judged by the treating physician. Refractory acute leukemia was defined as a failure to achieve remission following the last administered treatment. Relapsed disease was defined as recurrence after induction and consolidation. The study was approved by the Rambam IRB. Patients were enrolled into 4 Astarabine escalating dose cohorts, each composed of 3 patients. Treatment was administered as a 1-hour single daily infusion for 6 days. Astarabine doses for each infusion, measured as an equivalent to cytarabine dosing, for age ≤50 years were: 0.5g/m2, 1.5g/m2, 3g/m2 and 4.5g/m2. Astarabine doses for age >50 years were reduced by 50%. Results: The outcome of the first 3 cohorts (9 patients) is reported herein (table 1). Eight patients had AML, of whom 4 had refractory/relapsed and 4 had newly diagnosed secondary AML unfit for intensive therapy, while 1 patient had newly diagnosed ALL. Median age was 80 years (range 27-90). Four patients are alive with a follow-up of 1-10 months, 2 of whom are in continuous CR 4 and 6 months after treatment. Three patients died from disease progression; one died suddenly 7 days after treatment, an event not judged to be treatment-related. No significant adverse events were recorded during or after therapy apart from neutropenic fever. Conclusions: Astarabine, a pro-drug of cytarabine, is safe and very well tolerated, including patients over 80 years of age, and resulted in complete remission in 3 of 9 patients with acute leukemia. Further dose escalation studies are currently ongoing at a cytarabine-equivalent dose of 4.5 g/m2. A phase II study is planned to confirm these encouraging results and define the use of Astarabine for patients otherwise unable to receive high doses of cytarabine. Table 1. Patient No. Age in years Diagnosis BM blasts after treatment Outcome Follow-up duration in months Day 14 Day 30 1 75 Refractory AML 90% 83% Died- DP 3 2 81 Refractory AML 64% 70% Died - DP 2 3 27 Refractory AML 37% 60% Alive with disease 6 4 76 Secondary AML 39% 63% Died -DP 4 5 81 Secondary AML 5% 0% Alive in CR 6 6 63 Refractory AML 100% 100% Died -DP 1 7 90 ALL 3% 0.2% Alive in CR 4 8 86 Secondary AML 80% 8% Alive in PR 3 9 80 Secondary AML N/A N/A Died 1 DP: disease progression; PR: partial remission; CR: complete remission; N/A: non-applicable Disclosures Off Label Use: Astarabine, a Pro-Drug of Cytarabine. A noval therapy for acute leukemia. Ben Yakar:BioSight Ltd.: Employment, Equity Ownership. Gengrinovitch:BioSight Ltd.: Employment, Equity Ownership, Patents & Royalties.

The chemotherapy drug cytarabine is a standard of care in the treatment of Acute Myeloid Leukemia (AML) and relapsed Acute Lymphoblastic Leukemia (ALL), and is the backbone of induction and consolidation chemotherapy for AML. However, cytarabine is highly toxic, with severe side effects such as cerebellar toxicity and bone marrow suppression. Moreover, doses are significantly attenuated for older patients and patients with hepatic or renal dysfunction. Hence, the toxicity of cytarabine considerably limits its use. Astarabine is a construct of cytarabine covalently bound to asparagine. Unlike cytarabine, Astarabine's toxicity was shown to be mostly specific to leukemia cells. Leukemia cells lack asparagine synthetase and are dependent on external source for asparagine, hence asparagine was shown to be selectively taken up by leukemia cells by active transport. Astarabine is taken up by leukemia cells, where it is metabolized into the cytotoxic cytarabine molecules, resulting in leukemia cell death. The effect of Astarabine on 14 different cell lines was investigated. The studies demonstrated that most of the hematological cancer cell lines were sensitive to both Astarabine and cytarabine, while solid tumors cell lines were significantly less sensitive. Astarabine metabolite assay in human leukemia cell lines detected both Astarabine and free Cytarabine metabolites, indicating that Astarabine is a pro-drug of cytarabine. Animal pharmacokinetics studies were performed in mice and pigs. Pharmacokinetics analysis in mice was preformed by Astarabine single intraperitoneal (IP) injection. Astarabine half-life t1/2 of distribution and elimination in mice plasma ranged between 0.645-1.105 hours. Pharmacokinetics analysis in pigs preformed by Astarabine single intraveneous (IV) injection indicated that 50% (t1/2) of Astarabine is cleared from the pigs blood within 17.5-22.8 hours, a significantly higher t1/2 compared to the reported Cytarabine half-life. In vivo tolerability/toxicology studies determinedAstarabine IP repeated maximal tolerated dose (MTD) in IRC mice as 781 mg/kg/day, administrated for 7 consecutive days. IP repeated MTD of Astarabine in SCID mice was determined as 1275-1462 mg/kg/day, administrated for 7 consecutive days. IV repeated MTD in SCID mice was determined as 400 mg/kg/day, administrated for 14 days. Astarabine IV repeated MTD in young pigs was determinedto be 28 mg/kg/day, administrated for 6 consecutive days. Hence, it is concluded Astarabine improves drug tolerability and reduce toxicity in animals by 10-20 fold compared to the reported toxicity of cytarabine. In vivo efficacy studies were performed in a leukemia mouse model (L1210). The L1210 mouse leukemia creates a semi-solid tumor in the abdomen of the mice. Leukemia transplanted mice (12 mice per group) received 14 consecutive daily IP doses of 312 mg/kg/day or 1250 mg/kg/day of Astarabine, or saline control. The control mice died or sacrificed on day 17 due to cancer growth. The abdominal diameter of mice in the 312 mg/kg/day dose Astarabine and the control groups increased during the study (by 41% and 57.8%, respectively), while the abdominal diameter of the 1250 mg/kg/day dose Astarabine group decreased by 8.8%. The abdominal diameter results correlated with the rate of tumor growth: tumors were found in necropsies of mice of both control and 312 mg/kg/day dose Astarabine, however, no tumors were found in necropsies of mice treated with the 1250 mg/kg/day dose Astarabine during recovery period and on termination day. The results present a dose response of Astarabine in leukemia models. In conclusion, Astarabine may serve as a safer, non-toxic alternative to cytarabine for treatment of AML and ALL. Furthermore, Astarabine may offer effective treatment to older patients where current available treatment results in poor outcome. Studies in humans are ongoing. Disclosures Gengrinovitch: BioSight Ltd.: Employment, Equity Ownership, Patents & Royalties. Ben Yakar:BioSight Ltd.: Employment, Equity Ownership. Rowe:Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy.