Astarabine, a Pro-Drug of Cytarabine, Is Safe for Patients with Advanced Acute Leukemia. A Phase I/IIa Single Center Study in Relapsed/Refractory or Medically Unfit Patients
Authors: Zuckerman Tsila , Ben Yakar Ruth , Gengrinovitch Stela , Hoffman Ron , Henig Israel , Lavi Noa , Akria Luiza , Ofran Yishai , Nudelman Olga , Haddad Nuhad , Tallman Martin S , Rowe Jacob M. 
Published: October 2019

Abstract
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.