BST-236, a novel cytarabine prodrug for patients with acute leukemia unfit for standard induction: a phase 1/2a study

Abstract

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/m2 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/m2 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.

Conflict of interest statement

Conflict-of-interest disclosure: T.Z. and J.M.R. are consultants for BioSight Ltd. Y.O. received honoraria or consultation fees from Pfizer, Roche, AbbVie, and Astellas Pharma. S.G., L.F., S.T., and R.B.Y. are employees of BioSight Ltd. The remaining authors declare no competing financial interests.

© 2019 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

PK of BST-236 and cytarabine. (A) Mean time-concentration profiles of BST-236 and cytarabine following a single BST-236 infusion administration (day 1) for a patient receiving 6 g/m2. (B) Mean time-concentration profiles of BST-236 following repeated BST-236 infusion administration (days 1 to 6) for all treatment groups (n = 26).

Figure 2.

Change in BM blast percentage following BST-236 treatment (any dose). Representation of the maximal change in BM blast percentage from baseline to day 14 or day 30 BM examination of each treatment course per each assessable patient.

Figure 3.

OS of newly diagnosed patients with AML (de novo and secondary to MDS), unfit for standard therapy. (A) All patients. (B) Responders (CR/CRp) and nonresponders.