Background: Essential to cancer cell signaling, the Growth factor Receptor Bound protein-2 (Grb2) is utilized by oncogenic tyrosine kinases to activate Ras and ERK. BP1001is a liposome-incorporated antisense which inhibits Grb2 expression. The study aimed to define safety, maximum tolerated dose (MTD), pharmacokinetics, and anti-leukemic activity of BP1001 in patients (pts) with hematologic malignancies. Methods: This is a standard 3+3 phase I dose-finding study in pts with relapsed/refractory acute myeloid leukemia (AML), chronic myeloid leukemia in blast phase (CML-BP), and myelodysplastic syndrome (MDS). BP1001 was given twice weekly, IV over 2-3 hours for 28 days. Dose escalation proceeded through 5, 10, 20, 40, 60, and 90 mg/m². Upon completion of single agent phase I cohorts 1-6, the combination of cytarabine 20 mg SubQ BID x 10 days + 60 mg/m² BP1001 (cohort 7) or 90 mg/m² BP1001 (cohort 8) was studied. Results: A total of 38 pts were treated: AML (n = 29), CML-BP (n = 5) and MDS (n = 4). Cytogenetic / molecular abnormalities included: t(9;22) (n = 2), diploid (n = 11), complex (n = 7), BCR-ABL (n = 5; including T315I in 2), FLT3D835 (n = 1), FLT3ITD (n = 1), CEBPA (n = 1), NPM1 (n = 2), TP53 (n = 3), IDH1 (n = 1), IDH2 (n = 3), NRAS (n = 1), JAK2 (n = 2), GATA2 (n = 1), TET2 (n = 1), DNMT3A (n = 1). Of 38 pts, 26 were evaluable; 12 failed completion of a full cycle due to disease progression and were replaced per protocol. Only one pt on 5 mg/m² experienced a dose limiting toxicity (DLT), grade 3 mucositis and hand-foot syndrome, while on high-dose hydroxyurea for proliferative CML-BP. Among 26 evaluable pts, a median of 1 cycle was administered (1-5): 6 received 2 cycles, 4 received 5 cycles, and all others received 1 cycle. Among the 21 evaluable pts on single agent cohorts, 11 experienced ≥ 50% reduction in peripheral or bone marrow blasts; 2 had improvement of leukemia cutis; 6 had transient decline in blasts (n = 3) and/or stable disease (n = 3). Among the 5 evaluable pts on combination therapy, 2 achieved CR and 2 achieved PR. Conclusions: BP1001 at 5-90 mg/m² is well tolerated with no MTD identified. Results demonstrate the novel BP1001 + cytarabine combination is well tolerated with early evidence of anti-leukemic activity including CR in 2 relapsed AML pts. Clinical trial information: NCT01159028