Safety, Pharmacokinetics, and Efficacy Of BP-100-1.01 (Liposomal Grb-2 Antisense Oligonucleotide) In Patients With Refractory Or Relapsed Acute Myeloid Leukemia (AML), Philadelphia Chromosome Positive Chronic Myelogenous Leukemia (CML), Acute Lymphoblastic Leukemia (ALL), and Myelodysplastic Syndrome (MDS)

Essential to cancer cell signaling, the adaptor protein growth receptor bound protein-2 (Grb-2) is evolutionarily conserved. With SH2/SH3 domains and lacking enzyme activity, Grb-2 is utilized by oncogenic tyrosine kinases such as Bcr-Abl to activate Ras, ERK, and AKT during cancer progression. Thus, Grb2 suppression has therapeutic potential. BP-100-1.01 is a neutrally-charged, liposome-incorporated antisense designed to inhibit Grb-2 expression.

To define the safety, maximum tolerated dose, optimal biologically active dose, pharmacokinetics and anti-leukemia activity of BP-100-1.01 in patients (pts) with hematologic malignancies.

This is a standard 3+3 phase I dose-finding study in pts with relapsed or refractory acute myeloid leukemia (AML), chronic myeloid leukemia in blast phase (CML-BP), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS). The starting dose was 5 mg/m² twice weekly, intravenously (IV) over 2-3 hours for 28 days. Dose escalation has proceeded through 10, 20, 40, and 60 mg/m² and will proceed to 90 and 135 mg/m². Flow cytometric analysis was performed on peripheral blood samples from Cohorts 3, 4, & 5, collected prior to study initiation (baseline), on day 15 and on end-of-treatment day (EOT). Commercially available fluorescent-labeled antibodies specific for Grb-2 or phosphorylated Erk (pErk) were utilized to determine Grb-2 protein levels and pErk levels in CD33-expressing cells.

A total of 28 pts were included (13 in Cohort 1, 6 in Cohort 2, and 3 each in Cohorts 3, 4, and 5). The median age was 62 yrs (range, 32 - 89) and diagnoses were AML (n=19), CML-BP (n=5) and MDS (n=4). The median number of prior therapies was 4 (range, 1 to 8). Of 28 pts, 18 were evaluable and 10 failed completion of a full 28-Day cycle due to disease progression (with no toxicity) and were replaced, per protocol. Only one pt experienced dose limiting toxicity (DLT), grade 3 mucositis and hand-foot syndrome, while receiving concurrent hydroxyurea for proliferative CML-BP. The patient had a previous history of hydroxyurea-induced mucositis. Being the first patient to receive BP-100-1.01, these toxicities were considered possibly related to BP-100-1.01. The cohort was expanded to a total of 6 pts. No other drug related toxicities have been noted in any of the pts treated. No other DLT have occurred. Among 18 evaluable pts, 9 experienced at least a 50 percent reduction in peripheral or bone marrow blasts from baseline. Furthermore, 5 pts demonstrated transient improvement and/or stable disease, 3 of whom received a total of 5 cycles each while 2 pts with improvement in leukemia cutis lesions received 1 cycle each. The remaining patients received 1 cycle each. Notably patient 002 with CML-BP showed a significant reduction in blasts from 81% to 5%. Due to leptomeningeal disease progression he discontinued therapy before a full cycle.

The levels of Grb-2 and pErk proteins were indicated by their respective median fluorescent signals and are shown in the table. The median fluorescent signals of Grb-2 and pErk on days 15 and EOT were compared to baseline. On day 15, BP-100-1.01 decreased Grb-2 levels in 5 out of 8 samples tested, and pErk levels in 4 out of 8 samples. The average decrease in Grb-2 levels was 55% (range: 47 to 63%) and the average decrease in pErk levels was 54% (range: 28 to 82%). On EOT day, BP-100-1.01 decreased Grb-2 levels in 7 out of 8 samples, and pErk levels in 6 out of 8 samples. The average decrease in Grb-2 levels was 42% (range: 28 to 57%) and the average decrease in pErk levels was 50% (range: 27 to 91%).

Preliminary results suggest that BP-100-1.01, at dose range 5 mg/m² to 60 mg/m² is well tolerated with no MTD yet identified. There is suggestion of Grb-2 target protein down-regulation, and possible anti-leukemia activity. Accrual continues with cohort 6 open at 90 mg/m².

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