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)
Authors: Ohanian Maro , Kantarjian Hagop M. , Ravandi Farhad , Borthakur Gautam , Garcia-Manero Guillermo , Andreeff Michael , Jabbour Elias , Konopleva Marina , O'Brien Susan , Quintas-Cardama Alfonso , Somer Bradley G. , Tari Ana , Verstovsek Srdan , Wierda William G. , Cortes Jorge E. 
Published: October 2019

Abstract

Background
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.

Aim
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.

Methods
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.

Results
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%).

Conclusions
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.

Disclosures:
Tari: Bio-Path Holdings: Employment, Equity Ownership.