Safety, Pharmacokinetics, and Efficacy of BP-100.1.01 (L-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: Cortes Jorge E. , Garcia-Manero Guillermo , Ravandi Farhad , Andreef Michael , Borthakur Gautam , Jabbour Elias , Konopleva Marina , o'Brien Susan , Quintas-Cardama Alfonso , Verstovsek Srdan , Wierda William G. , Kantarjian Hagop M. 
Published: October 2019

Abstract
Abstract 3639

Background:
The adaptor protein Growth Receptor Bound protein-2 (Grb-2) is essential to cancer cell signaling. Grb-2 is conserved through evolution, contains SH2/SH3 domains, has no enzyme activity and is not phosphorylated. Grb-2 is utilized by oncogenic tyrosine kinases such as Bcr-Abl to activate Ras, ERK, and AKT to induce cancer progression. Suppressing the function or expression of Grb2 should interrupt its vital signaling function and have a therapeutic application in cancer. BP-100.1.01 is a neutral-charge, liposome-incorporated antisense drug substance designed to inhibit Grb-2 expression. BP-100.1.01 is systemically delivered by I.V. injection.

Aim:
To define the safety, maximum tolerated dose, optimal biologically active dose, pharmacokinetics and anti-leukemia activity of BP-100.1.01 in patients with hematologic malignancies.

Methods:
This clinical trial is a standard 3+3 dose-finding study in patients with refractory or relapsed AML, CML, ALL and MDS. The starting dose was 5 mg/m2 administered twice weekly, intravenously over 2–3 hours for 28 days. Dose escalation will proceed at doses of 10, 20, 40 and 50 mg/m2. Patients are allowed to receive hydroxyurea during the first cycle of therapy.

Results:
A total of 13 patients have been included, all of them in the first cohort. Their median age was 58 years (range, 32 – 85). Their diagnoses were AML in 7, CML blast phase in 5, and MDS in 1 patient. There have been no ALL patient enrolled to date. The median number of prior therapies was 5 (range, 1 to 9). Of the 13 patients treated, 6 were evaluable and 7 failed to complete a full 28-Day cycle because of disease progression and had to be replaced. One patient (the first patient on study) experienced grade 3 mucositis and hand-foot syndrome. This patient had a history of mucositis on prior exposure to hydroxyurea. The patient required administration of hydroxyurea to control rapidly proliferating CML in blast phase and developed mucositis and hand-foot syndrome. Being the first patient receiving therapy with this agent, this was considered possibly related to BP-100.1.01 and the cohort was expanded to a total of 6 patients. No other drug related toxicities were noted in any of the patients treated.
Lab parameters for blasts and bone marrow results for the six evaluable patients are shown below in Table 1. Two patients had transient improvement and/or stable disease and received a total of 5 cycles each. In addition, 2 patients had transient improvement in leukemia cutis lesions.
In addition to the six evaluable patients, patient 002 with CML blast phase who had failed all available TKI and other experimental options showed a significant reduction in blasts from 81% to 4%. Unfortunately, this patient discontinued study treatment due to progression in CNS.

Conclusions:
Preliminary results suggest that BP-100.1.01, at a dose of 5 mg/m2 is well tolerated and there is suggestion of some possible anti-leukemia activity. The study continues accruing and Cohort 2 is open with dosing at 10 mg/m2.

Disclosures:
Cortes: Bio-Path Holdings, Inc.: Research Funding.