Abstract CT240: A phase I clinical trial to study the safety, pharmacokinetics, and efficacy of BP1002 (L-Bcl-2) antisense oligonucleotide in patients with advanced lymphoid malignancies
Authors: Ashizawa Ana Tari , Bryan Locke , Wierda William 
Published: September 2020

Abstract
Background: Bcl-2 protein is essential for cancer cell survival. Inhibition of Bcl-2 expression may lead to cancer cell death. A nuclease-resistant, hydrophobic Bcl-2 antisense oligonucleotide (oligo) incorporated in a neutral dioleoylphosphatidylcholine liposome (L-Bcl-2, also known as BP1002) is utilized to inhibit Bcl-2 expression. Preclinical studies showed that L-Bcl-2 inhibited Bcl-2 protein expression and in vivo tumor growth. Bcl-2 expression is frequently altered in human cancers, including lymphomas. We postulate that BP1002 will have anti-tumor activity against lymphomas. This first-in-human BP1002 study is proposed as a dose-escalation monotherapy study in patients with advanced lymphoid malignancies.
Methods: Subjects: BP1002 will be given to adult subjects diagnosed with refractory/relapsed chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, non-Hodgkin lymphoma (B-cell and T-cell) and Waldenströms macroglobulinemia.
Study Design: The study will utilize a single-arm, sequential, dose-escalation design (3+3) to identify dose-limiting toxicities (DLTs), recommended Phase II dose (RP2D), pharmacokinetics (PK), pharmacodynamics, and efficacy of BP1002. BP1002 will be administered to subjects intravenously twice weekly per 28-day cycle (8 doses). There are 2 planned dose levels, 20 and 40 mg/m2. Successive cohorts of eligible patients will be treated with BP1002. A higher dose level cannot be opened until a minimum of three patients have completed an entire therapy cycle at the preceding dose level without having DLTs. Any DLT observed will trigger an expansion of a cohort from 3 to 6 patients. A second DLT at any dose level will identify the maximum dose. The dose below that will be the maximum tolerated dose (MTD). The RP2D will be determined using the MTD data and all information regarding safety, biological activity, PK and pharmacodynamics.
Primary objectives: To determine
• Safety and tolerability of escalating doses of BP1002
• RP2D of BP1002
• PK of BP1002
• BP1002 activity on Bcl-2 expression
Secondary objectives: To obtain evidence of tumor response (overall response rate = complete remission + partial remission + minor response), and estimates for other response parameters (time to progression, progression-free survival, event-free survival)
Exploratory objectives: To correlate treatment response with biological activity, cytogenetic and molecular characteristics
Safety assessments will include identification of DLTs, serious adverse events, treatment-emergent adverse events and treatment-emergent laboratory abnormalities
Response assessments will be determined per the 2018 International Workshop Group on CLL (iwCLL) response criteria, the International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017), or the Eighth International Workshop for Waldenströms Macroglobulinemia response criteria.
Citation Format: Ana Tari Ashizawa, Locke Bryan, William Wierda. A phase I clinical trial to study the safety, pharmacokinetics, and efficacy of BP1002 (L-Bcl-2) antisense oligonucleotide in patients with advanced lymphoid malignancies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT240.