Trial in Progress: Phase Ib/II Study of Bcl-2/Bcl-Xl Inhibitor Pelcitoclax (APG-1252) in Patients with Myelofibrosis (MF) That Progressed after Initial Therapy

Background:

Pelcitoclax (APG-1252), a novel dual inhibitor of Bcl-2/Bcl-xL, is active as monotherapy in patients with advanced solid tumors and well tolerated up to 240 mg twice weekly (NCT03387332). Preclinical data suggest that cells with Janus-associated kinase-2 (JAK2) mutations, including those associated with bone marrow fibrosis, are dependent on Bcl-2/Bcl-xL for survival and that addition of BH3 mimetics targeting Bcl-2/Bcl-xL induces apoptosis. Furthermore, in JAK2‒mutated cell models, apoptotic synergy is demonstrated when a JAK2 inhibitor and Bcl-2/Bcl-xL inhibitor are combined, as inhibition of Bcl-xL overcomes resistance to JAK2 inhibitors. Taken together, APG-1252 could overcome resistance to JAK2 inhibitors, and the combination could augment clinical benefit in patients with suboptimal responses to JAK2 inhibitor‒based therapy.

Study Objectives:

The primary objective of this open-label trial is to evaluate the safety and efficacy of APG-1252, as monotherapy and when combined with ruxolitinib, in adults with histologically or cytologically confirmed MF who require therapy and are ineligible for JAK2 inhibitors (and can receive single-agent APG-1252) or have had inadequate responses to ruxolitinib-based therapy (and can receive this treatment plus APG-1252). Secondary objectives include APG-1252 pharmacokinetics, time to response, and duration of response. Exploratory objectives include changes in cytogenetics and molecular mutations, bone marrow fibrosis, and cytokines on treatment.

Study Design:

The study is divided into Part 1 (APG-1252 monotherapy) and Part 2 (APG-1252 plus ruxolitinib). For Part 1, the key inclusion criterion is ineligibility for JAK2 inhibitors and for Part 2, inadequate responses to prior ruxolitinib-based therapy.

A standard 3+3 dose-escalation design is being implemented to determine the maximum tolerated dose (MTD) of APG-1252 monotherapy in Part 1 and APG-1252 combined with ruxolitinib in Part 2. APG-1252 will initially be administered at 160 mg intravenously by 30-minute injection once weekly in a 28-day cycle. The dose can be escalated to a maximum of 240 mg or reduced to a minimum of 80 mg, depending on tolerability. Part 2 will begin once the MTD and recommended phase 2 dose (RP2D) of APG-1252 monotherapy have been determined. In Part 2, ruxolitinib will be administered orally twice daily per the package insert. After the MTD for APG-1252 monotherapy has been determined, no additional patients will be enrolled in Part 1; however, up to 15 to 30 additional patients can be enrolled in Part 2, to further evaluate the safety and anticancer activity of the combination at MTD or RP2D. Patients will continue treatment until disease progression or unacceptable toxicity. Clinical responses are being assessed every 12 weeks according to criteria from the International Working Group‒Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet panels, while optimal clinical benefit will be evaluated at 24 weeks. Enrollment will be from September 2020 and preliminary results estimated in October 2022. For further information, contact: yzhai@ascentage.com. Registration: ClinicalTrials.gov Identifier NCT04354727.