Abstract: 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. Disclosures Pemmaraju: Pacylex Pharmaceuticals: Consultancy; Roche Diagnostics: Honoraria; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; DAVA Oncology: Honoraria; Blueprint Medicines: Honoraria; Novartis: Honoraria, Research Funding; Incyte Corporation: Honoraria; SagerStrong Foundation: Other: Grant Support. Mudenda:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Wang:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. JI:Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Lu:Ascentage Pharma Group: Current Employment, Current equity holder in publicly-traded company. Fu:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Liang:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. McClain:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Sheladia:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; PharmaEssentia: Research Funding; ItalPharma: Research Funding; AstraZeneca: Research Funding; Protagonist Therapeutics: Research Funding; Promedior: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; Genentech: Research Funding; CTI Biopharma Corp: Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Gilead: Research Funding. Yang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests. Zhai:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests.

Abstract: 3512 Background: APG-115 activates p53-mediated apoptosis in tumor cells retaining wild-type TP53. It also functions as a host immune modulator and enhances antitumor activities when combined with PD-1 blockade preclinically. MDM2 amplification is associated with hyperprogression in patients treated with checkpoint inhibitors. Methods: The Phase Ib / II study was designed to evaluate APG-115 combined with pembrolizumab in patients with metastatic solid tumors (NCT03611868). APG-115 was administered orally every other day for 2 weeks, at dose ranging from 50 mg – 200 mg, with pembrolizumab at 200 mg IV on Day 1 of a 21-day cycle. Study objectives were to assess safety including dose-limiting toxicity (DLT), serious adverse events (SAEs), treatment-related AEs (TRAEs), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy (assessed by RECIST v1.1), to determine recommended phase 2 dose (RP2D). Results: As of December 25, 2019, the enrollment of phase 1b study was completed. Total 19 patients had been treated in four APG-115 cohorts: 50 mg (n = 3), 100 mg (n = 3), 150 mg (n = 6), and 200 mg (n = 7). No DLT was observed, The TRAEs (≥15%) were nausea (47.4%), fatigue (36.8%), decreased platelet count (26.3%), and decreased appetite (21.1%), as well as diarrhea, vomiting, decreased neutrophil or white blood cell count, and hypothyroidism in 15.8% each. Grade 〉 3 TRAEs included decreased neutrophil and thrombocytopenia in 15.8% each. Two SAEs were treatment related: G3 febrile neutropenia and G3 adrenal insufficiency. No new safety finding from combination with Pembrolizumab. The RP2D of APG-115 was 150 mg. One patient with ovarian cancer has a CR lasting for 15 months, 2 patients had PR for 8-9 months: one NSCLC failed IO therapy, another with appendix cancer, and 7 had SD for 1.5-7 months. The objective response rate was 15.8%, and the disease control rate (DCR) was 52.6%. PK data indicated an approximately dose-proportional increase in APG-115 exposure over the range of 50-200 mg on Day 1. PD-PK analyses showed that serum macrophage inhibitory cytokine-1 (MIC-1) increase was time and dose dependent, the MIC-1 elevation correlated with APG-115 exposure, indicating p53 activation in these patients. Conclusions: APG-115 in combination with pembrolizumab is well tolerated. Encouraging antitumor effects were observed in several tumor types. The phase II study is ongoing in the cancer patients with specific bio-marker profiling. Clinical trial information: NCT03611868 .