Session: 631. Myeloproliferative Syndromes and Chronic Myeloid Leukemia: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, clinical trials, MPN, Clinical Research, Chronic Myeloid Malignancies, drug development, Diseases, Therapies, Myeloid Malignancies
Aims: To assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical effects of oral GB2064 (1000 mg twice daily [BID]), which was administered to participants with primary or secondary myelofibrosis (PMF/SMF) for 9 months.
Methods: Open-label study in 16 adult participants diagnosed with PMF or SMF in accordance with World Health Organization diagnostic criteria (Barbui et al., Blood Cancer 2018; Cruz et al., Expert Rev Hematol. 2020), who are not taking a JAK inhibitor and therefore are likely to be refractory, intolerant or ineligible for such inhibitors; participants had Eastern Cooperative Oncology Group performance status 0-2, and the clinical laboratory parameters were within appropriate limits per protocol. Primary endpoint is safety and tolerability. Safety and tolerability, PK, PD and appropriate MF-specific assessments will take place at all visits except Day 7, Day 15 and Month 4 when only safety and tolerability will be assessed (Fig A). Bone marrow biopsies, magnetic resonance imaging of spleen and quality of life measures, MPN-10 and EQ-5D-5L are performed at prespecified timepoints within the protocol. Exploratory endpoints include LOXL2 binding assay in the circulation, relationships between PK plasma exposure, PD markers, and markers of clinical activity, fibrosis and inflammation biomarkers (YKL-40, PAI-1, PDGF, CCN2, collagen formation and degradation neoepitopes). The study is not formally powered. Participants who derive benefit may continue therapy for an additional 3 years (Fig B).
Results: At least half of the intended participants have been enrolled and are on GB2064 treatment as of June 2022. One participant successfully completed the study in May 2022 and moved to the extension phase. GB2064 was detected in bone marrow biopsies at concentrations close to those in the plasma and demonstrated LOXL2 target engagement in the systemic compartment using a LOXL2 binding assay in plasma. No significant safety concerns were observed at a dose of 1000 mg BID to date.
Conclusions: MYLOX-1 is designed to explore the safety and clinical effects of GB2064, a novel small-molecule LOXL-2 inhibitor, addressing bone marrow fibrosis as a main element of MF, with the aim to decrease extramedullary haematopoiesis and improve haematological parameters, symptom burden and the quality of life for patients with MF.
Disclosures: Verstovsek: Protagonist Therapeutics: Research Funding; Promedior: Research Funding; Sierra Oncology: Consultancy, Research Funding; Roche: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; Novartis: Consultancy, Research Funding; ItalPharma: Research Funding; Incyte: Consultancy, Research Funding; Gilead: Research Funding; Genentech: Research Funding; CTI BioPharma Corp.: Research Funding; Celgene: Consultancy, Research Funding; Blueprints Medicines Corp.: Research Funding; AstraZeneca: Research Funding; Constellation Pharmaceuticals: Consultancy; Pragmatist: Consultancy. Mascarenhas: CTI BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janseen: Research Funding; Merus: Research Funding; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy; PharmaEssentia: Consultancy, Research Funding; Forbius: Research Funding; Merck: Research Funding; Galecto: Consultancy; GSK: Consultancy; Kartos: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Imago: Consultancy; Roche: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison: Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Keros: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; AOP Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Galecto: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Promedior: Membership on an entity's Board of Directors or advisory committees; EHA: Other: Leadership role; MPN voice: Other: Leadership role; Shire: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Sierra: Honoraria; Galacteo: Membership on an entity's Board of Directors or advisory committees; Constellation Pharmaceuticals, Inc., a MorphoSys Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings, Research Funding; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding. Jacoby: Galecto, Inc: Current Employment. Slack: Galecto: Current Employment. Aslanis: Galecto: Current Employment. Singh: Galecto: Current Employment. Lindmark: Galecto: Current Employment.