A Phase 1, Multicenter, Open-Label, Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Clinical Activity of Orally Administered LP-108 (Lacutoclax) As Monotherapy and in Combination with Azacitidine in Subjects with Relapsed or Refractory Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML)

Background: LP-108 (Lacutoclax) is a potent inhibitor of BCL-2. We explore the toxicity and tolerability of LP-108 as monotherapy and combined with azacitidine (Aza) in patients with relapse/refractory Acute Myeloid Leukemia (AML), Chronic Myelomonocytic Leukemia (CMML) and high-risk refractory/relapsed Myelodysplastic syndrome (MDS) (EudraCT 2021-001402-29, NCT04139434).

Description and aims of the trial: This is a First -in-human (FIH), Phase 1, multicenter, open-label study with dose-escalation of only lacutoclax phase (Phase 1a) and a cohort expansion phase (Phase 1b) combined with Aza. Inclusion criteria were AML, RAEB 1and 2, MDS with IPSS-R>4.5 and CMML with ≥5% of blasts in bone marrow, refractory or relapsed to previous treatment. The primary objective is to characterize safety and tolerability, to define maximum tolerability dose (MTD) recommended phase 2 dose (RP2D) and asses the pharmacokinetics of lacutoclax as monotherapy and combined with Aza. The secondary objective were Overall Response Rate (ORR) the Complete Remission (CR), minimal residual disease (MRD), complete remission with incomplete blood count recovery (CRi), morphologic leukemia free state (MLFS), partial remission (PR), the same in MDS (ORR, CR, PR and marrow CR), progression free survival (PFS), duration of response (DOR), event free survival (EFS) and overall survival (OS). The phase 1 was designed with two arms, monotherapy (Arm 1) and combination therapy with Aza (Arm 2) in a classic 3+3 in order to determine the MTD/OBD and RP2D starting with a dose of 100 mg q d in a 28 daily dosing schedule. Dose Limiting Toxicity (DLT) was described as any extra hematological toxicity ≥3 during the first 28 days of induction or prolonged grade 4 pancytopenia not due to active leukemia beyond 42 days. Adverse events were graded according to the NCI-CTCAE version 5.0.

Results: A total of 44 patients (18 Female, 26 Male) were screened. A total of 32 patients were enrolled due to 12 patients deemed screen failures. The median age of the patients was 70 years (40-88 years). The patient population previous diagnosis were AML (20), CMML (4) and MDS (8). The median number of previous lines of therapy were 2 (1-7). Total patients enrolled in the Arm 1 (monotherapy) were 20, and 12 patients were enrolled in Arm 2. Within Arm 1 the dose was increased from 100mg/day (7 patients) to 200 mg/4 patient then to 400 mg/day (4 patients) and finally up to 600 mg/day (3 patients). In Arm 2 (combination therapy) the dose was increase from 100 mg/day (4 patients), 200 mg/day (5 patients) and 400 mg/day (3 patients). No new TAE's of special interest were found. The number serious TAE's >3 were 5 (25%). In Arm 2 100% of the patients experience some type of AE. No TAE's that implies DLT were not seen. The more frequent AE's were gastrointestinal (vomiting 65%), hematological (thrombocytopenia 65%) and increase bilirubin (25%). COVID 19 was only detected in 1 patient. We observed 4 CRc, 1PR and 2MFLS and 2 patients with improvement in its MDS status.

Conclusions: Lacutoclax is safe with no apparent extra hematological toxicities and appears as a new anti BCL-2 agent in patients with refractory myeloid malignancies. This agent had encouraging efficacy as both monotherapy and in combination with azacitidine.

Montesinos:Janssen: Membership on an entity's Board of Directors or advisory committees, Other: research support, Speakers Bureau; Glycomimetics: Consultancy; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Speakers Bureau; Daiichi Sankyo, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Syndax: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: research support, Research Funding, Speakers Bureau; Kura Oncology: Consultancy; Jazzpharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Daver:Astellas: Consultancy, Research Funding; Glycomimetics: Research Funding; Arog: Consultancy; Celgene: Consultancy; Servier: Consultancy, Research Funding; KITE: Research Funding; Novartis: Consultancy; Genentech: Consultancy, Research Funding; Agios: Consultancy; Shattuck Labs: Consultancy; Pfizer: Consultancy, Research Funding; Syndax: Consultancy; Trillium: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Novimmune: Research Funding; FATE Therapeutics: Other: Consulting Fees, Research Funding; Hanmi: Research Funding; Trovagene: Research Funding; Menarini Group: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Jazz: Consultancy; Daiichi-Sankyo: Consultancy, Research Funding. Anthony:Newave Pharmaceutical Inc.: Current Employment, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Exact Sciences: Consultancy; Halia Therapeutics: Consultancy; Sumitomo Dainippon Pharma Oncology: Patents & Royalties. Tan:Guangzhou Lupeng Pharmaceutical Co: Current Employment, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Chen:Newave Pharmaceutical Inc.: Current Employment, Current holder of stock options in a privately-held company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Newave Pharmaceutical Inc. Chen:Newave Pharmaceutical Inc.: Current Employment, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Curran:Kite Pharmceuticals: Consultancy; Pfizer: Consultancy; Dava Oncology: Honoraria; Jazz Pharmaceuticals: Consultancy; Servier: Honoraria; Clincal Care Options: Honoraria.

LP-108Â . An inhibitor of BCL2