FCN-338

P1, N=316, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2024 --> Dec 2025

P1, N=99, Active, not recruiting, Fochon Pharmaceuticals, Ltd. | Trial completion date: Jun 2024 --> Dec 2024 | Recruiting --> Active, not recruiting

P1, N=316, Active, not recruiting, Eli Lilly and Company | Trial completion date: Dec 2023 --> Dec 2024

Among 52 patients with hematological malignancies the maximum tolerated dose (MTD) was not reached and no clinical TLS was observed.20 In this study of 22 evaluable patients with RR CLL there was an overall response rate (ORR) of 63.6% (14/22).20 A larger study of 114 patients with RR CLL evaluated lisaftoclax in combination with either the Bruton's tyrosine kinase inhibitor (BTKi) acalabrutinib or the anti CD20 monoclonal antibody rituximab (NCT04215809)...In CLL an overall response rate (ORR) to BGB-1147 of 100% as monotherapy was observed among 8 patients with RR disease.25 In 12 patients with RR MM, the ORR to BGB-1147 in combination with dexamethasone varied from 0–68% depending on the dose cohort.26 In combination with azacytidine in AML the ORR to BGB-11417 was 74% among those with treatment naïve (TN) disease (n=20/27) and 65% (n=13/20) in the cohort with RR disease.27 BGB-11417 monotherapy in 23 patients with RR NHL demonstrated responses in 2 patients with diffuse large B cell lymphoma (DLBCL) and one patient with marginal zone lymphoma (MZL).28 In 11 patients with RR MCL treated with BGB-11417 in combination with zanubrutinib there was a 55% (6/11) ORR.28 S55746 is a potent BAX/BAK dependent BCL2 inhibitor administered orally.18,29 Developed by Servier, it has been tested in phase I studies in CLL, NHL and AML. In a study of S55746 among 37 patients with RR NHL, no dose limiting toxicities (DLT) or TLS was observed after a medium duration of treatment of 42 days.30 FCN-338 is another orally available selective BCL2 inhibitor developed by Fochon currently undergoing phase I testing in RR CLL.18,31 Clinical outcomes with this drug are yet to be publicly reported...More recently navitoclax has been tested in RR myelofibrosis (MF) in combination with ruxolinitib with evidence of clinical response to the combination.35 AZD0466 by Astrazeneca is a nanomedicine potent dual BCL2/ BCLxL inhibitor that mediates BAX/BAK induced apoptosis36,37 and is administered intravenously...Among 9 patients reported undergoing testing for RR hematological malignancy the DLT had not yet been reached.38 Pelcitoclax or APG1252 by Ascentage is a more recent BAX/BAK dependent dual BCL2 and BCLxL inhibitor18,39,40 currently in phase I trials in RR NHL (NCT05186012)...There are multiple emerging BCL2 inhibitors currently undergoing clinical trial testing in hematological malignancies, and it remains too early to appreciate the differential efficacy and toxicity profiles that these agents may carry compared with venetoclax. It is hoped that the results seen with venetoclax can be improved upon across a raft of disease groups over the coming years.

P1, N=316, Active, not recruiting, Eli Lilly and Company | Trial completion date: Apr 2024 --> Dec 2023 | Trial primary completion date: Apr 2024 --> May 2023

LOXO-338 also demonstrated dose-dependent tumor growth inhibition in various murine xenograft models, and showed improved efficacy in combination with pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor (Brandhuber B. et al. LOXO-338 demonstrated a favorable safety profile and was well tolerated at tested dose levels. Preliminary efficacy was observed with LOXO-338 monotherapy in patients with CLL/SLL. BCL2, B-CLL, Waldenstrom's macroglobulinemia, B cell lymphoma

The primary objectives of Part 1 are to determine the RP2D of oral LOXO-338 monotherapy and LOXO-338 in combination with pirtobrutinib for previously treated pts and to evaluate the antitumor activity in pts with WM and AL amyloidosis. Secondary objectives include assessment of the safety profile and tolerability, pharmacokinetic characteristics, and antitumor activity of LOXO-338 monotherapy and in combination with pirtobrutinib based on investigatorassessed overall response rate (ORR), progression-free survival (PFS), time to progression (TTP) and duration of response (DOR) as per disease-specific response criteria.

LOXO-338 also demonstrated dose-dependent tumor growth inhibition in various murine xenograft models, and showed improved efficacy in combination with pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor (Brandhuber et al. Antitumor activity will be evaluated based on overall response rate (ORR), progression-free survival (PFS), time to progression (TTP) and duration of response (DOR) based on disease-specific response criteria per investigator assessment. Results N/A Conclusion N/A

The BCL2 inhibitor venetoclax is approved for the treatment of CLL/SLL and acute myeloid leukemia and has activity in other lymphoid malignancies. Antitumor activity will be evaluated based on overall response rate (ORR), progression-free survival (PFS), time to progression (TTP) and duration of response (DOR) based on disease-specific response criteria per investigator assessment. Key objectives of part 2 are to determine the safety profile and tolerability, PK properties, and anti-tumor activity of LOXO-338 in combination with pirtobrutinib.

Venetoclax is the only FDA-approved BCL2 inhibitor, indicated for use in CLL/SLL and acute myeloid leukemia (AML). This preclinical profile of LOXO-338 supports its nomination as a novel BCL2 inhibitor clinical candidate. A first-in-human Phase 1 clinical trial is planned for 2021.