P1/2, N=78, Recruiting, AB Science | Trial completion date: Dec 2024 --> Dec 2026 | Trial primary completion date: Dec 2024 --> Aug 2026

P1, N=17, Completed, Columbia University | Recruiting --> Completed | N=40 --> 17 | Trial completion date: Sep 2025 --> Jun 2024

Thus, C10 may be a colchicine binding site inhibitor with anticancer potential. Abbreviations: BAX, bcl-2-associated X protein; BCL-2, the B-cell lymphoma 2; BSA, bovine albumin; CBSIs, colchicine binding site inhibitors; CCK-8, cell counting kits-8; DAPI, 4',6-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide; EdU, 5-ethynyl-2'-deoxyuridine; FITC, fluorescein Isothiocyanate; GAPDH,glyceraldehyde-3-phosphate dehydrogenase; H-E, hematoxylin-eosin; HRP, horseradish Peroxidase; IHC, immunohistochemistry; MDAs, microtubule destabilizing agents; MSAs, microtubule stabilizing agents; MTAs, microtubule-targeting agents; PBS, phosphate buffered saline; PI, propidium Iodide; PVDF, polyvinylidenefluoride.

This multicenter phase 1 study sought to determine the MTD of oral Lisavanbulin in combination with standard RT (60 Gy/30 fractions) but without temozolomide in patients with newly diagnosed MGMT promoter unmethylated GBM (uGBM). Avanbulin exposures increased in a relatively dose-proportional manner with increasing oral dose of Lisavanbulin from 4 to 15 mg. Lisavanbulin in combination with RT was considered safe up to the highest predefined oral dose level of 15 mg daily.

P1, N=40, Recruiting, Columbia University | Trial primary completion date: Sep 2023 --> Sep 2024

P1/2, N=78, Recruiting, AB Science | Trial completion date: Jun 2023 --> Dec 2024 | Trial primary completion date: Jun 2023 --> Dec 2024

Due to its unique binding to the colchicine site of tubulin, differently from other MTAs, avanbulin has previously shown activity in solid tumor cell lines. Half of the cell lines tested showed an induction of apoptosis already in the first 24 h of treatment, the other half in the first 48 h. EB1 showed expression in DLBCL clinical specimens, opening the possibility for a cohort of patients that could potentially benefit from treatment with lisavanbulin. These data show the basis for further preclinical and clinical evaluation of lisavanbulin in the lymphoma field.

It has promising antitumoral activity in orthotopic glioblastoma (GBM) models in combination with radiation (RT) ± temozolomide (TMZ), including in MGMT promoter unmethylated (uMGMT) tumors. The maximum studied safe dose for Lisavanbulin in combination with RT in newly diagnosed uMGMT GBM was determined at 15 mg daily during radiation. Overall, the safety of this combination was acceptable. Next steps in developing Lisavanbulin in newly diagnosed GBM include safety studies in combination with TMZ and of TMZ+RT in MGMT promoter methylated GBM prior to formally studying efficacy in a prospective randomized trial.

Finally, the results from in silico studies revealed that the predicted absorption, distribution, metabolism, excretion, and the toxicity (ADMET) profile of the most potent MACs might have several advantages in addition to potential disadvantages, and compound 7h could bind into (ΔG -10.08 kcal·mol) and access wider space at the colchicine-binding site (CBS) than that of colchicine or nocodazole via molecular docking studies. In conclusion, our study serves as a basis for the design of promising synthetic compounds as anticancer agents in the future.

P1, N=26, Terminated, Basilea Pharmaceutica | Active, not recruiting --> Terminated; Due to the National Cancer Institute's (NCI)-mandated termination of the Adult Brain Tumor Consortium which was conducting the study

While examining the functional consequence in cell response to hypoxia, we discovered that PARP3 acts to maintain the cytoskeletal microtubule stability. As a result, the absence of PARP3 markedly increases the sensitivity of glioblastoma cells to microtubule-destabilizing agents providing a new therapeutic avenue for PARP3 inhibition in brain cancer therapy.

P1, N=26, Active, not recruiting, Basilea Pharmaceutica | Recruiting --> Active, not recruiting