luvixasertib (CFI-402257)

Here, we extended those studies into syngeneic murine models of TNBC using two TTK inhibitors: empesertib and the novel TTK inhibitor CFI-402257 (also known as luvixasertib) that was recently granted FDA fast track approval in breast cancer. Taken together, these studies demonstrate that TTK inhibition enhances radiosensitivity and TTK inhibition with RT modulates the immune landscape of TNBC. Collectively, this combination may represent a novel therapeutic strategy to improve outcomes for patients with TNBC by both direct tumor cytotoxicity and by promoting an immune-responsive environment.

P1/2, N=44, Active, not recruiting, Treadwell Therapeutics, Inc | Recruiting --> Active, not recruiting | Trial completion date: Aug 2025 --> Aug 2026 | Trial primary completion date: Aug 2025 --> Aug 2026

P1/2, N=37, Active, not recruiting, Canadian Cancer Trials Group | Trial completion date: Dec 2024 --> Dec 2025

CFI-402257, a specific inhibitor of TTK, is found to exhibit anti-tumor effects and exerted synergistic efficacy with PI3K inhibitor, Duvelisib, in TCL. The study shows that TTK contributes to the development of TCL by regulating p38α-mediated AMPK/mTOR pathway. CFI-402257 is expected to be a promising strategy for TCL treatment.

P1/2, N=37, Active, not recruiting, Canadian Cancer Trials Group | Phase classification: P2 --> P1/2 | Trial completion date: Dec 2023 --> Dec 2024

P1/2, N=44, Recruiting, Treadwell Therapeutics, Inc

CFI-402257 is a potent inhibitor of TTK. It is well tolerated with manageable TEAEs, no dose limiting or treatment limiting toxicities, and no treatment related deaths. Dose expansion in the patient population of interest will commence.

P2, N=37, Active, not recruiting, Canadian Cancer Trials Group | Trial primary completion date: Jun 2023 --> Nov 2022

This increase was induced by treatment with CFI-402257, a selective inhibitor of the mitotic kinase TTK, which plays a key role in spindle-assembly checkpoint (SAC) regulation...Overall, these results suggest that GSCs have an enhanced ability to tolerate the negative consequences of aneuploidy on survival as well as on radiosensitivity. Such aneuploid tolerance may provide a mechanism through which GBMs exploit karyotype diversity to survive under harsh environmental conditions and after treatment.

Background: TTK (also known as MPS1), a dual-specificity serine-threonine kinase, is critical for the spindle assembly checkpoint, chromosome alignment, and error correction in mitosis. CFI- 402257 is well tolerated as mono and combination with fulvestrant. Efficacy signals are emerging with pts in the combo cohort demonstrating anti-tumor activity. Additional efficacy will be updated at the time of the presentation.

CFI-402257 and paclitaxel was well tolerated, with neutropenia as the main toxicity. DL3 (168mg) was selected as RP2D. Phase 2 ORR and CBR was 5.9% and 58.8%, respectively; during Phase 2, the 17 evaluable patients from stage 1 did not meet the pre-specified threshold for anti-tumor activity to proceed to stage 2 and the trial was closed to accrual on April 7, 2022.

In these models, inhibition of TTK with CFI-402257 induces premature chromosome segregation, leading to excessive mitotic segregation errors, DNA damage, and cell death. These findings nominate the TTK inhibitor CFI-402257 as a therapeutic strategy for a defined subset of ER breast cancer patients who develop resistance to CDK4/6i.