luvixasertib (CFI-402257) / Treadwell Therap - LARVOL DELTA

CFI-402257-CL-001: A Study of Investigational Drug CFI-402257 in Patients With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=52 | Completed | Sponsor: University Health Network, Toronto | Active, not recruiting ➔ Completed

Trial completion • Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • HER-2

Computational exploration of quercetin derivatives from Azadirachta indica leaf as threonine tyrosine kinase inhibitors for potential lung and pancreatic cancer treatment. (PubMed, Comput Biol Chem) - "Quercetin-3-rhamnoside, quercetin-3-glucoside, quercetin-3-O-galactoside, and quercetin-3-rutinoside demonstrated superior binding affinities (-9.5 to -11.089 kcal/mol) compared to control drug Luvixasertib (-8.869 kcal/mol), with enhanced electronic properties (electrophilicity index: 3.53-4.67 compared to control 2.70)...Additionally, toxicity profiling revealed favorable safety profiles with no hepatotoxic, carcinogenic, or mutagenic potential for most derivatives. Therefore, Quercetin derivatives from A. indica leaf represent promising lead compounds for targeted TTK inhibitors in lung and pancreatic adenocarcinomas, highlighting their potential for further experimental validation against TTK."

Journal • Lung Adenocarcinoma • Lung Cancer • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Solid Tumor • TTK

cGAS-STING Signalling in the tumour microenvironment: Implications for immune surveillance and therapeutic strategies. (PubMed, Int Immunopharmacol) - "Pharmacological activation using cyclic dinucleotides (CDN) STING agonists (ADU-S100 and MK-1454) and non-CDN STING agonists (diABZI and MSA-2), as well as MPS1 inhibitors (CFI-402257, BAY-1217389, and CC-671), has effectively triggered strong type I interferon responses and caused tumour regression in preclinical and clinical trials. When combined with radiotherapy, PARP inhibitors, or immune checkpoint blockers, these agents exhibit enhanced synergy but are constrained by tumour heterogeneity and context-dependent toxicity. Here, we reviewed the complexity of the cGAS-STING and its potential as a double-edged sword in cancer treatment, underscoring the need for strict strategies to harness this pathway while enhancing antitumour immunity and mitigating pro-tumorigenic effects."

Journal • Review • Fibrosis • Immunology • Oncology • CGAS • STAT3 • STING • TGFB1

Spindle assembly checkpoint as a therapeutic target for TP53-mutated myeloid neoplasms (AACR 2024) - "The efficacy of TTKi CFI-402257 (AbMole) was tested using cell viability, apoptosis, and colony-forming unit (CFU) assays using the standard protocol...TTKi induced preferential and dose-dependent inhibition of viability and cell proliferation potential in TP53mut MN compared to healthy donor cells, implying a therapeutic window. Further pre-clinical and clinical studies are indicated to evaluate SAC inhibition as a therapeutic strategy for TP53mut MN."

Hematological Malignancies • Oncology • Solid Tumor • TP53 • TTK

Genome-Wide CRISPR Screens Identify ABCG2-Mediated Drug Resistance to the Threonine Tyrosine Kinase (TTK) Inhibitor CFI-402257 in Breast Cancer. (PubMed, Int J Mol Sci) - "However, overexpression of ABCG2 failed to confer resistance to 2257 in TNBC xenografts grown in mice and treated with a moderately active dose and schedule. Our results highlight the potential impact of drug transporters in in vitro CRISPR screens and the importance of confirming the relevance of drug response mechanisms identified in cultured cells using in vivo models that recapitulate drug pharmacokinetics and pharmacodynamics."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ABCG2

CCTG IND.236: CFI-402257 in Combination With Paclitaxel in Patients With Advanced/Metastatic HER2-Negative Breast Cancer (clinicaltrials.gov) - P1/2 | N=37 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial completion date: Dec 2025 ➔ Dec 2026

Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor

PELI1 in human cancers: a pan-cancer exploration of its molecular function, clinical significance, and immunomodulatory roles. (PubMed, Front Immunol) - "PELI1 expression was positively correlated with the IC50 of hepatocellular carcinoma investigational drug-CFI-402257. Experimental knockdown of PELI1 in LIHC cell lines suppressed proliferation, promoted apoptosis and induced G1-phase cell cycle arrest via MAPK-ERK pathway. This pan-cancer study revealed the diagnostic, prognostic and immunomodulatory potential, along with the biological function and mechanism of PELI1, supporting its role as a promising therapeutic target in LIHC."

Biomarker • Journal • Pan tumor • B Cell Lymphoma • Diffuse Large B Cell Lymphoma • Hematological Malignancies • Hepatocellular Cancer • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • Solid Tumor • Targeted Protein Degradation

Inhibition of Threonine Tyrosine Kinase Suppressed TP53-mutated Acute Myeloid Leukaemia Via Synergism with Venetoclax and Activation of the Cgas-Sting Pathway (ASH 2024) - "In vitro treatment of TP53-mutated AML cell lines with TTK inhibitors CFI-402257, AZ3146 and BAY1217389, or specific TTK knock-down significantly reduced cell viability. There was demonstrable synergism with venetoclax. Our results have provided important leads for further mechanistic and clinical studies."

Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ANXA5 • CCL2 • CXCL10 • CXCL8 • IL6 • LMNB1 • TNFA • TP53 • TTK

Targeting monopolar spindle kinase I (Mps1 or TTK) induces radiosensitization in syngeneic models of triple negative breast cancer (TNBC) and potentiates type I interferon (T1IFN) signaling. (PubMed, Neoplasia) - "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."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • TTK

TWT-203: CFI-402257, a Potent and Selective TTK Inhibitor, in Solid Tumors and With Fulvestrant in Breast Cancer (clinicaltrials.gov) - P1/2 | N=44 | Active, not recruiting | Sponsor: Treadwell Therapeutics, Inc | Recruiting ➔ Active, not recruiting | Trial completion date: Aug 2025 ➔ Aug 2026 | Trial primary completion date: Aug 2025 ➔ Aug 2026

Enrollment closed • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

Augmenting Type 1 interferon antitumoral immune signaling in triple-negative breast cancer (TNBC) via combined radiotherapy and monopolar spindle kinase I (Mps1) inhibition (IMMUNOLOGY 2025) - "Mps1 inhibition (via empesertib or CFI-402257) combined with RT inhibited TNBC growth in vitro and in vivo. These data demonstrate that Mps1 inhibition radiosensitizes TNBC models through increased micronuclei formation and induces T1IFN signaling, suggesting that combination therapy might more effectively treat TNBC and potentiate immune responses in women with TNBC. Future work will examine the underlying implications on the antitumoral immune response.Keywords: Animals Human Rodent; Molecules Cytokines MHC; Processes Cell Proliferation"

IO biomarker • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CXCL10 • IFNB1

Modulation of mitotic stress-induced activation of the cGAS/STING signaling pathway by DNA demethylation (EASL 2025) - "Inhibition of the spindle assembly checkpoint kinase TTK/MPS1 by novel compounds such as CFI-402257 targets these effects through deteriorated aneuploidy, followed by increased activation of the cGAS/STING signaling axis and Type I interferon expression. The present study demonstrates that decitabine is capable of reversing the epigenetic silencing of STING in Hep3B and THLE5B cells. However, this does not appear to be sufficient to restore the activation of the cGAS/STING signaling pathway and the associated innate immune response. Further investigation is required to evaluate the impact of decitabine on cGAS/STING activation, particularly with regard to its antiproliferative effect, which counteract mitotic stress-induced cytotoxicity."

Epigenetic controller • Gastrointestinal Cancer • Hepatocellular Cancer • Liver Cancer • Oncology • Solid Tumor • CGAS • CXCL10 • IFNB1

CCTG IND.236: CFI-402257 in Combination With Paclitaxel in Patients With Advanced/Metastatic HER2-Negative Breast Cancer (clinicaltrials.gov) - P1/2 | N=37 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial completion date: Dec 2024 ➔ Dec 2025

Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor

Targeting TTK Inhibits Tumorigenesis of T-Cell Lymphoma Through Dephosphorylating p38α and Activating AMPK/mTOR Pathway. (PubMed, Adv Sci (Weinh)) - "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."

Journal • Hematological Malignancies • Lymphoma • Non-Hodgkin’s Lymphoma • Oncology • T Cell Non-Hodgkin Lymphoma • Targeted Protein Degradation • TTK

TTK Inhibition Alleviates Postinjury Neointimal Formation and Atherosclerosis. (PubMed, Adv Sci (Weinh)) - "Notably, oral administration of the TTK inhibitor CFI-402257 mitigated neointimal formation without impairing reendothelialization and reduced atherosclerotic lesions in ApoE-/- mice without altering lipid levels. These findings suggest that targeting TTK, through inhibitors or alternative strategies, represents a promising approach to simultaneously prevent postinjury restenosis and treat atherosclerosis."

Journal • Atherosclerosis • Cardiovascular • Hematological Disorders • Thrombosis • APOE • CTNND1 • TTK

CCTG IND.236: CFI-402257 in Combination With Paclitaxel in Patients With Advanced/Metastatic HER2-Negative Breast Cancer (clinicaltrials.gov) - P1/2 | N=37 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Phase classification: P2 ➔ P1/2 | Trial completion date: Dec 2023 ➔ Dec 2024

Combination therapy • Metastases • Phase classification • Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor

TWT-203: CFI-402257, a Potent and Selective TTK Inhibitor, in Solid Tumors and With Fulvestrant in Breast Cancer (clinicaltrials.gov) - P1/2 | N=44 | Recruiting | Sponsor: Treadwell Therapeutics, Inc

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • HER-2 • PGR

TWT-203: PHASE 1b/2 STUDY OF CFI-402257 AS MONOTHERAPY IN ADVANCED SOLID TUMORS AND IN COMBINATION WITH FULVESTRANT IN PATIENTS WITH ER+/HER2- ADVANCED BREAST CANCER AFTER PROGRESSION ON PRIOR CDK4/6 INHIBITORS AND ENDOCRINE THERAPY (SABCS 2023) - P1 | "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."

Clinical • Combination therapy • Metastases • Monotherapy • P1/2 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Treadwell Announces Strategic Pipeline Prioritization and Leadership Transitions (GlobeNewswire) - "Treadwell Therapeutics...announced that it is realigning its pipeline, workforce and management structure to support its highest value program and extend its cash runway to prioritize the execution of key near term value drivers and clinical milestones. Treadwell has elected to focus on its first-in-class PLK4 inhibitor, CFI-400945, in relapsed/refractory AML by expanding the ongoing company sponsored TWT-202 study, building on exciting signals of efficacy seen at earlier phases, and advancing towards a potential pivotal study in 2025. The company will seek to capitalize on very promising proof-of-concept from sponsored clinical studies of CFI-402257 (TTK/Mps1 inhibitor) and CFI-402411 (HPK1 inhibitor) through further, innovative collaborative studies and work with potential partners to accelerate timelines."

New trial • Pipeline update • Trial status • Acute Myelogenous Leukemia • Solid Tumor

CCTG IND.236: CFI-402257 in Combination With Paclitaxel in Patients With Advanced/Metastatic HER2-Negative Breast Cancer (clinicaltrials.gov) - P2 | N=37 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial primary completion date: Jun 2023 ➔ Nov 2022

Combination therapy • Metastases • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor

Glioblastoma stem-like cells are resistant to the negative effects of increased aneuploidy on in vitro survival and radiosensitivity (AACR 2023) - "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."

Preclinical • Brain Cancer • CNS Tumor • Glioblastoma • Glioma • Oncology • Solid Tumor • CD133

An update to a Phase I trial of CFI-402257, an oral TTK inhibitor, in patients with advanced solid tumors with HER2-negative breast cancer expansion cohorts (SABCS 2022) - "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."

Clinical • P1 data • Breast Cancer • Gastrointestinal Cancer • Hepatocellular Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Ovarian Cancer • Pancreatic Cancer • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • RB1

CCTG IND.236: A Phase 1b trial of combined CFI-402257 and weekly paclitaxel in patients with HER2-negative (HER2-) advanced breast cancer (aBC) (SABCS 2022) - "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."

Clinical • P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor • ER • HER-2

Liquid-biopsy Informed Platform Trial to Evaluate CDK4/6-inhibitor Resistant ER+/HER2- Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=484 | Recruiting | Sponsor: Canadian Cancer Trials Group | Not yet recruiting ➔ Recruiting

Biopsy • Enrollment open • Liquid biopsy • Metastases • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor

CCTG IND.236: CFI-402257 in Combination With Paclitaxel in Patients With Advanced/Metastatic HER2-Negative Breast Cancer (clinicaltrials.gov) - P2 | N=37 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial completion date: Dec 2022 ➔ Dec 2023 | Trial primary completion date: Dec 2022 ➔ Jun 2023

Combination therapy • Metastases • Trial completion date • Trial primary completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Oncology • Solid Tumor