A Dose-confirming Study of CFI-402257 as a Single Agent in Advanced Solid Tumors and in Combination With Fulvestrant in Patients With ER+/HER2- Advanced Breast Cancer After Disease Progression on Prior CDK4/6 and Endocrine Therapy

The purpose of this study is to test the safety of an investigational drug called CFI-402257 alone in advanced solid tumors and in combination with Fulvestrant in advanced breast cancer patients.

Start Date27 May 2022

Sponsor / Collaborator

Treadwell Therapeutics, Inc.Startup

NCT03568422 / Active, not recruitingPhase 1/2

A Phase Ib and Open Label Phase II Study of CFI-402257 in Combination With Weekly Paclitaxel in Patients With Advanced/Metastatic HER2-Negative Breast Cancer

The standard or usual treatment for this disease is to undergo chemotherapy to slow the spread of disease and relieve some symptoms of cancer. One of the standard types of chemotherapy is a drug called paclitaxel (Taxol) given in a low dose every week for three out of four weeks.
CFI-402257 is a new type of drug for breast cancer. Laboratory tests show that it may help slow the growth of breast cancer. This drug has been shown to shrink tumours in animals. CFI-402257 has been studied in a few people and appears well tolerated with little side effects. CFI-402257 seems promising but it is not clear if it can offer better results when given with paclitaxel compared to paclitaxel alone.

Start Date05 Feb 2019

Sponsor / Collaborator

Canadian Cancer Trials Group

[+3]

NCT02792465 / Active, not recruitingPhase 1

An Open Label, Dose Escalation, Safety, and Pharmacokinetic Study of CFI-402257 Administered Orally to Patients With Advanced Solid Tumors

This is a phase 1 study of investigational agent CFI-402257 in patients with advanced cancer. The purpose of this study is to see how safe and tolerable CFI-402257 is in cancer patients as well as the pharmacokinetics (PK). This study is the first time that CFI-402257 is given to humans.

Start Date11 Nov 2016

Sponsor / Collaborator

University Health Network

100 Clinical Results associated with CFI-402257

100 Translational Medicine associated with CFI-402257

100 Patents (Medical) associated with CFI-402257

Literatures (Medical) associated with CFI-402257

01 Dec 2022·BMC Cancer

TTK Protein Kinase promotes temozolomide resistance through inducing autophagy in glioblastoma

Article

Author: Wei, Xiangpin ; Wang, Yang ; Gao, Ge ; Yu, Jian

AbstractBackgroundTemozolomide (TMZ) resistance remains the main therapy challenge in patients with glioblastoma multiforme (GBM). TTK Protein Kinase (TTK) contributes to the radioresistance and chemoresistance in many malignancies. However, the role of TTK in the TMZ resistance of GBM cells remains unknown.MethodsThe expression of TTK was measured by western blot. The proliferation of GBM cells was assessed through MTT assay and clonogenic assay. Cell apoptosis was evaluated using western blot. LC3B puncta were detected using immunohistochemistry staining. The mouse xenograft model was used to investigate the role of TTK in vivo.ResultsKnockdown of TTK increased the sensitivity of GBM cells to TMZ treatment, while overexpression of TTK induced TMZ resistance. Two specific TTK inhibitors, BAY-1217389 and CFI-402257, significantly inhibited GBM cell proliferation and improved the growth-suppressive effect of TMZ. In addition, the knockdown of TTK decreased the autophagy levels of GBM cells. Inhibition of TTK using specific inhibitors could also suppress the autophagy process. Blocking autophagy using chloroquine (CQ) abolished the TMZ resistance function of TTK in GBM cells and in the mouse model.ConclusionsWe demonstrated that TTK promotes the TMZ resistance of GBM cells by inducing autophagy in vitro and in vivo. The use of a TTK inhibitor in combination with TMZ might help to overcome TMZ resistance and improve therapy efficiency in GBM.

09 Sep 2022·Science Advances

The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor–resistant ER ⁺ breast cancer with mitotic aberrations

Article

Author: Elia, Andrea C. ; Fletcher, Graham C. ; Bray, Mark R. ; Cheng, Albert ; Silvester, Jennifer ; Rose, April A. N. ; Cruickshank, Jennifer ; El Ghamrasni, Samah ; Cescon, David W. ; Haibe-Kains, Benjamin ; Ba-alawi, Wail ; Elliott, Mitchell J. ; Mak, Tak W. ; Soria-Bretones, Isabel ; Kiarash, Reza ; Chalmers, Jordan J. ; Thu, Kelsie L.

Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER + breast cancer. However, acquired resistance to CDK4/6i invariably develops, and the molecular phenotypes and exploitable vulnerabilities associated with resistance are not yet fully characterized. We developed a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids and demonstrate that a subset of resistant models accumulates mitotic segregation errors and micronuclei, displaying increased sensitivity to inhibitors of mitotic checkpoint regulators TTK and Aurora kinase A/B. RB1 loss, a well-recognized mechanism of CDK4/6i resistance, causes such mitotic defects and confers enhanced sensitivity to TTK inhibition. 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.

09 Aug 2022·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

CFI-402257, a TTK inhibitor, effectively suppresses hepatocellular carcinoma

Q1 · CROSS-FIELD

Article

Author: Chan, Cerise Yuen-Ki ; Mak, Tak Wah ; Khong, Pek-Lan ; Lee, Derek ; Bray, Mark Robert ; Cheu, Jacinth Wing-Sum ; Wong, Carmen Chak-Lui ; Law, Cheuk-Ting ; Tan, Kel Vin ; Ng, Irene Oi-Lin ; Chiu, David Kung-Chun ; Soria-Bretones, Isabel ; Tse, Aki Pui-Wah ; Cescon, David Ward ; Zhang, Misty Shuo ; Yuen, Vincent Wai-Hin ; Wong, Bowie Po-Yee ; Thu, Kelsie Lynn ; Yau, Thomas Chung-Cheung

Deregulation of cell cycle is a typical feature of cancer cells. Normal cells rely on the strictly coordinated spindle assembly checkpoint (SAC) to maintain the genome integrity and survive. However, cancer cells could bypass this checkpoint mechanism. In this study, we showed the clinical relevance of threonine tyrosine kinase (TTK) protein kinase, a central regulator of the SAC, in hepatocellular carcinoma (HCC) and its potential as therapeutic target. Here, we reported that a newly developed, orally active small molecule inhibitor targeting TTK (CFI-402257) effectively suppressed HCC growth and induced highly aneuploid HCC cells, DNA damage, and micronuclei formation. We identified that CFI-402257 also induced cytosolic DNA, senescence-like response, and activated DDX41-STING cytosolic DNA sensing pathway to produce senescence-associated secretory phenotypes (SASPs) in HCC cells. These SASPs subsequently led to recruitment of different subsets of immune cells (natural killer cells, CD4 + T cells, and CD8 + T cells) for tumor clearance. Our mass cytometry data illustrated the dynamic changes in the tumor-infiltrating immune populations after treatment with CFI-402257. Further, CFI-402257 improved survival in HCC-bearing mice treated with anti-PD-1, suggesting the possibility of combination treatment with immune checkpoint inhibitors in HCC patients. In summary, our study characterized CFI-402257 as a potential therapeutic for HCC, both used as a single agent and in combination therapy.

News (Medical) associated with CFI-402257

20 Feb 2024

·www.biospace.com

Treadwell Announces Ocifisertib, a First-in-Class PLK4 Inhibitor, has Received Orphan Designation from U.S. FDA for the Treatment of Acute Myeloid Leukemia

With a Focus on Potential Pivotal Studies in 2025, Treadwell has Strengthened its Leadership Team by Appointing Brenda Marczi, PharmD, MBA as SVP and Head of Regulatory Affairs TORONTO & SAN FRANCISCO--(BUSINESS WIRE)-- Treadwell Therapeutics, a privately held clinical-stage biotechnology company pioneering and advancing novel first-in-class medicines for unmet needs in cancer, today announced the U.S. Food and Drug Administration (FDA) has granted orphan drug designation to ocifisertib (CFI-400945), a first-in-class, investigational PLK4 inhibitor for the treatment of acute myeloid leukemia (AML). Ocifisertib is currently being evaluated in a Phase 1b/2 study in adults with relapsed/refractory AML following standard of care therapy. Orphan drug designation is granted by the FDA to drugs intended for treatment, prevention or diagnosis of a rare disease or condition that affects fewer than 200,000 people in the U.S. at the time of designation. Under the FDA’s Orphan Drug Act, orphan drug status provides incentives, grants, tax credits and waiver of certain administrative fees as well as seven years of market exclusivity following marketing authorization. Treadwell also announced today the appointment of Brenda Marczi, as SVP and Head of Regulatory Affairs. Brenda comes to Treadwell with over 30 years of regulatory experience in the pharmaceutical and biotechnology industries. She most recently served as Senior Vice President, Regulatory Affairs at Tracon Pharmaceuticals, Inc., where she oversaw their regulatory function and led all of their strategies and filing activities in the US and UK. Brenda holds a Master of Science in Pharmaceutical Sciences from Rutgers University, a PharmD from the University of Maryland, and an MBA from Wharton, University of Pennsylvania. “The FDA’s decision to grant orphan drug designation, along with the previous FDA Fast Track designation for ocifisertib underscores Treadwell’s dedication to addressing this patient population with few treatment options. Patients with relapsed and/or refractory AML, in particular TP53 mutated disease suffer poor overall survival and represents a high unmet clinical need,” said Roger Sidhu, M.D., Acting CEO of Treadwell. “We look forward to advancing ocifisertib in partnership with investigators, regulators, patients and their families for those with limited treatment options in tough to treat AML. In addition, we are thrilled to have Brenda join us to lead Regulatory Affairs at Treadwell. She is a seasoned strategic leader with a broad experience in leading regulatory strategy from early development through approval. Her leadership will be invaluable to Treadwell as we advance ocifisertib into potentially pivotal studies in 2025.” About Treadwell Therapeutics Treadwell Therapeutics is a clinical-stage oncology company developing novel medicines to address unmet needs in patients with cancer. The Company's robust, internally developed clinical pipeline includes ocifisertib (PLK4 inhibitor), CFI-402257 (TTK/Mps1 inhibitor) and CFI-402411 (HPK1 inhibitor). Treadwell also has a broad pre-clinical pipeline with multiple biologic and next generation TCR based autologous cell therapy programs. For more information, please visit .

Orphan DrugFast Track

15 Dec 2023

·www.biospace.com

Treadwell Therapeutics Announces a Presentation at the 2023 ASH Annual Meeting and Advisory Board Meeting

TORONTO and SAN MATEO, Calif., Dec. 15, 2023 (GLOBE NEWSWIRE) -- Treadwell Therapeutics, a clinical-stage biotechnology company developing novel first-in-class medicines for unmet needs in cancer, today announced a presentation for the Company's lead program, CFI-400945, a first-in-class inhibitor of Polo-like Kinase 4 (PLK4) being advanced in relapsed/refractory AML, at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition being held from December 9-12, 2023. Treadwell also conducted a clinical advisory board meeting on December 10th at ASH with experienced experts in the treatment of AML and in clinical trials of novel agents, which included current investigators and thought leaders new to the program. "CFI-400945 is demonstrating complete remissions as a single agent and in combination with azacitadine in relapsed, adverse risk AML, including those with TP53 mutant disease. As we optimize dose and schedule, we are encouraged by the data with this oral dosing regimen," said Principal Investigator and Advisory Board Co-Chair Dr. Gautam Borthakur, MD, Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. “The advisory board confirmed the enthusiasm about the data to date in the relapsed AML setting, in particular with TP53 mutant disease and look forward to working with Treadwell to advance and shape this program.” "CFI-400945, our lead program and first-in-class PLK4 inhibitor, represents an opportunity to address a substantial unmet in relapsed/refractory AML, including TP53 mutant AML," said Roger Sidhu, MD, Acting CEO at Treadwell Therapeutics. “We look forward to advancing the program into key dose expansion studies in monotherapy and in combination in 2024 with a view to initiating pivotal studies in 2025.” 2023 ASH Poster Presentations and Details: Title: Preliminary Results from a Phase 1b/2 Open-Label, Multicenter, Dose Optimization Clinical Study of the Safety, Tolerability, and Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles of CFI-400945 As a Single Agent or in Combination with Azacitidine in Patients (Pts) with Acute Myeloid Leukemia, Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia (TWT-202) Session Name: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster III Publication Number: 4294 Session Date: Monday, December 11, 2023 Presentation Time: 6:00 PM - 8:00 PM Location: San Diego Convention Center, Halls G-H CFI-400945 has been generally well tolerated in this difficult to treat patient population, including patients whose disease has progressed on or following venetoclax based therapies. Three of 6 evaluable patients with AML achieved a response (MLFS=2, CRi=1 with MRD+) at the 96mg dose. After this data cut, one additional MLFS response (end of cycle 1) and two additional CRs (end of cycle 2) were seen in two patients treated with 80 mg + azacitidine combination cohort and became transplant eligible (PI communication). PK characteristics support daily dosing of CFI-400945 and PD studies are ongoing. Dose expansions are planned and enrollment continues. About Treadwell Therapeutics Treadwell Therapeutics is a clinical-stage oncology company developing novel medicines to address unmet needs in patients with cancer. The Company's robust, internally developed clinical pipeline includes CFI-400945 (PLK4 inhibitor), CFI-402257 (TTK/Mps1 inhibitor) and CFI-402411 (HPK1 inhibitor). Treadwell also has a broad pre-clinical pipeline with multiple biologic and next generation TCR based autologous cell therapy programs. For more information, please visit Contact ir@treadwelltx.com

Clinical ResultASHCell TherapyImmunotherapyAACR

06 Dec 2023

·www.biospace.com

Treadwell Announces Strategic Pipeline Prioritization and Leadership Transitions

– Treadwell to focus on advancing first-in-class PLK4 inhibitor CFI-400945 in AML towards potential pivotal studies in 2025 – Approximately 30% reduction in workforce to extend cash runway – Roger Sidhu, M.D. appointed as Acting CEO replacing founding Co-CEOs, Shane Burgess and Michael Tusche, Ph.D., Shane Burgess to transition to Executive Chair TORONTO and SAN FRANCISCO, Dec. 06, 2023 (GLOBE NEWSWIRE) -- Treadwell Therapeutics, a clinical-stage biotechnology company developing novel first-in-class medicines for unmet needs in cancer, today 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. Shane Burgess, co-CEO has transitioned to the role of Executive Chair, while Michael Tusche, Ph.D., co-CEO has left the company to pursue other endeavours. Roger Sidhu, M.D., Chief Medical Officer, has been appointed Acting CEO. Dr. Sidhu brings to Treadwell an extensive track record of success over the last nearly 20 years in hematologic and solid tumor oncology research and development. He is a seasoned leader with deep translational, clinical and regulatory experience across multiple therapeutic modalities and platforms including small molecules, biologics and cell and gene therapies. Most recently, Dr. Sidhu was the Chief Medical Officer at Eterna Therapeutics, a gene editing and cell therapy company where he advanced multiple novel programs. Previously, Dr. Sidhu served as Executive Vice President and Chief Medical officer at Roivant Sciences. Roger was also the Chief Medical Officer at Cell Design Labs, up until its acquisition by the Gilead subsidiary Kite, where he subsequently served as VP, Clinical Development. Dr. Sidhu also held various roles of increasing responsibility at Amgen over a nearly decade that included managing FDA and EU approval of panitumumab in metastatic colorectal cancer. Dr. Sidhu is a Fellow of the Royal College of Physicians and Surgeons of Canada in both internal medicine and medical oncology. He earned his medical degree from Queen's University in Kingston, Ontario Canada. “Roger brings a unique and broad set of skills and strategic thinking to Treadwell over a long and successful career. We are confident that under his leadership, Treadwell will aggressively advance into an exciting new chapter in our mission to address unmet needs in difficult to treat cancers with first-in-class medicines,” said Shane Burgess, Executive Chair of Treadwell Therapeutics. “In order to increase operational efficiency and to focus on key, value driving priorities, we have made the difficult business decision to reduce our workforce by approximately 30% and to redirect clinical efforts for several Treadwell-sponsored trials to other avenues. We would like to extend our deep gratitude to the Treadwell team, investigators and patients involved in our clinical programs. These actions allow us to focus on investing in key near term milestones for CFI-400945.” “Treadwell has developed a broad clinical and research-stage pipeline of first-in-class small molecules, biologics and TCR-based cell therapies. We have reached an inflection point which allows us to focus on the most near-term path to value with CFI-400945 in relapsed/refractory AML with a view to advancing to pivotal stage studies,” said Roger Sidhu, M.D., Acting CEO of Treadwell Therapeutics. “Given the very promising clinical data we have generated, we also look forward to advancing CFI-402257 (TTK inhibitor) and CFI-402411 (HPK1 inhibitor) with external collaborators and investigators moving forward in breast cancer and immunotherapy-based treatment of cancer, respectively, in addition to actively seeking partners for our pre-clinical programs.” About Treadwell Therapeutics Treadwell Therapeutics is a clinical-stage oncology company developing novel medicines to address unmet needs in patients with cancer. The Company's robust, internally developed clinical pipeline includes CFI-400945 (PLK4 inhibitor), CFI-402257 (TTK/Mps1 inhibitor) and CFI-402411 (HPK1 inhibitor). Treadwell also has a broad pre-clinical pipeline with multiple biologic and next generation TCR based autologous cell therapy programs. For more information, please visit . Contact ir@treadwelltx.com

Executive ChangeGene TherapyCell TherapyImmunotherapy

100 Deals associated with CFI-402257

R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Advanced Malignant Solid Neoplasm	Phase 2	US	Treadwell Therapeutics, Inc.Startup	27 May 2022
ER-positive/HER2-negative Breast Cancer	Phase 2	US	Treadwell Therapeutics, Inc.Startup	27 May 2022
FGF19 positive Solid Tumors	Phase 2	US	Treadwell Therapeutics, Inc.Startup	27 May 2022
HER2-negative breast cancer	Phase 2	CA	Canadian Cancer Trials Group	05 Feb 2019
Breast Cancer	Phase 2	-	University Health Network	-

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


TWT-203 (SABCS2023)	Phase 1/2	Advanced Malignant Solid Neoplasm \| ER-positive/HER2-negative Breast Cancer TTK tumor levels	14	CFI-402257 monotherapy	(lslkrdkrko) = Most pts (12, 86%) experienced ≥1 treatment emergent adverse event (TEAE). More than half of pts (8, 57%) experienced ≥1 treatment related TEAE. Most common TEAEs were fatigue (5, 36%) and nausea (4, 29%). 5 pts (36%) experienced TEAEs grade ≥3, most common were fatigue, neutrophil count decrease, white blood cell count decrease (2 pts each, 14.3%). 1 pt (7%) experienced a serious adverse event (hematuria), not related to study therapy. No patients discontinued treatment due to TEAE. All pts who ended treatment were due to disease progression (8, 57%). No grade 5 TEAEs occurred. No dose limiting toxicities were reported. boudveclab (jvrrfkzzhv )	Positive	11 May 2023
TWT-203 (ASCO2022)	Phase 1/2	HR-positive/HER2-low Solid Tumors \| ER-positive/HER2-negative Breast Cancer	-	CFI-402257 monotherapy	(iufjeshkom) = Safety endpoints include incidence of treatment emergent adverse events zeetiaeknu (urkdliozxh )	-	02 Jun 2022

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