ocifisertib (CFI-400945) / Treadwell Therap - LARVOL DELTA

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) (ASH 2023) - P1/2 | "Background: CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase Polo-like kinase 4 (PLK4), a unique Polo-like kinase family member, that is a conserved upstream regulator of centriole duplication. CFI-400945 has been generally well tolerated in this difficult to treat patient population, including patients whose disease progressed on or following venetoclax based therapies. Three of 6 evaluable patients with AML achieved a response (MLFS=2, CRi=1) at the 96mg dose. PK characteristics support daily dosing of CFI-400945 and PD studies are ongoing."

Clinical • Combination therapy • P1/2 data • PK/PD data • Acute Myelogenous Leukemia • Anemia • Chronic Myelomonocytic Leukemia • Fatigue • Febrile Neutropenia • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Myelodysplastic Syndrome • Neutropenia • Oncology • Pneumonia • Renal Disease • Respiratory Diseases • Septic Shock • IDH2 • PLK4 • RUNX1 • SRSF2 • TP53

Polo-like Kinase 4 (PLK4) as a Therapeutic Target in Breast Cancer. (PubMed, Carcinogenesis) - "Various compounds, such as CFI-400945, centrinone B, and others have been developed to inhibit PLK4 activity...Clinical studies have been initiated with some of these compounds in cancer patients, including those with breast cancer. This manuscript discusses the role of PLK4 as a promising therapeutic target in breast cancer, one of the most common causes of morbidity and mortality in women."

Journal • Breast Cancer • Oncology • Solid Tumor • PLK4

Prostate Cancer Biomarker Enrichment and Treatment Selection (clinicaltrials.gov) - P2 | N=200 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial primary completion date: Jun 2025 ➔ Oct 2024

Biomarker • Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

Polo-like Kinase 4: A Molecular Culprit in Skin Cancer Pathogenesis. (PubMed, Cells) - "Further, several small-molecule PLK4 inhibitors such as centrinone, YLZ-F5, CFI-400945, and RP-1664 have demonstrated efficacy in targeting PLK4...In this review, we provide a comprehensive overview of the known functions of PLK4 in skin cancer. Additionally, we discuss potential mechanistic insights into PLK4's involvement in skin cancer progression by extrapolating evidence from studies in other cancer types including colorectal cancer, thyroid cancer, lymphomas, leukemia, etc., while identifying gaps for future research."

Journal • Review • Colorectal Cancer • Genetic Disorders • Hematological Malignancies • Leukemia • Lymphoma • Melanoma • Oncology • Skin Cancer • Solid Tumor • Thyroid Gland Carcinoma • PLK4

CFI-400945 and Durvalumab in Patients With Advanced Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=15 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial completion date: Jun 2025 ➔ Dec 2025

Trial completion date • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR • PLK4

CFI-400945 in Patients With Advanced/Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=51 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial primary completion date: Jun 2025 ➔ Dec 2025

Trial primary completion date • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PGR • PTEN

PLK4 as a Key Regulator of Neuroblastoma Differentiation and a Promising Therapeutic Target. (PubMed, Int J Biol Sci) - "The selective PLK4 inhibitor CFI-400945 exhibits dual anti-tumor activity by promoting terminal differentiation and suppressing proliferation. Our study identifies PLK4 as a potential molecular switch governing NB differentiation and a promising therapeutic target to overcome resistance to 13-cis RA."

Journal • Neuroblastoma • Oncology • Solid Tumor • CCND1 • PI3K • PLK4

Investigation of effects of CFI-400945 and ionizing radiation on DNA damage response in triple-negative breast cancer. (PubMed, Transl Cancer Res) - "Notably, despite activation of the DDR responses, DNA damage persisted for 24 or more hours after RT. While some of these observations were cell-line dependent (emphasizing known molecular heterogeneity of TNBC), we highlight that canonical DDR pathways activity in response to RT might be inefficient and modulated by drugs, such as CFI-400945-a cancer cell vulnerability that warrants further investigations for better understanding the biology of TNBC, its responses to treatment and novel drug development."

Journal • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • PLK4 • RAD51

PLK4 is a potential therapeutic target in nonmelanoma skin cancers: Evidence from molecular and in vivo studies. (PubMed, Photochem Photobiol) - "Further, small molecule inhibition of PLK4 activity with centrinone, a specific and reversible inhibitor, and CFI-400945, an ATP-competitive inhibitor, decreased cell viability, proliferation, and clonogenic survival of human cSCC and BCC cells...Overall, this study suggested that PLK4 is a potential therapeutic target and a biomarker for NMSC management. However, additional studies are needed to validate and expand these findings in additional model systems."

IO biomarker • Journal • Preclinical • Basal Cell Carcinoma • Genetic Disorders • Non-melanoma Skin Cancer • Skin Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • PLK4

Polo-like kinase 4 (PLK4) inhibition reverses the loss of primary cilia in human melanoma cells (SID 2025) - "We found that small molecule inhibition of PLK4 (CFI-400945 or centrinone B) or its CRISPR/CAS9 knockout significantly increased the number and length of cilia in A375 and G361 melanoma cells...Taken together, our study suggests that PLK4 is involved in cilia loss in melanoma and its inhibition causes cilia reappearance and an anti-melanoma response. Further functional validation of these targets in PLK4-induced cilia loss in melanoma cells is currently ongoing in our laboratory."

Melanoma • Oncology • Solid Tumor • ARL13B • CDKN1A • PKHD1 • PLK4 • PTCH1

TWT-202: A Study of CFI-400945 With or Without Azacitidine in Patients With AML, MDS or CMML (clinicaltrials.gov) - P1/2 | N=72 | Active, not recruiting | Sponsor: Treadwell Therapeutics, Inc | Recruiting ➔ Active, not recruiting

Enrollment closed • Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

PLK4 inhibition as a strategy to enhance non-small cell lung cancer radiosensitivity. (PubMed, Mol Cancer Ther) - "Lastly, CFI-400945 treatment enhanced the radiation-induced tumor growth delay of NSCLC tumor xenografts. These data indicate that targeting PLK4 is a novel approach to enhance the radiation sensitivity of NSCLC in vitro and in vivo through potentiation of centrosome amplification and cell death through mitotic catastrophe."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PLK4

Ocifisertib alleviates the gasdermin D-independent pyroptosis of nucleus pulposus cells by targeting GSDME. (PubMed, Sci Rep) - "Ocifisertib alleviated pyroptosis-mediated IDD by inhibiting GSDME cleavage in annulus fibrosus puncture-induced IDD rat model. Our study provides evidence that the cleavage of GSDME aggravates IDD by accelerating NP cell pyroptosis and demonstrates that Ocifisertib has therapeutic potential in IDD treatment."

Journal • Fibrosis • GSDME

Prostate Cancer Biomarker Enrichment and Treatment Selection (clinicaltrials.gov) - P2 | N=200 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial primary completion date: Dec 2024 ➔ Jun 2025

Trial primary completion date • Castration-Resistant Prostate Cancer • Genito-urinary Cancer • Oncology • Prostate Adenocarcinoma • Prostate Cancer • Solid Tumor

CFI-400945 and Durvalumab in Patients With Advanced Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=15 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial completion date: Dec 2024 ➔ Jun 2025

Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR • PLK4

PLK4 inhibition as a strategy to enhance non-small cell lung cancer radiosensitivity. (PubMed, bioRxiv) - "Lastly, CFI-400945 treatment enhanced the radiation-induced tumor growth delay of NSCLC tumor xenografts. These data indicate that targeting PLK4 is a novel approach to enhance the radiation sensitivity of NSCLC in vitro and in vivo through potentiation of centrosome amplification and cell death through mitotic catastrophe."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • PLK4

CFI-400945 in Patients With Advanced/Metastatic Breast Cancer (clinicaltrials.gov) - P2 | N=51 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial primary completion date: Dec 2024 ➔ Jun 2025

Trial primary completion date • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • HER-2 • PGR • PTEN

Overcoming Olaparib Resistance in BRCA-Mutated Triple-Negative Breast Cancer: Synergistic Potential of DNA Repair Pathway Inhibitors (SABCS 2024) - "Two PARP inhibitors (olaparib and talazoparib) are FDA-approved for patients with metastatic gBRCA mutated breast cancer...Based on target identification, we selected inhibitors of ATR (elimusertib, gartisertib), ATM (AZD1390), PLK4 (CFI-400945), CDK12 (SR-4835), PI3KCA (copanlisib), and AKT (capivasertib) for proliferation assays... Our preclinical study identified DNA repair pathways as potential targets to enhance the efficacy of olaparib in both parent and olaparib-refractory gBRCA mutated TNBC cell lines. Future in vivo studies, including patient-derived xenografts and additional mechanistic analyses to further understand dual DNA targeting synergy, are warranted to validate this therapeutic approach for TNBC with gBRCA mutation."

Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • BRCA • CDK12 • DRD • HER-2 • PIK3CG • PIK3R3 • PLK4

TARGETING CHROMOSOME ABERRATIONS TO TREAT VERY HIGH RISK MEDULLOBLASTOMA (SIOP 2024) - "CFI-400945 monotherapy conferred a significant survival advantage in a human orthotopic model of TP53 mutant SHH RCMB18 (p=0.0204), but not for the TP53 wild-type BT126.Conclusions We show that in both murine and human models of high-risk SHH medulloblastoma, PLK4 inhibition is highly effective. Our data reveals PLK4 inhibition as a novel and rational therapeutic target for a subset of very high risk MB harboring TP53 mutation."

Brain Cancer • Medulloblastoma • Metabolic Disorders • Oncology • Solid Tumor • PLK4 • PTEN • SHH • TP53

Study of CFI-400945 Fumarate in Patients With Relapsed or Refractory AML or MDS (clinicaltrials.gov) - P1 | N=13 | Completed | Sponsor: University Health Network, Toronto | Active, not recruiting ➔ Completed

Trial completion • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

CFI-400945 and Durvalumab in Patients With Advanced Triple Negative Breast Cancer (clinicaltrials.gov) - P2 | N=15 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Trial completion date: Dec 2022 ➔ Dec 2024

Metastases • Trial completion date • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ER • HER-2 • PGR • PLK4

Inhibition of aberrantly overexpressed Polo-like kinase 4 is a potential effective treatment for DNA damage repair-deficient uterine leiomyosarcoma. (PubMed, Clin Cancer Res) - "Uterine LMS with DNA repair defects is sensitive to PLK4 inhibition because of the effects of chromosome missegregation and increased DNA damage. Loss-of-function BRCA2 alterations or pharmacological inhibition of ATM enhanced the efficacy of PLK4 inhibitor. Genomic profiling of an advanced-stage or recurrent uterine LMS may guide therapy."

Journal • Ataxia • Immunology • Leiomyosarcoma • Movement Disorders • Oncology • Primary Immunodeficiency • Sarcoma • Solid Tumor • Uterine Corpus Leiomyosarcoma • BRCA2 • PLK4

Study of CFI-400945 Fumarate in Patients With Relapsed or Refractory AML or MDS (clinicaltrials.gov) - P1 | N=13 | Active, not recruiting | Sponsor: University Health Network, Toronto | Trial completion date: Mar 2024 ➔ Jun 2024 | Trial primary completion date: Jun 2021 ➔ Jun 2024

Trial completion date • Trial primary completion date • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology

ORIC Pharmaceuticals Presents Preclinical Data on Two Programs at the 2024 American Association for Cancer Research (AACR) Annual Meeting (GlobeNewswire) - "ORIC-613 is an orally bioavailable, potent and exquisitely selective small molecule inhibitor of PLK4, which is synthetic lethal in tumor cells with high levels of TRIM37....ORIC-613 has superior kinome selectivity versus comparator compounds CFI-400945 and RP-1664....Preclinical assessment in cancer cell lines revealed synthetic lethality, with ORIC-613 inducing apoptotic tumor cell death specifically in TRIM37-high breast cancer and neuroblastoma cells versus TRIM37-wildtype cells....Oral dosing of ORIC-613 at 150 mg/kg QD resulted in tumor regressions and tumor growth inhibition in TRIM37-high xenograft breast tumors."

Preclinical • Breast Cancer • Oncology • Solid Tumor

Prostate Cancer Biomarker Enrichment and Treatment Selection (clinicaltrials.gov) - P2 | N=200 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Recruiting ➔ Active, not recruiting | N=600 ➔ 200

Enrollment change • Enrollment closed • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor