ocifisertib (CFI-400945)

P1, N=13, Completed, University Health Network, Toronto | Active, not recruiting --> Completed

P2, N=15, Active, not recruiting, Canadian Cancer Trials Group | Trial completion date: Dec 2022 --> Dec 2024

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.

P1, N=13, Active, not recruiting, University Health Network, Toronto | Trial completion date: Mar 2024 --> Jun 2024 | Trial primary completion date: Jun 2021 --> Jun 2024

P2, N=200, Active, not recruiting, Canadian Cancer Trials Group | Recruiting --> Active, not recruiting | N=600 --> 200

In our previous studies, we showed that inhibition of Polo-like Kinase 4 (PLK4) by a novel drug, CFI-400945 significantly enhances the anticancer effects of radiotherapy (RT) compared to single treatment alone...Our data suggest that PLK4 is a promising target for enhancing the anticancer effects of RT in TNBC that, at least in part, is modulated by the overamplification of centrioles. These results support further mechanistic and translational studies of anti-PLK4 agents and RT as an anticancer combination treatment strategy.

P1/2, N=72, Recruiting, Treadwell Therapeutics, Inc | Trial completion date: Jan 2024 --> Jan 2026 | Trial primary completion date: Jan 2024 --> Jan 2026

P2, N=51, Active, not recruiting, Canadian Cancer Trials Group | Trial completion date: Jun 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=600, Recruiting, Canadian Cancer Trials Group | Trial completion date: Jul 2024 --> Dec 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P1, N=13, Active, not recruiting, University Health Network, Toronto | Trial completion date: Dec 2023 --> Mar 2024

As such, numerous small-molecule inhibitors with distinct chemical scaffolds targeting PLK4 have been extensively investigated for the treatment of different human cancers, with several undergoing clinical evaluation (e.g., CFI-400945). Here, we review the structure, distribution, and biological functions of PLK4, encapsulate its intricate regulatory mechanisms of expression, and highlighting its multifaceted roles in cancer development and metastasis. Moreover, the recent advancements of PLK4 inhibitors in patent or literature are summarized, and their therapeutic potential as monotherapies or combination therapies with other anticancer agents are also discussed.

P1/2, N=72, Recruiting, Treadwell Therapeutics, Inc

Dose-limiting toxicity was enteritis/colitis. A monotherapy and combination therapy study with a newer crystal form of CFI-400945 in patients with AML, MDS and chronic myelomonocytic leukemia (CMML) is ongoing (NCT04730258).

P1/2, N=72, Recruiting, Treadwell Therapeutics, Inc | Phase classification: P1b/2 --> 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.

P2, N=51, Active, not recruiting, Canadian Cancer Trials Group | Trial completion date: Jun 2023 --> Jun 2024 | Trial primary completion date: Jun 2023 --> Dec 2023

To examine the therapeutic mechanisms, transcriptome analyses were performed and differentially expressed genes (DEGs) induced by PLK4 inhibitor CFI-400945 were examined in TP53 mutated AML cell line (KO52)... The observations supported a novel PLK4/PRMT5/EZH2/H3K27me3 axis that might account for the anti-leukemiceffects of PLK4 inhibition on TP53 mutated AML. Acknowledgements: This research was supported by Health@InnoHK, Innovation and Technology Commission of the HKSAR, Theme- based Research Scheme (T12-702/20-N), HMRF (08191906), Li Shu Fan Medical Foundation, Ying Wan Leung Research Fund and Collaborative Research Fund (C7028-19G), and Tang King Ying Research Fund.

P2, N=51, Active, not recruiting, Canadian Cancer Trials Group | Recruiting --> Active, not recruiting | Trial primary completion date: Dec 2022 --> Jun 2023

P2, N=72, Recruiting, Canadian Cancer Trials Group | Trial completion date: Jan 2023 --> Jun 2023 | Trial primary completion date: Sep 2022 --> Dec 2022

CFI-400945 has been generally well tolerated and TWT-202 continues to enroll in Part 1. There have been no responses per ELN to date but there was SD in 2 pts (48 mg dose). Lack of DLTs suggest dose level is still suboptimal at time of submission.

CFI- 400945 and durvalumab was well tolerated, with no unexpected toxicities of the combination. However, in this heavily pretreated and PD-L1 unselected TNBC population, no responses were observed and the pre-specified threshold for anti-tumor activity for stage 2 was not met. The trial was closed to accrual on April 26, 2022.

The RP2D for CFI-400945 in patients with advanced breast cancer is 32mg/day. This is 50% lower than the RP2D previously established in the phase I study due to an unexpected increase in exposure resulting from tablets containing a more stable polymorph of CFI-400945 drug substance.Acknowledgements: Sponsored by CCTG. Research supported by a Stand Up to Cancer Canada (SU2C), Canadian Breast Cancer Foundation Breast Cancer Dream Team Research Funding, with supplemental support of the Ontario Institute for Cancer Research through funds provided by the Government of Ontario (Funding Award Number: SU2C-AACR-DT-18-15).

P2, N=15, Active, not recruiting, Canadian Cancer Trials Group | Trial primary completion date: May 2022 --> Aug 2022

P2, N=72, Recruiting, Canadian Cancer Trials Group | Trial completion date: Sep 2022 --> Jan 2023

To date, some small-molecule inhibitors with different chemical scaffolds targeting PLK4 have been reported, among which, CFI-400945 has entered clinical trials for the treatment of various solid tumors, myeloid leukemia, and myelodysplastic syndrome...Used alone or in combination with other anticancer drugs in preclinical and clinical studies, PLK4 inhibitors have shown significant efficacy in the treatment of different cancers, demonstrating that PLK4 could be a critical target for cancer diagnosis and therapy. However, our understanding of PLK4 is still limited, and novel mechanisms of PLK4 should be identified in future studies.

CA is prevalent in PCa and arises predominantly by centriole overduplication as opposed to cell doubling events. Loss of centrioles is cellular stress that can promote senescence and suggests that PLK4 inhibition may be a viable therapeutic strategy in PCa.

PLK4 inhibitor plus bortezomib shows synergy in decreasing cell viability and enhancing cell apoptosis via repressing PI3K/AKT signaling in MM.

Here we show that by targeting a centrosome regulator, PLK4, to activate the cytosolic DNA sensing-mediated immune response, CFI-400945 effectively restrained tumor progression through cell cycle inhibition and inducing anti-tumor immunity to achieve a durable suppressive effect even in late-staged mouse HCC.

Its inhibition by the PLK4 inhibitor, CFI-400945 resulted in centriole dysregulation, increased in double-strand DNA damage, and ultimately, mitotic catastrophe and cell death... PLK4 inhibitor induced DNA double-strand breaks in LMS and the repair of these breakages was dependent on HR repair. In vitro, LMS with BRCA1 or BRCA2 deficiencies were more sensitive to the effect of PLK4 inhibitor.

The selective BCL2 inhibitor, venetoclax, acts in a synthetic lethal manner with PLK4 inhibition in both CFI-400945 sensitive and in CFI-400945 resistant lymphomas. As PLK4 is dispensable in non-proliferating cells, synthetic lethality is preferentially observed in tumor cells, while sparing vital organs. Hence, B cell lymphomas are ill-prepared for the rapid, pharmacologic induction of polyploidy resulting in a synthetic and tumor-specific dependency on BCL2.

P2, N=15, Active, not recruiting, Canadian Cancer Trials Group | Recruiting --> Active, not recruiting | N=28 --> 15

As of June 21, 2021, 2 patients had been enrolled into the study, one of the patients (50%) received >3 prior therapies (including venetoclax). CFI-400945 has been generally well tolerated and TWT-202 continues to enroll in the Part 1A and Part 1B monotherapy cohorts. Updated safety, efficacy, PK, and PD data for the study will be presented at the time of the meeting.

While numerous novel treatment regimens, including the combination of the BCL2 inhibitor venetoclax (VEN) and hypomethylating agents (HMA), have emerged as partially effective treatments and resulted in higher remission rates in patients with TP53 -mutant AML, full clearance of the mutant TP53 clone is rarely achieved and the majority of patients relapse (Short et al., 2021; Takahashi et al., 2016). Our data suggest that TP53 -mutant AML expresses higher levels of PLK4 in comparison to TP53 -wt AML, and targeting PLK4 triggers polyploidy and apoptotic cell death in TP53 -mutant AML. A clinical trial is ongoing testing the efficacy of PLK4 inhibition (CFI-400945) in AML (Clinical Trial ID: NCT04730258, TWT-202).

P2, N=72, Recruiting, Canadian Cancer Trials Group | Trial completion date: Sep 2021 --> Sep 2022 | Trial primary completion date: Sep 2021 --> Sep 2022

High levels of PLK4 expression were associated with poor survival in the patients receiving CHOP-based treatment, implicating PLK4 as a predictive biomarker of DLBCL chemosensitivity. These results provide the therapeutic potential of CFI-400945 both as monotherapy or in combination with doxorubicin for the treatment of DLBCL.

The shortlisted molecules were docked into PLK-4 active site and were validated using molecular docking and molecular dynamics simulations studies. MM-PBSA calculations revealed the stability of hit molecules and PLK-4 complexes in comparison with CFI-400945 and the contribution to binding from key active site residues.

Here we show that a novel inhibitor of Polo-Like Kinase 4 (PLK4), CFI-400945, in combination with radiation, exhibits a synergistic anti-cancer effect in TNBC cell lines and patient-derived organoids in vitro and leads to a significant increase in survival to tumor endpoint in xenograft models in vivo, compared to control or single-agent treatment. Further preclinical and proof-of-concept clinical studies are warranted to characterize molecular mechanisms of action of this combination and its potential applications in clinical practice.