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ACUTE MYELOID LEUKEMIA

Preclinical characterization and clinical trial of CFI-400945, a polo-like kinase 4 inhibitor, in patients with relapsed/refractory acute myeloid leukemia and higher-risk myelodysplastic neoplasms

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Abstract

CFI-400945 is a selective oral polo-like kinase 4 (PLK4) inhibitor that regulates centriole duplication. PLK4 is aberrantly expressed in patients with acute myeloid leukemia (AML). Preclinical studies indicate that CFI-400945 has potent in vivo efficacy in hematological malignancies and xenograft models, with activity in cells harboring TP53 mutations. In this phase 1 study in very high-risk patients with relapsed/refractory AML and myelodysplastic syndrome (MDS) (NCT03187288), 13 patients were treated with CFI-400945 continuously in dose escalation from 64 mg/day to 128 mg/day. Three of the 9 efficacy evaluable AML patients achieved complete remission (CR). Two of 4 AML patients (50%) with TP53 mutations and complex monosomal karyotype achieved a CR with 1 patient proceeding to allogenic stem cell transplant. A third patient with TP53 mutated AML had a significant reduction in marrow blasts by > 50% with an improvement in neutrophil and platelet counts. Responses were observed after 1 cycle of therapy. 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).

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Fig. 1: Response profile of CFI-400945 in human leukemia cell lines.
Fig. 2: In vivo characterization of the anticancer potential CFI-400945 on human AML xenograft tumors.
Fig. 3: Oncoprint representing distribution of oncogenic and variants of uncertain significance (VUS) in responders and nonresponders.

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Data availability

Proposals for data access should be submitted to KWLY (karen.yee@uhn.ca) and MRB (m.bray@treadwelltx.com) for consideration. Access to de-identified participant data can be granted if the proposal is approved by the Ontario Cancer Research Ethics Board (OCREB).

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Acknowledgements

The authors gratefully acknowledge the contributions of Hans de Haan (Synteract) as the medical monitor for the study; Ritu Kushwaha (UHN/Princess Margaret Cancer Centre) and Trisha Denny (Campbell Family Institute for Breast Cancer Research, UHN/Princess Margaret Cancer Centre) for providing support with this submission; and Emily Roberts-Thomson, Roger Sidhu and Glenn Michelson (Treadwell Therapeutics) for reviewing the manuscript. This work was supported by Princess Margaret Cancer Foundation (PMCF).

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Authors and Affiliations

  1. Leukemia Program, Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Tracy Murphy, Steven M. Chan, Vikas Gupta, Dawn Maze, Caroline J. McNamara, Aaron D. Schimmer, Andre C. Schuh, Hassan Sibai, Kylie Martin, Mark D. Minden & Karen W. L. Yee

  2. Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada

    Jacqueline M. Mason, Mark R. Bray & Tak W. Mak

  3. Treadwell Therapeutics Canada Inc, Toronto, Canada

    Jacqueline M. Mason, Mark R. Bray & Tak W. Mak

  4. Division of Hematology, Juravinski Cancer Centre, McMaster University, Hamilton, ON, Canada

    Brian Leber, Dina Khalaf, Michael Trus & Debbie Valiquette

  5. Treadwell Therapeutics Inc., San Mateo, CA, USA

    Linh Nguyen

  6. Department of Biostatistics, University Health Network, Toronto, ON, Canada

    Xuan Li

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Contributions

Conception and design: TM, JMM, MRB, MDM, KWLY; Collection and assembly of data: JMM, LN, XL, KWLY; Provision of study materials or patients: all authors; Data analysis and interpretation: TM, JMM, MRB, LN, XL, KWLY; Manuscript writing: All authors; Final approval of manuscript: All authors.

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Correspondence to Karen W. L. Yee.

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Competing interests

The authors declare the following potential conflicts of interest: JMM is an employee of Treadwell Therapeutics. BL was a consultant for AbbVie, Novartis, and Pfizer; and has received speakers’ fees or honoraria from AbbVie, Alexion, Amgen, Astellas, Astex, Bristol Myers Squibb/Celgene, Gilead/KITE, Jazz Pharmaceuticals, Janssen, Novartis, Otsuka, Paladin, Pfizer, Roche, and Treadwell Therapeutics. MRB is a co-founder and an employee of Treadwell Therapeutics. SMC has received research funding from AbbVie, Agios, Bristol Myers Squibb/Celgene, and Servier. VG has received research funding through his institution and honoraria from Novartis; and has served on the advisory board of AbbVie, Bristol Myers Squibb/Celgene, GSK, Incyte, Morphosys, Novartis, and Pfizer. DM has received research support from Bristol Myers Squibb/Celgene, Novartis, PharmaEsentia, and Takeda; has participated in advisory boards and received honoraria from Bristol Myers Squibb/Celgene, Jazz, and Novartis; and has participated in consultancy for Pfizer. ADS has received research funding from Takeda Pharmaceuticals, BMS and Medivir AB, and consulting fees/honorarium from Takeda, Novartis, Jazz, and Otsuka Pharmaceuticals; is named on a patent application for the use of DNT cells to treat AML; and is a member of the Medical and Scientific Advisory Board of the Leukemia and Lymphoma Society of Canada. ACS has consulted for and/or received honoraria from and/or received research support from AbbVie, Agios, Amgen, Astellas, Celgene/BMS, GlycoMimetics, Jazz, Novartis, Paladin, Phebra, Pfizer, Servier, and Teva. MT has received research funding from Jazz. LN is an employee of Treadwell Therapeutics. TWM is a co-founder of Treadwell Therapeutics. KWLY was a consultant for Bristol Myers Squibb/Celgene, F. Hoffmann-La Roche, GSK, Jazz Pharmaceuticals, Novartis, Pfizer, Shattuck Labs, Taiho Oncology, and Takeda; received research funding from Astex Pharmaceuticals, Forma Therapeutics, F. Hoffmann-La Roche, Forma Therapeutics, Genentech, Geron Corporation, Gilead Sciences, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Novartis, Shattuck Labs, and Treadwell Therapeutics; and received honoraria from AbbVie, TaiHo, and Novartis. TM, DK, CJM, HS, DV, KM, XL, and MDM declare no competing interests.

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Murphy, T., Mason, J.M., Leber, B. et al. Preclinical characterization and clinical trial of CFI-400945, a polo-like kinase 4 inhibitor, in patients with relapsed/refractory acute myeloid leukemia and higher-risk myelodysplastic neoplasms. Leukemia 38, 502–512 (2024). https://doi.org/10.1038/s41375-023-02110-9

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