Background: CFI-400945 is a potent, selective, orally administered, first-in-class inhibitor of the serine/threonine kinase, Polo-like kinase 4 (PLK4). PLK4 is a highly conserved master upstream regulator of centriole duplication and is critical for maintenance of genomic integrity. Aberrant expression of PLK4 results in centrosome amplification, often seen in aneuploid cancers, pointing to a potentially causative role for PLK4 in genome instability and cancer progression. An investigator-initiated study using a 28-day continuous CFI-400945 dosing schedule at the Princess Margaret Cancer Center (PMCC) demonstrated clinical activity in AML [Murphy et al., 2020] and responses were seen in high-risk pts with adverse cytogenetics, including those with TP53 mutations. CFI-400945 was tolerated with clinically manageable toxicities and the dose limiting toxicity (DLT) was colitis. The recommended phase 2 dose was 96mg. A newer crystal form of CFI-400945 was introduced after the PMCC study. Consequently, the optimal dosing of CFI-400945, including as a combination agent, are not yet clinically defined and are the rationale for this study.

Study Design and Methods: This study is a multi-part phase 1/2 study of CFI-400945 as a single agent and in combination with hypomethylating agents (HMA) (NCT04730258). For Part 1, pts with relapsed and/or refractory AML, MDS, or CMML after >1 prior therapy will be included. Pts with MDS or CMML must have progressed or had a lack of response after at least 4 cycles of hypomethylating agents. For Part 2, pts should have relapsed and/or refractory AML or untreated MDS or CMML. Untreated pts who decline or are ineligible for intensive therapy may be included. The study uses a standard 3 + 3 design, and the dosing schedule is 21 days on and 7 days off (28-day cycle) - this is to potentially avoid the colitis seen in the study at PMCC. The maximum tolerated dose (MTD) will be defined as the dose level where the number of dose-limiting toxicities (DLTs) is <1 out of 6 at highest dose level at or below the maximally administered dose. Pharmacokinetics (PK) and pharmacodynamic (PD) markers will be assessed.

Results: As of the 30Jun22 data cut off, 9 pts had been enrolled into the study. Four (44%) pts had AML, 2 (22%) had MDS, 3 (33%) had CMML. The median number of prior therapies was 2 (range 1-4), and 2 (22%) pts had received a stem cell transplant. Six (66%) were male and the median age was 69 (range 22-75). Three of 4 AML pts had unfavorable risk cytogenetics by ELN 2017 criteria, and 2 pts (1 each with MDS, CMML) with TP53 mutations. Five pts received 32mg and 4 pts 48mg. There have been no DLTs. There have been 8 (89%) SAEs with the following occurring in >2 pts (febrile neutropenia (6 pts), pneumonia (2 pts)). Common treatment emergent adverse events (TEAE) in > 2 pts were febrile neutropenia 6 pts (67%), hypokalemia 5pts (56%), anemia and hypomagnesemia 4 pts each (44%), hypophosphatemia, diarrhea, abdominal pain, nausea, vomiting, dyspnea, peripheral edema 3 pts each (33%). Thirty-three percent (20 events, 3 pts) of the grade 3 or greater TEAE's were considered related to CFI-400945. There have been no CR or PR per ELN response criteria observed to date, however, there were 2 (50%) SD per IWG criteria at the 48 mg dose level (1-MDS, 1-CMML). Pharmacokinetic (PK) evaluations indicated that the mean terminal-life ranged from 7 - 10 hours. Low accumulation was observed after 21 days of daily dosing (AR <2-fold). In general, exposure in this study is overlapped with that observed in the PMCC study. PD studies evaluating the effect of CFI-400945 on markers of mitosis, ploidy, and centriole function are ongoing.

Conclusion: 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. PK characteristics support daily dosing of CFI-400945 and PD studies are ongoing. Dose escalation continues in this study and updated data will be presented.

References:Murphy et al, Preliminary Results from a Phase 1 Study of CFI-400495, a PLK4 Inhibitor, in Patients with Acute Myeloid Leukemia and High Risk MDS Blood (2020) 136 (Supplement 1): 1-2

Jonas:AbbVie: Consultancy, Other: Travel Reimbursement, Research Funding; Jazz: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; 47: Research Funding; Pfizer: Consultancy, Research Funding; GlycoMimetics: Consultancy, Other: protocol steering committee , Research Funding; Gilead: Consultancy, Other: data monitoring committee , Research Funding; Servier: Consultancy; Takeda: Consultancy; Tolero: Consultancy; Treadwell: Consultancy; Accelerated Medical Diagnostics: Research Funding; Amgen: Research Funding; AROG: Research Funding; BMS: Consultancy, Research Funding; Celgene: Research Funding; Daiichi Sankyo: Research Funding; F. Hoffmann-La Roche: Research Funding; Forma: Research Funding; Roche: Research Funding; Hanmi: Research Funding; Immune-Onc: Research Funding; Incyte: Research Funding; Loxo Oncology: Research Funding; LP Therapeutics: Research Funding; Pharmacyclics: Research Funding; Sigma Tau: Research Funding. Yee:Bristol-Myers Squibb/Celgene: Consultancy; Jazz: Consultancy, Research Funding; Abbvie: Honoraria; Takeda: Consultancy; Karyopharm: Research Funding; Treadwell: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; GlaxoSmithKline: Consultancy; F. Hoffmann La Roche: Consultancy, Research Funding; TaiHo: Consultancy; Shattuck Labs: Consultancy; Forma Therapeutics: Research Funding; Astex: Research Funding; Gilead: Research Funding; Geron: Research Funding; Janssen: Research Funding; Astellas: Consultancy. Koller:Treadwell Therapeutics: Other: Safety Review Committee; Takeda: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Brandwein:Pfizer: Honoraria; Taiho: Honoraria; BMS/Celgene: Honoraria; Abbvie: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Jazz: Honoraria; Merck: Honoraria. Mims:AbbVie: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Other: Data Safety and Monitoring Board; Zentalis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Ryvu: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Other: Data Safety and Monitoring Board; Astellas: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Michelson:Treadwell Therapeutics: Consultancy. Nguyen:Treadwell Therapeutics: Current Employment. Bray:Treadwell Therapeutics: Current Employment. Roberts-Thomson:Treadwell Therapeutics: Current Employment. Borthakur:Pacylex, Novartis, Cytomx, Bio Ascend: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals, Ryvu, PTC Therapeutics: Research Funding; Catamaran Bio, Abbvie, PPD Development, Protagonist Therapeutics, Janssen: Consultancy.

Author notes


Asterisk with author names denotes non-ASH members.

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