Abstract P1-18-17: Phase I study of cfi-402257, an oral ttk inhibitor, in patients with advanced solid tumors with breast cancer expansion cohorts
Authors: Hilton John , Renouf Daniel J , Cescon David W , Hansen Aaron R , Razak Albiruni RA , Stayner Lee-Anne , Denny Trisha , Fletcher Graham , Mak Tak W , Bray Mark , Bedard Philippe L 
Published: March 2022

Abstract
Background: TTK (also known as Mps1), a dual-specificity serine-threonine kinase, is critical for the spindle assembly checkpoint (SAC), chromosome alignment and error correction in mitosis. Inhibition of TTK causes premature mitotic exit with unattached chromosomes, resulting in chromosomal missegregation, aneuploidy and cell death. CFI-402257 is a potent (Ki = 0.09 nM, IC50 = 1.2 nM), highly selective and orally active inhibitor of TTK. Robust suppression of tumor growth was achieved upon oral dosing of single agent CFI-402257 in ER+/HER2- and triple negative breast cancer (TNBC) cell line and patient derived xenograft models. CFI-402257 demonstrated enhanced cytotoxicity in CDK4/6 inhibitor resistant ER+ breast cancer cell line models compared to parental cell lines, including those with RB1 loss. Methods: This multi-center Phase I dose escalation study (3+3 design) was designed to determine the safety, tolerability and maximum tolerated dose (MTD) of CFI-402257 and evaluate anti-tumor activity at the RP2D. CFI-402257 was dosed once daily on a continuous schedule in 28-day cycles at a starting dose of 5mg based on preclinical toxicology. Dose escalation included patients with advanced solid tumors and dose expansion at the RP2D into three expansion cohorts - Cohort A advanced solid tumors, Cohort B advanced ER+ or TNBC with 1-4 prior lines of chemotherapy for metastatic disease and Cohort C ER+/HER2- breast cancer in combination with Fulvestrant (500mg IM Day 1, 15 and 29 and then every 28 days) who have had prior treatment with an aromatase inhibitor in combination with a CDK4/6 inhibitor (&gt;= 3 months) and =&lt;1 prior chemotherapy for metastatic disease. Results: As of May 25, 2021, 66 patients had been enrolled, majority (76%) of patients received &gt;3 prior therapies before study entry and 37% of patients’ (23/66) primary malignancy was breast cancer. The maximum administered dose was 294 mg and the study has continued enrolling at the recommended phase 2 dose of 168 mg with grade 3 Neutropenia, grade 3 Febrile Neutropenia and grade 3 Colitis as the dose limiting toxicities. Only 1/6 patients experienced a DLT at 168 mg (grade 3 Neutropenia, &gt;7 days) The most common treatment emergent AEs (Gd3, &gt;5%) were Neutropenia (15.6%), Anaemia (7.8%), Hypophosphataemia and Febrile Neutropenia (6.3%). PR’s confirmed by the Investigator have been seen to date in 33% of the cohort C subjects (2/6 patients), with an additional two cPR’s seen in the breast cancer population (ER+/HER2-) from the expansion cohorts. Conclusion: CFI-402257 is generally well tolerated and continues to enroll at 168mg daily with a manageable AE profile and early signs of anti-tumor activity. Enrollment in the expansion cohorts is ongoing and updated safety and efficacy data for the previously treated ER+/HER2- population will be presented at the time of the meeting. A multi-center phase II clinical trial is planned.
Citation Format: John Hilton, Daniel J Renouf, David W Cescon, Aaron R Hansen, Albiruni RA Razak, Lee-Anne Stayner, Trisha Denny, Graham Fletcher, Tak W Mak, Mark Bray, Philippe L Bedard. Phase I study of cfi-402257, an oral ttk inhibitor, in patients with advanced solid tumors with breast cancer expansion cohorts [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-18-17.