87 (PB077) - Optimal dosing of a novel PLK4 inhibitor nested in a phase II study of CFI-400945 in patients with Advanced/Metastatic Breast Cancer (MBC): Canadian Cancer Trials Group (CCTG) IND.237

Abstract

Background: CFI-400945 is a selective oral inhibitor of Polo-like Kinase 4 (PLK4), a controller of centriole duplication and mitotic progression. CFI-400945 was identified by functional screening of genomically unstable breast cancer (BC). The phase I study escalated doses from 3 to 96 mg/d in a 3 + 3 design; dose-dependent neutropenia (ANC) was noted, and the recommended phase 2 dose (RP2D) declared at 64 mg. IND.237 (NCT01954316) is a phase 2 study in MBC with 3 cohorts, 2 enriched for PTEN status. Enrollment started in 2018 at 64 mg. The initial patients had higher than expected grade 3/4 ANC. Materials and Methods: The primary endpoint of the safety cohort was to confirm the RP2D for CFI-400945. Patients with MBC who met inclusion criteria for CCTG IND.237 were enrolled. A reverse 3 + 3 design was used, and patients enrolled at 64 mg, 48 mg, 40 mg and 32 mg dose levels (DL). In cycle (C)1, patients were treated 7 days on 7 days off for 28 d; for c2 onwards, CFI-400945 was administered continuously. Results: The most common severe adverse event (AE) was dose dependent ANC (table 1). After 80% of the first 5 patients developed grade 3 or 4 ANC, accrual was held while the protocol was amended to add a dose exploration cohort with pharmacokinetics in a reverse dose-finding approach. Based on the frequency of ANC and dose intensity, 32 mg was declared the new RP2D for CFI-400945. There were no non-hematologic severe AEs. PK analysis confirmed similar AUC for the 32 mg DL compared to the PK from the phase I study RP2D.Table 1Frequency of severe neutropenia by DL during C1 and C2 of safety cohort of IND.237DL# PatientsGrade 3 ANC(n(%))Grade 4 ANC(n(%))64 mg51 (20%)3(60%)48 mg65 (50%)2(33%)40 mg82 (25%)2(25%)32 mg60 (0%)0(0%) Open table in a new tab Refinement of the manufacturing process used for IND.237 and subsequent studies incorporated a more stable polymorph of CFI-400945 drug substance had the unexpected property of higher exposure at a given dose and was hypothesized to be due to slightly faster dissolution of the new tablets in the acidic environment of the stomach. Conclusions: The RP2D for CFI-400945 in patients with advanced breast cancer is 32 mg/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). Research funding is administered by the American Association for Cancer Research International - Canada, the scientific partner of SU2C Canada. Conflict of interest: Ownership: none Advisory Board: Anthony Lott - Novartis, Eisai, Astra-Zeneca, Ipsen Terry Ng - Novartis, Knight Therapeutics, Boehringer-Ingelheim Arif Awan - AstraZeneca, Eli Lily, Exact Sciences, Exactis, Novartis, Pfizer, Roche Honoraria: Apotex, Roche Rossanna Pezo - Merck, Novartis, Pfizer, Astra Zeneca, Lilly, BMS, Exact Sciences, Myriad Genomics, Mylan Philippe Bedard - Seattle Genetics, Lilly, Amgen, Merck, Gilead Sciences, BMS, Pfizer John Hilton - Bristol-Myers-Squibb (BMS), AstraZeneca (AZ), Pfizer, Novartis, Eli Lilly, Puma, and Genomic Health Jacques Antoun Raphael - Lilly, Merck, AstraZeneca and Novartis. Moira Rushton - Gilead, Pfizer, Viatris David Cescon - Pfizer, AstraZeneca, Novartis, GlaxoSmithKline, Merck, Roche/Genentech, Exact Sciences, Gilead Sciences, Eisai Board of Directors: none Corporate-sponsored Research: Terry Ng - Takeda Oncology Rossanna Pezo - Merck and Novartis Philippe Bedard - Bristol-Myers Squibb, Sanofi, AstraZeneca, Genentech/ Roche, GlaxoSmithKline, Novartis, Nektar, Merck, Seattle Genetics, Immunomedics, Lilly, Amgen, Bicara, Zymeworks David Cescon - Merck, Roche/Genentech, GlaxoSmithKline, Pfizer, Inivata, AstraZeneca, Gilead Sciences Other Substantive Relationships: Terry Ng - Pharma-sponsored education session - ARIAD and Takeda Oncology Arif Awan - Travel: Roche Mark Bray - Full time employee of Treadwell Therapeutics Lesley Seymour & Pierre-Olivier Gaudreau - Funding to CCTG from UHN to partially support trial conduct Moira Rushton - Medical Montior: Pharmamatrix, Edmonton, Alberta David Cescon - Patent (US62/675,228) for methods of treating cancers characterized by a high expression level of spindle and kinetochore associated complex subunit 3 (ska3) gene. note CFI-402257 // CFI-400945 were developed at UHN