FDA Grants Fast Track Designation to Novel PLK4 Inhibitor for R/R AML

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The FDA has granted fast track designation to CFI-400945 which has shown encouraging signs of monotherapy activity in patients with acute myeloid leukemia with adverse cytogenetics.

The FDA has granted fast track designation to a first-in-class inhibitor of polo-like kinase 4 (PLK4), CFI-400945, for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML), according to a press release from Treadwell Therapeutics.1

"Although several exciting new classes of medicines have emerged in the past decade for patients with AML, there still remains an unmet need for certain patient segments, where survival rates remain low," said Michael Tusche, MD, co-chief executive officer of Treadwell Therapeutics, in the press release. "CFI-400945, has shown encouraging signs of monotherapy activity in AML patients with adverse cytogenetics. We are grateful for the Fast Track Designation for this exciting program and look forward to frequent interactions with the FDA to chart our regulatory path forward, as we continue the development of '945 in leukemia."

CFI-400945 is a selective, highly potent, oral inhibitor of the serine/threonine kinase PLK4. It is a cell cycle kinase and is also known as the master upstream regulator of centriole duplication. The inhibitor has proven to be critical for the maintenance of genomic integrity.

Within the phase 1b/2 TWT-202 trial (NCT04730258), the safety and tolerability of CFI-400945 as a single agent or in combination with azacitidine or decitabine is being evaluated in patients with AML, myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML).2 CFI-400945 is currently in multiple investigator-initiated studies within both solid and liquid malignancies.

The open-label, multicenter, dose optimization study has an estimated enrollment of 72 patients at up to 20 sites across North America and Asia. The estimated date for completion of the study is January of 2024.

There are 3 arms included in the study which consist of the agent as monotherapy, as a combination dose optimization and expansion, or as a food effect study. The starting dose for escalation arms and the recommended starting dose for the expansion arms is 32 mg/day.

Participants eligible for enrollment in the trial must be aged 18 and older and in parts 1A and 1B of the trial, patients must have either relapsed/refractory AML, MDS after hypomethylating agents, or CMML with progressive disease or lack of response after hypomethylating agents. In part 2A and 2B, malignancies included in the trial will consist of relapsed/refractory AML, MDS patients limited to high-risk disease, and MDS or CMML that is previously untreated. Other requirements include clinically acceptable laboratory screening results and an ECOG status of 0 or 1.

Those who have received investigational therapy, radiotherapy, immunotherapy, monoclonal antibodies, or chemotherapy within 14 days or 5 half-lives, and who have any grade 2 or higher persistent non-hematological toxicity related to allogeneic transplant, including those requiring systemic immunosuppressive therapy, were excluded from the trial. Additionally, patients who have had an allogeneic or autologous transplant for AML with infusion of stem cells within 90 days before cycle 1 on day 1, or on active immunosuppressive therapy for graft-versus-host disease (GVHD) or GVHD prophylaxis within 2 weeks of day 1 of cycle 1 were not included.

Primary end points include incidence of treatment adverse events as well as treatment-emergent changes in vital signs, clinical laboratory tests, physical examinations, ECOG performance status, electrocardiograms, echocardiograms, and cardiac troponins. Secondary end points consist of composite complete remission, overall response rate, pharmacodynamics profiles, and pharmacokinetics.

References
  1. Treadwell therapeutics announces fast track designation granted by the FDA to CFI-400945 for the treatment of acute myeloid leukemia. News Release. Treadwell Therapeutics. April 26, 2022. Accessed April 27, 2022. https://prn.to/3ETqEDZ
  2. A study of CFI-400945 with or without azacitidine or decitabine in patients with AML, MDS or CMML (TWT-202). Clinicaltrials.gov. Accessed April 27, 2022. https://bit.ly/3LnLKN4
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