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

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 unfavorable cytogenetics.

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

“While several exciting new drug classes have emerged over the past decade for AML patients, there is still an unmet need for certain patient segments, where survival rates remain low,” said Michael Tusche. , MD, co-CEO 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 as we continue to develop ‘945 in leukemia.”

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

As part of the phase 1b/2 trial TWT-202 (NCT04730258), the safety and tolerability of CFI-400945 as monotherapy or in combination with azacitidine or decitabine are being evaluated in patients with AML, myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML).2 CFI-400945 is currently the subject of several investigator-initiated studies in solid and liquid malignancies.

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

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

Participants eligible for trial enrollment must be at least 18 years of age, and in Part 1A and 1B of the trial, patients must have relapsed/refractory AML, MDS after agents hypomethylating agents or CMML with active disease or lack of response after hypomethylating agents. In Parts 2A and 2B, malignancies included in the trial will include relapsed/refractory AML, patients with MDS restricted to high-risk disease, and previously untreated MDS or CMML . Other requirements include clinically acceptable laboratory screening results and an ECOG status of 0 or 1.

Those who have received experimental therapy, radiation therapy, immunotherapy, monoclonal antibodies, or chemotherapy within 14 days or 5 half-lives, and who have persistent grade 2 or greater non-hematological toxicity related to allogeneic transplantation, including including those requiring systemic immunosuppressive therapy, were excluded from the trial. Additionally, patients who have undergone allograft or autograft for AML with stem cell infusion within 90 days prior to 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 endpoints include incidence of treatment-related adverse events as well as treatment-related changes in vital signs, clinical laboratory tests, physical examinations, ECOG performance status, electrocardiograms, echocardiograms and cardiac troponins. Secondary endpoints include composite complete remission, overall response rate, pharmacodynamic profiles and pharmacokinetics.

References
  1. Treadwell Therapeutics Announces Fast Track FDA Designation of CFI-400945 for the Treatment of Acute Myeloid Leukemia. Press 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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