FDA Grants Orphan Drug Designation to Onvansertib for Chronic Myelomonocytic Leukemia

The FDA has granted orphan drug designation to onvansertib for the treatment of patients with chronic myelomonocytic leukemia (CMML).¹

The designation follows data from an investigator-sponsored phase 1 dose-escalation trial (NCT05549661) evaluating onvansertib monotherapy in patients with relapsed/refractory myeloproliferative CMML, findings from which were presented at the 2025 ASH Annual Meeting and Exposition. In the trial (n = 9), onvansertib was relatively well tolerated and demonstrated preliminary efficacy in approximately 40% of patients.^1,2 Three patients (38%) experienced clinical benefit, with one patient each achieving a 100% platelet response, normalization of white blood cell (WBC) count from a baseline WBC count above 50 × 10⁹/L, and a spleen response. One patient (12.5%) had an optimal marrow response at the 9 mg/m² dose, with bone marrow blasts reduced from 8% to 2%, facilitating allogeneic hematopoietic stem cell transplant, and 3 patients (38%) experienced stable disease.^1,2

"Receiving orphan drug designation for onvansertib in CMML further validates the therapeutic potential of PLK1 inhibition in cancers with significant unmet need and adds to the growing body of evidence supporting this mechanism across both solid tumors and hematologic malignancies," Mani Mohindru, PhD, president and chief executive officer of Cardiff Oncology, stated in a news release.¹

What is the mechanism of action of onvansertib?

Onvansertib is an oral, highly specific inhibitor of PLK1, a mitotic serine/threonine kinase. In proliferative CMML, RAS-pathway mutations have been associated with a gene expression profile enriched in mitotic kinases such as PLK1, with PLK1 transcript levels regulated by unmutated KMT2A through increased promoter monomethylation of lysine 4 of histone 3, according to findings published in Nature Communications.³ In the same work, pharmacologic PLK1 inhibition was evaluated in RAS-mutant patient-derived xenograft models of proliferative CMML.

How was the phase 1 trial designed?

The Mayo Clinic–sponsored, single-center trial, conducted in collaboration with the National Cancer Institute, is enrolling adults with a WHO-defined diagnosis of proliferative CMML or a myelodysplastic/myeloproliferative overlap neoplasm (MDS/MPN), including atypical chronic myeloid leukemia and MDS/MPN not otherwise specified.⁴ Patients must have relapsed or refractory disease following hydroxyurea or at least 4 cycles of a hypomethylating agent, or be intolerant to either therapy, and have an ECOG performance status of 0 to 2 and a platelet count of at least 20,000/mm³. Key exclusions include prior exposure to an investigational PLK1 inhibitor, prior transformation to acute leukemia, and active graft-vs-host disease after allogeneic transplant.

The study consists of dose escalation followed by dose expansion, with onvansertib administered orally once daily.

The primary end point is the incidence of adverse effects (AEs). Secondary end points include complete response rate and overall remission rate per 2015 MDS/MPN International Working Group criteria, volumetric spleen response by ultrasound, and constitutional symptoms by the MPN-Symptom Assessment Form total symptom score. Exploratory objectives include onvansertib activity in RAS-mutant subtypes and the relationship between circulating tumor DNA changes and response.

What are the next steps for onvansertib’s development?

The company's lead indication for onvansertib is first-line RAS-mutated metastatic colorectal cancer (mCRC). In a randomized phase 2 trial (NCT06106308), onvansertib plus FOLFIRI and bevacizumab (Avastin) demonstrated dose-dependent improvements in overall response rate and progression-free survival vs standard of care alone, and the company has selected the 30-mg dose in combination with FOLFIRI/bevacizumab for a planned registrational trial in this population.¹

Onvansertib is also being evaluated in investigator-initiated studies in metastatic pancreatic ductal adenocarcinoma, small cell lung cancer, triple-negative breast cancer, and CMML.

References

1. Cardiff Oncology receives FDA orphan drug designation for onvansertib in chronic myelomonocytic leukemia. News release. Cardiff Oncology. October 21, 2026. Accessed October 22, 2026. https://investors.cardiffoncology.com/news-releases/news-release-details/cardiff-oncology-receives-fda-orphan-drug-designation
2. Cardiff Oncology announces clinical data from investigator-sponsored trial with onvansertib in chronic myelomonocytic leukemia at ASH 2025. News release. Cardiff Oncology. December 8, 2025. Accessed October 22, 2026. https://investors.cardiffoncology.com/news-releases/news-release-details/cardiff-oncology-announces-clinical-data-investigator-sponsored
3. Carr RM, Vorobyev D, Lasho T, et al. RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis. Nat Commun. 2021;12(1):2901. doi:10.1038/s41467-021-23186-w
4. Onvansertib for the treatment of recurrent or refractory chronic myelomonocytic leukemia and myelodysplastic syndrome/MPN overlap neoplasms. ClinicalTrials.gov. Accessed October 22, 2026. https://clinicaltrials.gov/study/NCT05549661