NEW YORK – OnKure Therapeutics on Thursday said it has dosed the first patient in a Phase Ib/II trial of the HDAC inhibitor OKI-179 in combination with Pfizer's Mektovi (binimetinib) in patients with advanced NRAS-mutated melanoma.
In the Phase Ib portion of the trial, called Nautilus, OnKure will initially enroll patients with RAS pathway-mutated solid tumors, including mutations in RAS, BRAF, NF1, and GNAQ/11, who are refractory to standard treatment and determine OKI-179's dosage. The Phase II portion of the study will then enroll a cohort of patients with previously treated NRAS-mutated melanoma who haven't responded to checkpoint inhibitors.
The primary endpoint in the Phase II portion of the study is objective response rate, and secondary objectives include progression-free survival, clinical benefit rate, duration of response, measures of plasma concentration, and incidence of adverse events. The trial will enroll up to 73 patients across both stages.
OKI-179 inhibits histone deacetylases (HDAC), which is involved in tumor cell differentiation and progression. The company presented preclinical research in melanoma tumor models in April showing that adding OKI-179 to either Mektovi or Mektovi plus Pfizer's BRAF inhibitor Braftovi (encorafenib) increased tumor regressions compared to either drug alone.
"The combination of HDAC inhibition with MEK inhibition is synthetically lethal in RAS pathway-mutated cancers, resulting in increased tumor regressions by inducing DNA damage that is not seen with either agent alone," OnKure Chief Medical Officer Jennifer Diamond said in a statement. "Given the favorable safety and tolerability profile of OKI-179, we believe its synergistic combination with binimetinib has the potential to be an effective treatment option for patients diagnosed with this highly aggressive melanoma."
Initial results from the Phase I study of OKI-179 in RAS-mutant solid tumors showed the drug was well tolerated and had "robust target engagement" at doses of 120 mg and above.
OKI-179 is Boulder, Colorado-based OnKure's lead candidate and its first candidate to enter the clinic. The company has eight other programs in its pipeline in the preclinical discovery stage.