Discussion
bleeding, DLTs, tumor, neurotoxicity, tumors
BLEEDING, TUMOR, SOLID TUMORS, DRUG EFFECT, EVENTS, TUMOR GROWTH, TUMORS
In this phase I study, orally administered M8891 was clinically manageable in patients with advanced solid tumors. Among the 27 patients enrolled into the study, only two DLTs were observed, and, after enrolling a confirmatory cohort, the RP2D was determined as 35 mg once daily based on the absence of DLTs at doses ≤35 mg and a dose-proportional increase in M8891 exposure and Met-EF1α pharmacodynamic biomarker levels in tumors up to 35 mg once daily.TEAEs were generally grade 1–2 in severity and most were unrelated to M8891. Platelet count decrease was the most common TEAE, but these events were generally manageable clinically, and no associated bleeding events were observed. These results compare favorably with the safety profile of irreversible MetAP2 inhibitors, such as TNP-470, which showed considerable neurotoxicity in phase I studies (Exposure to M8891 increased by dose level and showed low-to-moderate interpatient variability following multiple doses based on pharmacokinetic parameters. The multiple-dose pharmacokinetics of M8891 compared favorably with high pharmacokinetic variability found in phase I studies with TNP-470 (M8891 treatment resulted in the accumulation of Met-EF1α in tumors in a dose-dependent manner, demonstrating inhibition of MetAP2 by M8891, consistent with preclinical studies (Although M8891 had shown significant tumor growth inhibition in preclinical models (As this was a phase I dose-escalation study, limitations include the open-label design and small sample size. The heterogeneity of tumor types enrolled in the study made it challenging to assign the efficacy or pharmacodynamic data to specific patient populations that may benefit more than others.In conclusion, M8891 is the first orally available, reversible MetAP2 inhibitor that has entered clinical development. This FIH study allowed determination of an RP2D based on relevant pharmacokinetics, pharmacodynamics, and safety observations; M8891 demonstrated a manageable safety profile with TEAEs in line with the patient population, drug effect, dose-proportional exposure up to 35 mg, Met-EF1α accumulation, and low-to-moderate interpatient variability of plasma concentration and corresponding parameters of pharmacokinetics. In addition, the observed exposure and target engagement anticipated to be required for 