Safety
bleeding, DLTs, thrombocytopenia, TEAEs, decreased appetite
DISEASE PROGRESSION, BLEEDING, DEEP VEIN THROMBOSIS, THROMBOCYTOPENIA, ADVERSE EVENT, EVENTS
Overall, most patients (96.3%, 26/27) experienced a TEAE, with 21 (77.8%) reporting at least one TEAE considered related to M8891 by investigators (Overview of TEAEs for M8891Abbreviations: TEAE, treatment-emergent adverse event; QD, once daily.
TEAEs occurring in ≥15% patients are presented by dose level and overall, in TEAEs occurring in ≥15% of patients overall by dose levelAbbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; QD, once daily; TEAE, treatment-emergent adverse event.

In 4 patients, platelet count decrease or thrombocytopenia led to M8891 dose interruption [1 patient each in the 20 mg (thrombocytopenia) and 80 mg once daily (platelet count decrease) dose group] or study treatment discontinuation [1 patient each in the 35 mg and 60 mg once daily dose groups (both platelet count decrease)], with 3 patients subsequently recovering during the study period. Eight patients continued treatment with M8891 without dose interruption or reduction in response to platelet count decrease. One of these patients recovered while on treatment, 3 patients recovered after the last dose of M8891, and 4 patients had not recovered by the end of the study. In 1 patient in the 60 mg once daily dose group, platelet count decrease was detected 1 day after the last dose was administered; the patient subsequently recovered. The mean relative reduction in platelet count from baseline was greater with increasing dose levels (Mean relative change in platelet count from baseline per dose level in cycle 1 (%). C, cycle; D, day.Other common TEAEs were decreased appetite (Thirteen of 27 patients discontinued treatment due to disease progression (48.1%, all groups), 7 (25.9%) patients withdrew consent due to TEAEs, and another 7 (25.9%) patients experienced TEAEs that led to treatment discontinuation. Both, TEAEs leading to M8891 treatment discontinuation and M8891-related grade ≥3 TEAEs generally occurred more frequently at higher doses of M8891 (>20 mg once daily) than at lower doses (≤20 mg once daily). Six patients experienced TEAEs leading to study discontinuation that were considered M8891-related: deep vein thrombosis (Two DLTs of grade 4 platelet count decrease were reported in the study, one each in the 60 and 80 mg groups. Both patients were initially reported as having grade 1 platelet count decrease after 7 and 14 days of treatment, respectively, and subsequently developed grade 4 platelet count decrease. The DLTs were manageable, not complicated by bleeding events, and their severity decreased within 1 week after discontinuation of M8891.No clinically meaningful changes were observed in vital signs or ECG values from baseline to any postdose values. Most postdose laboratory tests values were rated grade 0 or 1 in severity. Three patients had shifts in baseline ECOG performance status to values ≥2.Taking into consideration the less than dose-proportional increase in exposure combined with safety observations at doses of 60 to 80 mg, the SMC recommended to de-escalate from 80 to 35 mg to further explore this dose as a potential RPD2. As a result, the DLT probability estimation by the BLRM did not reach sufficient precision due to the limited number of DLTs and sample size, and the MTD was not determined.