Assessments and Endpoints
nausea or vomiting, death, DLTs, bleeding, neutropenia, fever, fatigue, toxicity, Tumor, thrombocytopenia, TEAEs, SD, rash, treatment-emergent adverse events, hypertension
BLEEDING, NEUTROPENIA, TUMOR, ADVERSE EVENTS, BLOOD, THROMBOCYTOPENIA, DISEASE, EVENTS, HYPERTENSION, HEPATOCELLULAR INJURY
The primary endpoint was DLTs during the first 21-day treatment cycle of M8891, based on a predefined set of treatment-emergent adverse events (TEAE) with the aim to determine the MTD of M8891. At each dose level, the first patient was observed for DLTs for ≥7 days before the dosing of 2 subsequent patients was commenced. DLTs were defined as any of the following adverse events observed during the first 21-day treatment cycle and judged to be M8891-related or clinically relevant: death; events of clinical significance that would expose patients to unacceptable risk if dose escalation continued; treatment-related hepatocellular injury, for example, ALT/AST >3 × ULN with elevation of serum total bilirubin to >2 × ULN, without findings of clinical causality; grade 4 liver enzyme elevation; Grade 4 neutropenia or thrombocytopenia lasting >5 days; grade 3 neutropenia with fever; grade ≥3 thrombocytopenia with bleeding; treatment interruption of >7 days or >30% of total dose due to adverse events not related to the underlying disease or concomitant medication; grade ≥3 non-hematologic toxicity (excluding grade 3 nausea or vomiting lasting <48 hours and resolving to grade ≤1 spontaneously or with conventional medical intervention; grade 3 fatigue or rash of <5 days duration; grade 3 hypertension in the absence of maximal medical therapy; and grade 3 electrolyte abnormality that lasted <72 hours, was not clinically complicated, and resolved spontaneously or responded to conventional medical intervention). In addition, the SMC could define as a DLT any TEAE that impaired daily function, or any abnormality that occurred in patients treated with M8891 at any time in cycle 1 during the dose-escalation part of the trial.Secondary objectives included evaluating the safety, tolerability, pharmacokinetics, antitumor activity, and determining the RP2D of M8891. Safety evaluations included incidence and severity of TEAEs. All TEAEs were coded according to the Medical Dictionary for Regulatory Activities v23.0 (Efficacy endpoints included best overall response [BOR: complete response (CR), partial response (PR), stable disease (SD), or progressive disease] according to the RECIST v1.1. criteria (Blood samples for M8891 pharmacokinetic analysis were collected on cycle 1, day 1 at 0 hour (predose within 60 minutes prior to treatment administration) and at 1, 2, 3, 4, 5, 6, 8, and 12 hours postdose; on cycle 1, day 8 at 0 hour (predose within 60 minutes prior to treatment administration); on cycle 1, day 15 at 0 hour (predose within 60 minutes prior to treatment administration) and at 1, 2, 3, 4, 6, 8, and 12 hours postdose; and on cycle 1, day 16 at 24 hours postdose (±60 minutes). From cycle 2 onward, blood samples for pharmacokinetic analysis were collected on day 1 at 0 hour (predose within 60 minutes prior to treatment administration). Validated LC/MS-MS bioanalytical methods were used to quantify concentrations of M8891 in plasma samples obtained from these blood samples. Pharmacokinetic parameters evaluated included observed maximum plasma concentration (Exploratory objectives included measuring the levels of the pharmacodynamic biomarker, methionylated elongation factor 1α (Met-EF1α), before and during M8891 treatment. Tumor biopsies were collected during the screening period and on cycle 2, day 1. White blood cell (WBC) samples were collected during the screening period, predose on days 1, 2, 8, and 15 of cycle 1 and postdose on days 1 and 15 of cycle 1. In addition, WBC samples were collected predose on days 1 and 15 of cycle 2.