Overall safety profile
anaemia, diarrhoea, nausea, treatment-emergent QTcF, myocardial infarction, neutropenia, fatigue, cardiac serious adverse events, abnormal left ventricular ejection, chest pain, vomiting, complaints of chest pain, cardiomyopathy, left ventricular systolic dysfunction, decreased appetite, acute coronary syndrome, systolic dysfunction, shortness of breath
ANAEMIA, MYOCARDIAL INFARCTION, LEFT VENTRICULAR SYSTOLIC DYSFUNCTION, NEUTROPENIA, ADVERSE EVENTS, ADVERSE EVENT, CARDIOMYOPATHY, ACUTE CORONARY SYNDROME, SYSTOLIC DYSFUNCTION
The most common treatment-emergent adverse events (TEAEs) attributed to SRA737 irrespective of SRA737 dose level were diarrhoea (63%), nausea (60%), vomiting (46%), fatigue (38%), decreased appetite (18%), neutropenia (16%) and anaemia (15%) (Table SRA737-related treatment-emergent adverse events of any grade reported by ≥10% of overall patient group.SRA737-related treatment-emergent adverse events of Grade 3 or higher reported by 2 or more patients overall.Cardiac safety parameters were monitored closely in this study since cardiac side effects have been seen previously with Chk1 inhibitors. The studied doses had no clinically relevant effects on heart rate, PR interval, or QRS duration and there were no individual subjects with treatment-emergent QTcF values >500 ms or a change from baseline in QTcF (ΔQTcF) of >60 ms on central ECG monitoring. Four cardiac serious adverse events were evaluated to be possibly related to SRA737. At 800 mg SRA737, 1 case of asymptomatic myocardial infarction was diagnosed by the detection of elevated troponins on routine monitoring concurrent with ECG changes and mild systolic dysfunction and apical akinesis on echocardiogram, and 1 case of acute coronary syndrome with complaints of chest pain associated with elevated troponin but no ischemic changes noted on ECG occurred. At 1000 mg SRA737, 1 case of cardiomyopathy manifested by chest pain and shortness of breath with echocardiographic findings of left ventricular systolic dysfunction and asymptomatic myocardial infarction, and 1 case of asymptomatic QT prolongation with no cardiac signs or symptoms reported including during a period of in-hospital observation occurred. In all cases, administration of the drug was permanently discontinued. Based on an analysis of the relationship of SRA737 plasma concentration and QT interval corrected for heart rate using Fridericia’s formula (QTcF) measured in 79 patients, the QTcF least squares (LS) mean change from baseline (ΔQTcF) was similar across all dose groups and indicated that SRA737 has an effect on QTcF. The largest LS mean ΔQTcF at the recommended Phase 2 dose level of 800 mg QD was observed at 2 h post dose on Cycle 1 Day 22, corresponding to the time of maximum plasma concentration (A review of echocardiogram data obtained on 83 evaluable patients revealed that no additional patients (other than the cases mentioned above of clinically evident cardiomyopathy and myocardial infarction) had a > 10% absolute drop from baseline resulting in abnormal left ventricular ejection fraction.Adverse events (AE) leading to treatment discontinuation were reported by a total of 34 patients (31.8%), 16 of whom (15.0%) discontinued due to SRA737-related TEAEs. Fatal adverse events AE were reported for ten patients; none were attributed to SRA737.