Safety and tolerability
blurred vision, pneumonitis, dyspnea, arrhythmia, fatigue, heart toxicity, abdominal tumor rupture, mediastinal disorders, retinal aneurysm, hemorrhage, cataract, cough, deaths, acne-like dermatitis
DISEASE PROGRESSION, PNEUMONITIS, ARRHYTHMIA, RETINAL HEMORRHAGE, ADVERSE EVENTS, PERIPHERAL EDEMA, SKIN TOXICITY, EVENT, EYE, RETINAL ARTERY OCCLUSION, HEMORRHAGE, CHORIORETINOPATHY, MACULAR EDEMA, CATARACT, INTERSTITIAL LUNG DISEASE, HYPERTENSION, SEQUELAE
Safety data for all patients in the study were combined. Table Drug-related adverse events reported in ≥ 10% of patients during the treatment periodData are number of patients (%)Drug-related AEs leading to drug interruption or dose reduction were observed in 19 patients (19/42, 45.2%); all dose occurred, except 0.5 mg, 1 mg, and 2 mg dose group. The most common AE include the following: increased CK (6/42, 14.3%), fatigue (3/42, 7.1%), peripheral edema, acne-like dermatitis, ambiguous state of consciousness 4.8% (2/42). In this trial, ambiguous state of consciousness were observed in 2 patients, 12 mg and 18 mg dose group respectively. The one occurred in 12 mg dose, died 8 days later due to extensive disease progression and abdominal tumor rupture and hemorrhage; the investigators evaluated that the ambiguous state of consciousness was associated with disease progression. The other one occurred in 18 mg dose, symptoms disappeared and no sequelae after 5 days later. All the others occurred in 1 case.Drug-related AEs leading to drug discontinuation were only observed in 3 patients (3/42, 7.1%) due to ejection fraction decreased (15 mg cohort), interstitial lung disease (18 mg cohort), and retinal artery occlusion (18 mg cohort). According to the study, DLT were evaluate from 7-day run-in period to the end of the first 28-day treatment cycle. However, the 3 AEs were not occurred during the DLT evaluation period, so they were not considered DLT. No drug-related deaths occurred.Skin toxicity were the most frequent treatment-related AEs in this study (Table Treatment-related ocular AEs were recorded in 8 patients (8/42, 19%), such as eye discomfort, blurred vision, retinal aneurysm, retinal artery occlusion, retinal hemorrhage, chorioretinopathy, macular edema, cataract, and intraocular hypertension. Most cases of ocular AEs were grade 1–2 and did not require drug suspension or dose reduction; only one patient (retinal artery occlusion, 18 mg cohort) required discontinuation of HL-085 and received concomitant medications (such as Compound Tropicamide Eye Drops, Timolol Maleate Eye Drops, Triamcinolone acetonide acetate injection, compound betamethasone injection).Most of heart toxicity AEs were grade 1–2 and asymptomatic such as electrocardiogram ST-T segment abnormality, electrocardiogram T wave abnormality, and arrhythmia (grade 1, symptomatic resolution without sequelae). Only one patient with decreased ejection fraction (15 mg cohort) required discontinuation of HL-085.Respiratory, thoracic, and mediastinal disorders include pneumonitis, dyspnea, interstitial lung disease, and productive cough (each event only in one patient), most of which were grade 1–2. Grade 3 interstitial lung disease (18 mg cohort) was resolved upon discontinuation of HL-085.