Study procedures
bleeding, diarrhea, toxicity, thrombocytopenia, cardiac dysfunction, rash, ocular disorders, nausea, vomiting
THROMBOCYTOPENIA, BLEEDING
HL-085 (Shanghai Kechow Pharmaceutical Research & Development Co., Ltd, Shanghai, China) was administered as 0.5 mg, 2.0 mg, and 6.0 mg capsules, twice daily (BID), orally, with a cup of warm water on an empty stomach (≥ 2 ours before or after a light meal). Based on prior data on the pharmacodynamics, pharmacokinetics, and toxicity of HL-085 in vivo and in vitro, as well as the efficacy and safety of MEK inhibitors currently under development, a starting dose of 0.5 mg BID was selected for the dose-escalation phase. The dose was then escalated in the following sequence: 1 mg BID, 2 mg BID, 3 mg BID, 4 mg BID, 6 mg BID, 9 mg BID, 12 mg BID, 15 mg BID, and 18 mg BID. The study planned to enroll at least three evaluable patients in each dose group.Patients were evaluable if they had DLT from 7-day run-in period to the end of the first 28-day treatment cycle. DLT included the following conditions: grade 4 hematologic toxicity or grade 3 thrombocytopenia with bleeding; any grade ≥ 3 non-hematologic AEs which could not recover to ≤ 2 after treatment or with interruption of HL-085 for ≥ 14 days, including nausea, vomiting, rash, diarrhea, aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevation) abnormality; any grade ≥ 3 ocular disorders and cardiac dysfunction AEs which could not recover to grade ≤ 2 after treatment or resulted in treatment interruption for ≥ 14 days due to toxicity.