Study design and intervention
pneumonitis, DLTs, diarrhea, toxicity, toxicities, rash, Tumors, nephritis, hypertension, hepatitis, nausea, vomiting
PNEUMONITIS, FEBRILE NEUTROPENIA, ADVERSE EVENTS, ENTEROCOLITIS, TUMORS, MALIGNANCIES, NEPHRITIS, SECONDARY, HYPOTHYROIDISM, HYPERTENSION, HEPATITIS
APPEASE was designed as a Phase I, single-site trial utilizing a standard 3 + 3 design, with the primary objective to assess the safety and maximum tolerated dose (MTD) of rivoceranib in combination with pembrolizumab in subjects with select advanced malignancies. The Phase I primary endpoints included adverse events (AEs), serious adverse events (SAEs), and the rate of dose-limiting toxicities (DLTs).DLTs were defined as an AE causally related to rivoceranib and / or pembrolizumab during the 6 weeks of treatment (between the first day of the first cycle and the first day of the third cycle). Additionally, one of the following criteria had to be fulfilled: any grade 4 toxicity; grade 3 febrile neutropenia; grade 3 hematologic toxicity lasting > 7 days; uncontrollable hypertension defined as Stage 2 hypertension requiring a dose reduction; other grade 3 toxicities including nausea, vomiting, and diarrhea, continuing for more than 72 h despite optimal medical management; grade 2 toxicity warranting a preemptive dose reduction of rivoceranib in the opinion of the investigator; any toxicity of any grade warranting a dose reduction of rivoceranib; any toxicity of any grade warranting withholding or delaying a pembrolizumab infusion; immune-related toxicities which do not resolve to grade ≤ 1 within 14 days, including grade ≥ 2 pneumonitis, grade ≥ 2 enterocolitis, grade ≥ 2 nephritis, grade ≥ 2 hepatitis, grade ≥ 3 rash, grade ≥ 3 hypothyroidism, and any immune- related toxicity requiring systemic steroid treatment; Hy’s Law (3 × ULN elevation of transaminases and concomitant 2 × ULN elevation of bilirubin without alternative etiology); failure to receive at least 80% of the expected doses of rivoceranib due to toxicity.The secondary objectives of the trial were to assess the efficacy of the combination. Objective response rate and progression-free survival were evaluated per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) criteria.Eligible patients were treated with 300 mg rivoceranib (LSK BioPartners) orally once daily, with a minimum of 16 h between doses, and 200 mg pembrolizumab IV infusion on the first day of each 21-day cycle. It was planned to increase the dose of rivoceranib by 100 mg, up to a maximum daily dose of 700 mg was reached, every three to six patients providing that at most one out of six patients treated experienced DLTs.