Design and participants
DLTs, neutropenia fever, pneumonia, toxicity, hematological toxicity, thrombocytopenia, hypertention, vomiting, bacteremia, sepsis, asthenia/fatigue, Cancer
RENAL, DISEASE PROGRESSION, PNEUMONIA, NEUTROPENIA FEVER, BRAIN METASTASES, ADVANCED CANCER, THROMBOCYTOPENIA, BLEEDING TENDENCY, ADVERSE EFFECTS, SECONDARY, EVENTS, SEPSIS, CANCER
This was a multicenter, phase I, open-label, dose-escalation and dose-expansion study that aimed to evaluate the safety, tolerability and anti-tumor activity of sintilimab as a single agent in pediatric patients with advanced cancers refractory to standard therapy. Sintilimab was administered to all patients via intravenous (IV) infusion once every 3 weeks (Q3W). The study protocol received approval from the review boards of the Sun Yat-sen University Cancer Center and Children’s Hospital of Chongqing Medical University. A data safety monitoring board oversaw the study, which was conducted in accordance with the Declaration of Helsinki and international standards of good clinical practice.To be eligible for the study, all participants were required to meet certain criteria. These included having an adequate performance status, which was assessed using the ECOG score ranging from 0 to 1. In addition, patients needed to have satisfactory hematological function, with an absolute neutrophil count of at least 1000 cells per μL, platelet count of at least 100,000 per μL, and hemoglobin level of at least 9 g/dL for all patients. Renal function was also assessed, with a creatinine clearance of ≤1.5 times the upper limit of normal for the patient’s age. Hepatic function was evaluated based on the total bilirubin level, which had to be ≤2.5 times the upper limit of normal for the patient’s age. Furthermore, patients were required to have a minimum of 42 days elapsed since their last autologous stem cell transplant, stem cell infusion, or cellular therapy before they were eligible for enrollment in the study. Initially, patients with allogenic stem cell transplants were not included. There were certain exclusion criteria as well. Patients with active brain metastases, individuals requiring daily systemic corticosteroids, those who had received systemic corticosteroids within 7 days prior to the study, and individuals who had previously undergone treatment with an anti-PD-1, anti-PD-L1, or anti-CTLA-4 medication were deemed ineligible for participation in the study. Before enrollment, all patients or their legal guardians were required to provide written informed consent. The study protocol underwent comprehensive review and received approval from the central institutional review board.The dose escalation phase, referred to as Part A, followed a traditional ‘3 + 3’ design. The intended dose groups for Part A were 1 mg/kg, 3 mg/kg, and 10 mg/kg administered Q3W. Each dose level enrolled a minimum of three patients, who received a single IV infusion of sintilimab over 30-60 minutes. These patients were closely monitored for any signs of toxicity during a 28-day observation period. The dose escalation process followed a predefined protocol: if no DLTs occurred in the initial three patients at a particular dose level, the trial progressed to the next higher dose cohort. If one DLT emerged in the initial 3 patients, an additional 3 patients were enrolled, totaling six. If only one of these 6 patients experienced a DLT, dose escalation continued. However, if two or more DLTs occurred in a cohort, the previous lower dose level was established as the maximum tolerated dose (MTD), and further escalation was halted. Enrollment could extend to up to 12 patients in Part B, which focused on additional safety and efficacy assessments. During Part B, patients were administered IV infusions of sintilimab at doses of 1, 3, or 10 mg/kg Q3W. Radiologic evaluations were performed until indications of disease progression, intolerable adverse effects, or voluntary study withdrawal. The latest survival follow-up data was available as of December 15, 2022. The study is no longer ongoing and is closed to new participants. The primary endpoints involved identifying DLTs at the highest administered dose, evaluating safety and tolerability, while the secondary endpoints included assessing the proportion of patients with objective responses, PFS and OS.Within 28 days following the initial administration of the investigational drug, a DLT was characterized by the occurrence of specific events associated with sintilimab. These events included grade 4 hematological toxicity lasting for over 7 days, grade 3 thrombocytopenia with bleeding tendency or requiring platelet transfusion, grade 3 neutropenia fever with bacteremia or sepsis, grade 3 pneumonia, other grade 3 or 4 non-hematological toxicity excluding grade 3 arthralgia/myalgia/myositis, grade 3 asthenia/fatigue, manageable grade 3 vomiting, grade 3 or 4 liver transaminase elevation lasting <7 days, manageable grade 3 hypertention).