Efficacy and safety of low doses of olanzapine for the prevention of nausea and vomiting in children and adolescents receiving highly emetogenic chemotherapy. The interim results of a randomized trial

International studies and the analysis of our own data demonstrate that the standard three-drug (5-HT3 receptor antagonist, aprepitant and dexamethasone) regimen used for the prevention of chemotherapy-induced nausea and vomiting (CINV) gives the possibility to achieve complete CINV control in less than 50% of children receiving highly emetogenic chemotherapy. According to the results of randomized trials in adult patients, the addition of low doses of olanzapine increases the efficacy of CINV prophylaxis. There is no data on the efficacy and safety of low-dose olanzapine used for the prevention of CINV in children. The aim of this study is to assess the efficacy and safety of adding low doses (0.07 mg/kg, maximum 5 mg) of olanzapine to the standard regimen used for CINV prophylaxis after highly emetogenic chemotherapy in children. The study includes patients receiving highly emetogenic chemotherapy at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation, in case of which there are no other (except for chemotherapy) obvious reasons for nausea and vomiting and no contraindications for the use of olanzapine. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation, and registered in the US National Library of Medicine clinical trials registry (http://clinicaltrials.gov), the identification number is NCT05346731. Patients were randomized in a 1:1 ratio and stratified (previously received highly emetogenic therapy or not; regimens with high doses of cisplatin/carboplatin and without it) to receive the first cycle of highly emetogenic chemotherapy with standard three-drug prophylaxis with the addition of low doses of olanzapine or without it. Then, the patients underwent a second similar cycle of highly emetogenic chemotherapy with a change in the antiemetic prophylaxis option (crossover). For the assessment of CINV, we used the Pediatric Nausea Assessment Tool (PeNAT). Adverse events were assessed using CTCAE v.5.0. This is an interim analysis and it was carried out in order to assess whether it was reasonable to continue the study. From March to August 2022, 31 patients were included in the study, the median age was 14 (5–18) years, the ratio of boys:girls was 15:16; all patients suffered from extracranial solid tumors. Considering crossover, 31 patients included in the study received 62 cycles of chemotherapy (31 cycles with olanzapine and 31 cycles without it). Out of 31 cycles of chemotherapy with standard three-drug prophylaxis, complete CINV control was achieved in 16 (52%) cases, out of 31 cycles with prophylaxis, which included low doses of olanzapine – in 24 (77%) cases (p = 0.027). Adverse events associated with olanzapine were quite common (sedation - 97%, weight gain -76%), but mild ( Grade III). According to the patient survey results, 30/31 (97%) patients preferred the regimen with olanzapine, and only 1 patient preferred neither of the regimens. The interim analysis of the study results shows that the addition of low doses of olanzapine significantly increases the efficacy of CINV prophylaxis in pediatric patients receiving highly emetogenic chemotherapy, is well tolerated, safe and preferred by the vast majority of patients. It is necessary to continue the study until the planned number of patients for the final analysis is included.