Mortality and survival rates in children and adolescents enrolled in early phase trials with a dose-finding/dose-confirmation component: An innovative therapies for children with cancer (ITCC) study.

Abstract

e21509 Background: Participation of children with advanced solid cancers in phase I trials raises ethical and logistic dilemmas. Life-expectancy beyond 8-12 weeks is a common inclusion criterion, but it can be difficult to gauge. This multicentric European study assessed the mortality and survival rates in pediatric phase I trials. Methods: Retrospective study of patients aged < 18 years with solid tumors enrolled in phase I trials in ITCC centres between 2015-2017. Outcome variables were described and prognostic factors analysed. Results: 256 patients across 12 centres in 5 countries were eligible. Median age 11.8 years (range, 0.5-17.9). Female:Male ratio 1:1.9. Tumor location: central nervous system (CNS) 66% vs extra-CNS 34%. Main diagnoses: 22% soft tissue sarcomas, 13% high grade gliomas, 11% osteosarcomas. Most frequent therapy: single targeted agent (63%). Ten cases (4%) were not evaluable for response and 128 (50%) had progressive disease at first evaluation. Best responses were complete in 12 cases (5%), partial in 29 (11%) and stable disease in 77 (30%). Median follow-up 7 months (range, 0.5-42.4). Median Time On Study (TOS) 2.1 months (range, 0.2-38.1). The 30 and 90-day mortality on trial were 3% (8/256) and 21% (54/256), respectively. The 90-day survival (95%CI) for patients with CNS vs extra-CNS tumors was 88% (78-93) vs 76% (68-82), respectively. One-year Overall Survival (95%CI) for the whole sample was 40% (33-46). No toxic deaths on trial were reported. Twenty-five cases (10%) survived ≥365 days on trial. Median TOS 21.5 months (range, 12.3-38.1). Compared to patients who died within 365 days from Cycle1-Day1, those on trial ≥365 days had lower rates of metastatic disease (74% vs 28%, respectively, p < 0.001), higher objective response rates (13% vs 44%, respectively, p < 0.001) and higher disease stabilization (27% vs 56%, respectively, p < 0.001). Conclusions: Currently few patients die within the first cycle of treatment. However a fifth of all patients died within 3 months from trial initiation. Patients with CNS tumors have comparable survival rates to those with extra-CNS and should not be excluded from phase I trials solely because of their diagnosis. The survival rates beyond one year remain modest.

Off‐label and compassionate use of targeted anticancer therapies: The experience of an Italian pediatric cancer center

“…In fact, only 23% of discontinued treatments were suspended due to toxicity. The rate of interruption of treatment due to toxicity is similar to that reported in the study by Lim et al., 12 but it is higher than that reported in a study conducted between 2015 and 2017 in 12 Innovative Therapies for Children with Cancer in Europe (ITCC) centers in 240 patients enrolled in early‐phase dose‐finding clinical trials, in which the treatment was discontinued in 6% of cases 18 . In this same study, the dose was reduced due to development of toxicity in 15% of cases.…”

“…Similarly to other studies on this subject, 12,15,18 in this retrospective analysis also most of the off-label/compassionate therapies were permanently suspended due to disease progression. In fact, only 23% of discontinued treatments were suspended due to toxicity.…”

“…In most cases in which the dose had been modified following the onset of toxicity, the administration of the drug was temporarily suspended. Similarly to other studies on this subject, 12,15,18 in this retrospective analysis also most of the off‐label/compassionate therapies were permanently suspended due to disease progression. In fact, only 23% of discontinued treatments were suspended due to toxicity.…”

“…The rate of interruption of treatment due to toxicity is similar to that reported in the study by Lim et al, 12 but it is higher than that reported in a study conducted between 2015 and 2017 in 12 Innovative Therapies for Children with Cancer in Europe (ITCC) centers in 240 patients enrolled in early-phase dose-finding clinical trials, in which the treatment was discontinued in 6% of cases. 18 In this same study, the dose was reduced due to development of toxicity in 15% of cases. The multivariate analysis showed that the most significantly correlated factor related to the toxicity is the number of treatment lines prior to the administration of the targeted therapy.…”