A Systematic Review of Pediatric Phase I Trials in Oncology: Toxicity and Outcomes in the Era of Targeted Therapies.

BACKGROUND: Pediatric phase I oncology trials have historically focused on safety and toxicity, with objective response rates (ORRs) <10%. Recently, with an emphasis on targeted approaches, response rates may have changed. We analyzed outcomes of recent phase I pediatric oncology trials. MATERIALS AND METHODS: This was a systematic review of phase I pediatric oncology trials published in 2012-2017, identified through PubMed and EMBASE searches conducted on March 14, 2018. Selection criteria included full-text articles with a pediatric population, cancer diagnosis, and a dose escalation schema. Each publication was evaluated for patient characteristics, therapy type, trial design, toxicity, and response. RESULTS: Of 3,431 citations, 109 studies (2,713 patients) met eligibility criteria. Of these, 78 (72%) trials incorporated targeted therapies. Median age at enrollment/trial was 11 years (range 3-21 years). There were 2,471 patients (91%) evaluable for toxicity, of whom 300 (12.1%) experienced dose-limiting toxicity (DLT). Of 2,143 patients evaluable for response, 327 (15.3%) demonstrated an objective response. Forty-three (39%) trials had no objective responses. Nineteen trials (17%) had an ORR >25%, of which 11 were targeted trials and 8 were combination cytotoxic trials. Targeted trials demonstrated a lower DLT rate compared with cytotoxic trials (10.6% vs. 14.7%; p = .003) with similar ORRs (15.0% vs. 15.9%; p = .58). CONCLUSION: Pediatric oncology phase I trials in the current treatment era have an acceptable DLT rate and a pooled ORR of 15.3%. A subset of trials with target-specific enrollment or combination cytotoxic therapies showed high response rates, highlighting the importance of these strategies in early phase trials. IMPLICATIONS FOR PRACTICE: Enrollment in phase I oncology trials is crucial for development of novel therapies. This systematic review of phase I pediatric oncology trials provides an assessment of outcomes of phase I trials in children, with a specific focus on the impact of targeted therapies. These data may aid in evaluating the landscape of current phase I options for patients and enable more informed communication regarding risk and benefit of phase I clinical trial participation. The results also suggest that, in the current treatment era, there is a rationale to increase earlier access to targeted therapy trials for this refractory patient population.

Semaglutide in Cystic Fibrosis-Related Diabetes.

CONTEXT AND OBJECTIVE: In spite of the evidence that inadequately controlled glycemia is associated with worse clinical outcomes, cystic fibrosis-related diabetes (CFRD) is not well controlled in a majority of patients. The objective of this report is to demonstrate the effect of the addition of semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA), to basal insulin to control glycemia in one such patient. DESIGN, INTERVENTION, AND THE MAIN OUTCOME MEASURES: The replacement of rapidly acting prandial insulin with semaglutide weekly with continuation of basal insulin. Glycated hemoglobin A1c (HbA1c) was measured and continuous glucose monitoring (CGM) was conducted. RESULTS: There was a significant improvement in glycemic control, reduction in HbA1c from 9.1% to 6.7% and stable euglycemic pattern on CGM (mean glucose, 142 mg/dL; SD, 51) within 3 months of starting treatment. There was no increase in plasma pancreatic enzyme concentrations. CONCLUSIONS: Semaglutide at a low dose was able to replace prandial insulin and control glycemia in combination with basal insulin.