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

Abstract

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.

Risk and benefit for umbrella trials in oncology: a systematic review and meta-analysis

“…This also raises the question if biomarkers used to define the target in precision oncology may be suboptimal [79]. However, other systematic reviews analyzing pediatric phase I [80] and phase II [27] cancer trials showed high objective response rates in trials with target-specific enrolment [80] or in trials adopting personalized treatment approach [27]. Fig.…”

Extrapleural Pneumonectomy for Sarcoma of the Lung in a Pediatric Patient

“… 3 As in adult patients, targeted therapy has moved to the center of interest in pediatric oncology. 6 7 Many current pediatric oncology trials investigate the application of targeted therapy or the combination of conventional chemotherapy with targeted drugs. 7 The reported case is particularly interesting and innovative because molecular pathology confirmed ALK-EML4 translocation opening up the possibility for targeted therapy with a proteinase inhibitor.…”

“… 6 7 Many current pediatric oncology trials investigate the application of targeted therapy or the combination of conventional chemotherapy with targeted drugs. 7 The reported case is particularly interesting and innovative because molecular pathology confirmed ALK-EML4 translocation opening up the possibility for targeted therapy with a proteinase inhibitor. 8 As a consequence, the applied systemic therapy was from the outset combining conventional chemotherapy with targeted drugs as crizotinib.…”

Paediatric pharmacotherapy and drug regulation: Moving past the therapeutic orphan

“…25 To address these issues and to meet the challenges of the new revolution in therapeutics, investigators have developed a number of novel clinical trial designs tailored to the unique problems in paediatric drug research. [53][54][55][56] Examples of these include adaptive design, in which trial design is changed over the course of a trial based on interim analysis; this is a different approach to the conventional randomized double blind trial and requires meticulous prestudy planning. 53 A challenge for drug regulatory agencies is how to best accept the results of these studies for drug approval and to inform product monographs, although recent work exploring the experience of the FDA for placebo controlled studies conducted pursuant to BPCA or PREA has demonstrated that placebo controlled trials can frequently be conducted in a manner that minimizes risk to children while also satisfying federal regulations for drug development and protection of vulnerable human subjects.…”