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Background: For research with human participants to be ethical, risk must be in a favorable balance with potential benefits. Little is known about the risk/benefit ratio for pediatric cancer phase II trials testing targeted therapies., Objective: Our aim was to conduct a systematic review of preliminary efficacy and safety profiles of phase II targeted therapy clinical trials in pediatric oncology., Methods: Our protocol was prospectively registered in PROSPERO (CRD42020146491). We searched EMBASE and PubMed for phase II pediatric cancer trials testing targeted agents. We included solid and hematological malignancy studies published between 1 January, 2015 and 27 February, 2020. We measured risk using drug-related grade 3 or higher adverse events, and benefit by response rates. When possible, data were meta-analyzed. All statistical tests were two-sided., Results: We identified 34 clinical trials (1202 patients) that met our eligibility criteria. The pooled overall response rate was 24.4% (95% confidence interval [CI] 14.5-34.2) and was lower in solid tumors, 6.4% (95% CI 3.2-9.6), compared with hematological malignancies, 55.1% (95% CI 35.9-74.3); p < 0.001. The overall fatal drug-related (grade 5) adverse event rate was 1.6% (95% CI 0.6-2.5), and the average drug-related grade 3/4 adverse event rate per person was 0.66 (95% CI 0.55-0.78)., Conclusions: We provide an estimate for the risks and benefits of participation in pediatric phase II cancer trials. These data may be used as an empirical basis for informed communication about benefits and burdens in pediatric oncology research.

Objectives: Drug development trials must fulfill social value requirement but no estimates of value provided by pediatric Phase 1 trials in oncology exist. These trials involve a particularly vulnerable population. Our objective was to assess of surrogates of social value of Phase 1 trials performed in pediatric oncology: rates of approval of tested interventions, transition to further phases of testing and citation in subsequent primary research reports., Methods: We performed an analysis on a subset of eligible trials included in a previous meta-analysis. That study systematically searched EMBASE and PubMed for small sample size, non-randomized, dose escalation pediatric cancer Phase 1 studies of any malignancy, assessing chemotherapy and/or targeted therapy and looked at risk and benefit. The current analysis assessed all studies in that review published between January 1st 2004 and December 31st 2013 for predictors of social value. This time range allowed for at least five years of subsequent development activity. Sources of data included FDA and EMA medicine databases (for approval), ClinicalTrials.gov and EU Clinical Trials Register (for transition) and Google Scholar (for citation)., Results: One hundred thirty-nine trials enrolling 3814 patients met the eligibility criteria. Seven trials (5%) led to drugs being registered for pediatric use in therapy of cancer. Fifty-two (37%) transitioned to later phases of pediatric oncology trials according to ClinicalTrials.gov and/or EU Register. Over 90% of trials were cited by at least one subsequent primary research report or systematic review. Most of the citations were preclinical studies., Conclusions: Our analysis shows that treatments tested in pediatric Phase 1 trials in oncology have low rates of regulatory approval. However, a large proportion of Phase 1 trials inform further testing and development of tested interventions., Competing Interests: Marcin Waligora reports personal fees from Advisory Bioethics Council, Sanofi outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. Other authors have declared that no competing interests exist.

Background: Pediatric Phase I cancer trials are critical for establishing the safety and dosing of anti-cancer treatments in children. Their implementation, however, must contend with the rarity of many pediatric cancers and limits on allowable risk in minors. The aim of this study is to describe the risk and benefit for pediatric cancer Phase I trials., Methods and Findings: Our protocol was prospectively registered in PROSPERO (CRD42015015961). We systematically searched Embase and PubMed for solid and hematological malignancy Phase I pediatric trials published between 1 January 2004 and 1 March 2015. We included pediatric cancer Phase I studies, defined as "small sample size, non‑randomized, dose escalation studies that defined the recommended dose for subsequent study of a new drug in each schedule tested." We measured risk using grade 3, 4, and 5 (fatal) drug-related adverse events (AEs) and benefit using objective response rates. When possible, data were meta-analyzed. We identified 170 studies meeting our eligibility criteria, accounting for 4,604 patients. The pooled overall objective response rate was 10.29% (95% CI 8.33% to 12.25%), and was lower in solid tumors, 3.17% (95% CI 2.62% to 3.72%), compared with hematological malignancies, 27.90% (95% CI 20.53% to 35.27%); p < 0.001. The overall fatal (grade 5) AE rate was 2.09% (95% CI 1.45% to 2.72%). Across the 4,604 evaluated patients, there were 4,675 grade 3 and 4 drug-related AEs, with an average grade 3/4 AE rate per person equal to 1.32. Our study had the following limitations: trials included in our review were heterogeneous (to minimize heterogeneity, we separated types of therapy and cancer types), and we relied on published data only and encountered challenges with the quality of reporting., Conclusions: Our meta-analysis suggests that, on the whole, AE and response rates in pediatric Phase I trials are similar to those in adult Phase I trials. Our findings provide an empirical basis for the refinement and review of pediatric Phase I trials, and for communication about their risk and benefit.