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Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis.

ABSTRACT: 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.

SUBMITTER: Waligora M

PROVIDER: S-EPMC5819765 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis.

Waligora Marcin M Bala Malgorzata M MM Koperny Magdalena M Wasylewski Mateusz T MT Strzebonska Karolina K Jaeschke Rafał R RR Wozniak Agnieszka A Piasecki Jan J Sliwka Agnieszka A Mitus Jerzy W JW Polak Maciej M Nowis Dominika D Fergusson Dean D Kimmelman Jonathan J

PLoS medicine 20180220 2

<h4>Background</h4>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.<h4>Methods and findings</h4>Our protocol was prospectively registered in PROSPERO (CRD42015015961). We systematically searched Embase and ...[more]

PMID: 29462168

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Project description:BackgroundUmbrella clinical trials in precision oncology are designed to tailor therapies to the specific genetic changes within a tumor. Little is known about the risk/benefit ratio for umbrella clinical trials. The aim of our systematic review with meta-analysis was to evaluate the efficacy and safety profiles in cancer umbrella trials testing targeted drugs or a combination of targeted therapy with chemotherapy.MethodsOur study was prospectively registered in PROSPERO (CRD42020171494). We searched Embase and PubMed for cancer umbrella trials testing targeted agents or a combination of targeted therapies with chemotherapy. We included solid tumor studies published between 1 January 2006 and 7 October 2019. We measured the risk using drug-related grade 3 or higher adverse events (AEs), and the benefit by objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). When possible, data were meta-analyzed.ResultsOf the 6207 records identified, we included 31 sub-trials or arms of nine umbrella trials (N = 1637). The pooled overall ORR was 17.7% (95% confidence interval [CI] 9.5-25.9). The ORR for targeted therapies in the experimental arms was significantly lower than the ORR for a combination of targeted therapy drugs with chemotherapy: 13.3% vs 39.0%; p = 0.005. The median PFS was 2.4 months (95% CI 1.9-2.9), and the median OS was 7.1 months (95% CI 6.1-8.4). The overall drug-related death rate (drug-related grade 5 AEs rate) was 0.8% (95% CI 0.3-1.4), and the average drug-related grade 3/4 AE rate per person was 0.45 (95% CI 0.40-0.50).ConclusionsOur findings suggest that, on average, one in five cancer patients in umbrella trials published between 1 January 2006 and 7 October 2019 responded to a given therapy, while one in 125 died due to drug toxicity. Our findings do not support the expectation of increased patient benefit in cancer umbrella trials. Further studies should investigate whether umbrella trial design and the precision oncology approach improve patient outcomes.

Project description:BackgroundClinical significance in a randomized controlled trial (RCT) can be determined using the minimal clinically important difference (MCID), which should inform the delta value used to determine sample size. The primary objective was to assess clinical significance in the pediatric oncology randomized controlled trial (RCT) treatment literature by evaluating: (1) the relationship between the treatment effect and the delta value as reported in the sample size calculation, and (2) the concordance between statistical and clinical significance. The secondary objective was to evaluate the reporting of methodological attributes related to clinical significance.MethodsRCTs of pediatric cancer treatments, where a sample size calculation with a delta value was reported or could be calculated, were systematically reviewed. MEDLINE, EMBASE, and the Cochrane Childhood Cancer Group Specialized Register through CENTRAL were searched from inception to July 2016.ResultsRCTs (77 overall; 11 and 66), representing 95 (13 and 82) randomized questions were included for non-inferiority and superiority RCTs (herein, respectively). The minority (22.1% overall; 76.9 and 13.4%) of randomized questions reported conclusions based on clinical significance, and only 4.2% (15.4 and 2.4%) explicitly based the delta value on the MCID. Over half (67.4% overall; 92.3 and 63.4%) reported a confidence interval or standard error for the primary outcome experimental and control values and 12.6% (46.2 and 7.3%) reported the treatment effect, respectively. Of the 47 randomized questions in superiority trials that reported statistically non-significant findings, 25.5% were possibly clinically significant. Of the 24 randomized questions in superiority trials that were statistically significant, only 8.3% were definitely clinically significant.ConclusionsA minority of RCTs in the pediatric oncology literature reported methodological attributes related to clinical significance and a notable portion of statistically insignificant studies were possibly clinically significance.

Project description: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.

Project description:BackgroundPhase II clinical trials are a cornerstone of the development in experimental treatments They work as a "filter" for phase III trials confirmation. Surprisingly the attrition ratio in Phase III trials in oncology is significantly higher than in any other medical specialty. This suggests phase II trials in oncology fail to achieve their goal. Objective The present study aims at estimating the quality of reporting in published oncology phase II clinical trials.Data sourcesA literature review was conducted among all phase II and phase II/III clinical trials published during a 5-year period (2010-2015).Study eligibility criteriaAll articles electronically published by three randomly-selected oncology journals with Impact-Factors>4 were included: Journal of Clinical Oncology, Annals of Oncology and British Journal of Cancer.InterventionQuality of reporting was assessed using the Key Methodological Score.Results557 articles were included. 315 trials were single-arm studies (56.6%), 193 (34.6%) were randomized and 49 (8.8%) were non-randomized multiple-arm studies. The Methodological Score was equal to 0 (lowest level), 1, 2, 3 (highest level) respectively for 22 (3.9%), 119 (21.4%), 270 (48.5%) and 146 (26.2%) articles. The primary end point is almost systematically reported (90.5%), while sample size calculation is missing in 66% of the articles. 3 variables were independently associated with reporting of a high standard: presence of statistical design (p-value <0.001), multicenter trial (p-value = 0.012), per-protocol analysis (p-value <0.001).LimitationsScreening was mainly performed by a sole author. The Key Methodological Score was based on only 3 items, making grey zones difficult to translate.Conclusions & implications of key findingsThis literature review highlights the existence of gaps concerning the quality of reporting. It therefore raised the question of the suitability of the methodology as well as the quality of these trials, reporting being incomplete in the corresponding articles.

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Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis.

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Risk and surrogate benefit for pediatric Phase I trials in oncology: A systematic review with meta-analysis.

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