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ObjectivesSeamless clinical trials have received much attention as a possible way to expedite drug development. The growing importance of seamless design can be seen in oncology research, especially in the early stages of drug development. Our objective is to examine the basic characteristics of seamless early-phase oncology trials registered on the ClinicalTrials.gov database and to determine their results reporting rates. We also aim to identify factors associated with results reporting.MethodsCross-sectional study. We defined seamless early-phase trials as either those registered as Phase 1/2 or Phase 1 with planned expansion cohort(s). Using the ClinicalTrials.gov registry, we searched for interventional cancer clinical trials with primary completion date (PCD) between 2016 and 2020. After trial selection, we performed manual data extraction based on the trial record description and the results posted in the trial registry. We used logistic regression to search for predictors of results reporting. Protocol: https://osf.io/m346x/.ResultsWe included 1051 seamless early-phase oncology trials reported as completed (PCD) between 2016 and 2020. We provided descriptive statistics including the number of patients enrolled, study start date, primary completion date, funding, type of intervention, cancer type, design details, type of endpoints, recruitment regions, and number of trial sites. Overall, only 34.7% trials reported results on ClinicalTrials.gov. The results reporting rates for 24 months was 24.0%. The overall reporting rate for Phase 1/2 studies was over three times higher than for seamless Phase 1.ConclusionsOur study provides cross-sectional data on seamless early-phase oncology trials registered on ClinicalTrials.gov. We highlight the challenges of the evolving clinical trial design landscape and the problem of missing results in the seamless design context, which raises serious ethical concerns. Efforts should be made to adapt the functionality of the ClinicalTrials.gov database to emerging clinical trial models.

Abstract Background Umbrella 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. Methods Our 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. Results Of 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). Conclusions Our 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.

Abstract Background Novel precision oncology trial designs, such as basket and umbrella trials, are designed to test new anticancer agents in more effective and affordable ways. However, they present some ethical concerns referred to scientific validity, risk-benefit balance and informed consent. Our aim is to discuss these issues in basket and umbrella trials, giving examples of two ongoing cancer trials: NCI-MATCH (National Cancer Institute – Molecular Analysis for Therapy Choice) and Lung-MAP (Lung Cancer Master Protocol) study. Main body We discuss three ethical requirements for clinical trials which may be challenged in basket and umbrella trial designs. Firstly, we consider scientific validity. Thanks to the new trial designs, patients with rare malignancies have the opportunity to be enrolled and benefit from the trial, but due to insufficient accrual, the trial may generate clinically insignificant findings. Inadequate sample size in study arms and the use of surrogate endpoints may result in a drug approval without confirmed efficacy. Moreover, complexity, limited quality and availability of tumor samples may not only introduce bias and result in unreliable and unrepresentative findings, but also can potentially harm patients and assign them to an inappropriate therapy arm. Secondly, we refer to benefits and risks. Novel clinical trials can gain important knowledge on the variety of tumors, which can be used in future trials to develop effective therapies. However, they offer limited direct benefits to patients. All potential participants must wait about 2 weeks for the results of the genetic screening, which may be stressful and produce anxiety. The enrollment of patients whose tumors harbor multiple mutations in treatments matching a single mutation may be controversial. As to informed consent – the third requirement we discuss, the excessive use of phrases like “personalized medicine”, “tailored therapy” or “precision oncology” might be misleading and cause personal convictions that the study protocol is designed to fulfill the individual health-related needs of participants. Conclusions We suggest that further approaches should be implemented to enhance scientific validity, reduce misunderstandings and risks, thus maximizing the benefits to society and to trial participants.

Objectives To establish the rates of publication and reporting of results for interventional clinical trials across Polish academic medical centres (AMCs) completed between 2009 and 2013. We aim also to compare the publication and reporting success between adult and paediatric trials.Design Cross-sectional study.Setting AMCs in Poland.Participants AMCs with interventional trials registered on ClinicalTrials.gov.Main outcome measure Results reporting on ClinicalTrials.gov and publishing via journal publication.Results We identified 305 interventional clinical trials registered on ClinicalTrials.gov, completed between 2009 and 2013 and affiliated with at least one AMC. Overall, 243 of the 305 trials (79.7%) had been published as articles or posted their summary results on ClinicalTrials.gov. Results were posted within a year of study completion and/or published within 2 years of study completion for 131 trials (43.0%). Dissemination by both posting and publishing results in a timely manner was achieved by four trials (1.3%).Conclusions Our cross-sectional analysis revealed that Polish AMCs fail to meet the expectation for timely disseminating the findings of all interventional clinical trials. Delayed dissemination and non-dissemination of trial results negatively affects decisions in healthcare.

ObjectivesDrug 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.MethodsWe 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).ResultsOne 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.ConclusionsOur 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.

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.