Abstract A100: Seamless phase I/II clinical trials in oncology: retrospective analysis of the last 7 years
Authors: Barata Pedro , Hobbs Brian , Rini Brian , Paller Channing , Normolle Dan , Garrett-Mayer Elizabeth , Rubin Eric , Rosner Gary , Pond Greg , Perlmutter Jane , Seymour Lesley , Siu Lillian , Wages Nolan , Ivy Percy , Prowell Tatiana , Yap Timothy , Hong David 
Published: August 2018

Abstract
Introduction: Drug development has evolved from the conventional sequence of three-phase clinical trial process to a seamless approach of adding cohorts to first-in-human trials to investigate both safety and efficacy in various cancers. In this retrospective study, we evaluated the prevalence of large early-phase studies in adult cancer patients; described the clinical characteristics, design, and statistical plan of these studies; and identified which investigational drugs using this seamless strategy were included in the accelerated approval program by the Food and Drug Administration (FDA).
Methods: All abstracts presented at the American Society of Clinical Oncology (ASCO) annual meetings from 2010 to 2017 were reviewed. Clinical studies conducted in the pediatric population as well as abstracts reporting trials in progress were excluded. Seamless clinical trials were defined as any phase I/II studies with a sample size of 100 or more patients. The Center for Drug Evaluation and Research (CDER) drug approvals report was used to access the list of drugs included in the accelerated approval program by FDA.
Results: We identified a total of 1786 early-phase trials enrolling more than 57,500 patients with malignant neoplasms. More frequently these studies included patients with advanced solid tumors (87%) and targeted therapy and immunotherapy agents were investigated in 64% and 15% of the cases, respectively. Of the 1786 trials, 51 were identified as seamless phase I/II with a sample size of 100 or more patients, representing only 3% of the total number of trials (n=1786) but 15% of the total number of patients (n=57,559). These seamless trials had a median number of 3 (1-13) expansion cohorts and a higher fraction (65%) were presented in the last 3 years (2014-2017), compared with 35% of the studies with results presented between 2010-2013. Fifty active investigational new drugs (67% targeted therapy, 18% immunotherapy, 10% antibody-drug conjugate, 2.0% chemotherapy, 3.9% other) were studied as single agents (53%) or in combination with other therapies (47%). Of the 51 identified large seamless phase I/II trials, only 29 (57%) studies had published results. Further, of these 29 studies, a planned statistical analysis for the calculation of the expansion cohorts’ sample-size was not available in 69% of the cases. The overall rate of significant (grade 3-4) adverse events was 49% (range, 0-100%), and at least one toxic death was reported in 5 of these studies. The pooled response rate (CR+PR) per study was 20% (range, 0.9-77). Considering the group of drugs studied in the 51-seamless phase I/II trials identified here, the FDA granted accelerated approval to 8 drugs and 1 other agent was given priority review.
Conclusions: Approximately two-thirds of the studies identified were presented after the year 2014, suggesting an increased use of the seamless approach. While the high rate of accelerated approvals granted by the FDA endorses the observed preliminary clinical benefit of these drugs, the absence of a prespecified statistical plan is a weakness of most of the published studies.
Citation Format: Pedro Barata, Brian Hobbs, Brian Rini, Channing Paller, Dan Normolle, Elizabeth Garrett-Mayer, Eric Rubin, Gary Rosner, Greg Pond, Jane Perlmutter, Lesley Seymour, Lillian Siu, Nolan Wages, Percy Ivy, Tatiana Prowell, Timothy Yap, David Hong. Seamless phase I/II clinical trials in oncology: retrospective analysis of the last 7 years [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A100.