Kathleen Dorris1, Chunyan Liu2, Dandan Li3, Trent R Hummel4, Xia Wang5, John Perentesis4, Mi-Ok Kim6, Maryam Fouladi4. 1. Section of Pediatric Hematology, Oncology, Bone Marrow Transplantation, Children's Hospital Colorado, Aurora, Colorado. 2. Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 3. Consumer Credit Risk Management, Fifth Third Bank, Cincinnati, Ohio. 4. Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. 5. Department of Mathematical Sciences, University of Cincinnati, Cincinnati, Ohio. 6. Department of Epidemiology and Biostatistics, University of California San Francisco.
Abstract
BACKGROUND: Prior reviews of phase I pediatric oncology trials involving primarily cytotoxic agents have reported objective response rates (ORRs) and toxic death rates of 7.9-9.6% and 0.5%, respectively. These data may not reflect safety and efficacy in phase I trials of molecularly targeted (targeted) drugs. METHODS: A systematic review of pediatric phase I solid tumor trials published in 1990-2013 was performed. The published reports were evaluated for patient characteristics, toxicity information, and response numbers. RESULTS: A total of 143 phase I pediatric clinical trials enrolling 3,896 children involving 53 targeted and 48 cytotoxic drugs were identified. A meta-analysis demonstrated that the ORR is 2.1-fold higher with cytotoxic drugs (0.066 vs. 0.031 per subject; P = 0.007). By contrast, the pooled estimate of the stable disease rate (SDR) is similar for cytotoxic and targeted drugs (0.2 vs. 0.23 per subject; P = 0.27). The pooled estimate of the dose-limiting toxicity rate is 1.8-fold larger with cytotoxic drugs (0.24 vs. 0.13 per subject; P = 0.0003). The hematologic grade 3-4 (G3/4) toxicity rate is 3.6-fold larger with cytotoxic drugs (0.43 vs. 0.12 per treatment course; P = 0.0001); however, the nonhematologic G3/4 toxicities and toxic deaths occur at similar rates for cytotoxic and targeted drugs. CONCLUSIONS: In phase I pediatric solid tumor trials, ORRs were significantly higher for cytotoxic versus targeted agents. SDRs were similar in targeted and cytotoxic drug trials. Patients treated with cytotoxic agents were more likely to experience hematologic G3/4 toxicities than those patients receiving targeted drugs.
BACKGROUND: Prior reviews of phase I pediatric oncology trials involving primarily cytotoxic agents have reported objective response rates (ORRs) and toxic death rates of 7.9-9.6% and 0.5%, respectively. These data may not reflect safety and efficacy in phase I trials of molecularly targeted (targeted) drugs. METHODS: A systematic review of pediatric phase I solid tumor trials published in 1990-2013 was performed. The published reports were evaluated for patient characteristics, toxicity information, and response numbers. RESULTS: A total of 143 phase I pediatric clinical trials enrolling 3,896 children involving 53 targeted and 48 cytotoxic drugs were identified. A meta-analysis demonstrated that the ORR is 2.1-fold higher with cytotoxic drugs (0.066 vs. 0.031 per subject; P = 0.007). By contrast, the pooled estimate of the stable disease rate (SDR) is similar for cytotoxic and targeted drugs (0.2 vs. 0.23 per subject; P = 0.27). The pooled estimate of the dose-limiting toxicity rate is 1.8-fold larger with cytotoxic drugs (0.24 vs. 0.13 per subject; P = 0.0003). The hematologic grade 3-4 (G3/4) toxicity rate is 3.6-fold larger with cytotoxic drugs (0.43 vs. 0.12 per treatment course; P = 0.0001); however, the nonhematologic G3/4 toxicities and toxic deaths occur at similar rates for cytotoxic and targeted drugs. CONCLUSIONS: In phase I pediatric solid tumor trials, ORRs were significantly higher for cytotoxic versus targeted agents. SDRs were similar in targeted and cytotoxic drug trials. Patients treated with cytotoxic agents were more likely to experience hematologic G3/4 toxicities than those patients receiving targeted drugs.
Authors: Julia W Cohen; Srivandana Akshintala; Eli Kane; Helen Gnanapragasam; Brigitte C Widemann; Seth M Steinberg; Nirali N Shah Journal: Oncologist Date: 2020-01-14
Authors: Theodore W Laetsch; Steven G DuBois; Julia Glade Bender; Margaret E Macy; Lucas Moreno Journal: Cancer Discov Date: 2020-12-04 Impact factor: 38.272
Authors: Bushra Weidenbusch; Günther H S Richter; Marie Sophie Kesper; Monika Guggemoos; Katja Gall; Carolin Prexler; Ilya Kazantsev; Alexandra Sipol; Lars Lindner; Michaela Nathrath; Olaf Witt; Katja Specht; Frigga Beitinger; Carolin Knebel; Stuart Hosie; Rüdiger von Eisenhardt-Rothe; Wilko Weichert; Irene Teichert-von Luettichau; Stefan Burdach Journal: Oncotarget Date: 2018-04-17