Michael P Mackley1, Nicholas R Fernandez2, Benjamin Fletcher3,4, Christy G Woolcott5,6,7, Conrad V Fernandez5,6,8. 1. Faculty of Medicine, Dalhousie University, Halifax, NS, Canada. 2. Department of Chemistry and Biochemistry, Mount Allison University, Sackville, NB, Canada. 3. Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, United Kingdom. 4. Centre for Patient Reported Outcome Research (CPROR), Institute of Applied Health Research (IAHR), University of Birmingham, Birmingham, United Kingdom. 5. IWK Health Centre, Halifax, NS, Canada. 6. Department of Pediatrics, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada. 7. Department of Obstetrics and Gynaecology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada. 8. Department of Bioethics, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
Abstract
PURPOSE: Phase I trials are a crucial step in the evaluation of new cancer therapies. Historically, low rates of response (5%) and comparably high rates of death from toxicities (0.5%) have contributed to debates on the ethics and orientation of these trials. With the introduction of novel targeted therapies, a contemporary estimate is needed. METHODS: We systematically searched PubMed, Embase, and ClinicalTrials.gov for reports of phase I oncology trials of single-agent targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents, published between January 2015 and July 2018. Adult and pediatric trials of solid and hematological malignancies were eligible. Treatment-related adverse events (grades 3, 4, and 5) and response rates (objective, complete, and partial) were extracted and analyzed. RESULTS: One hundred and fifty-eight trial reports, covering 6,707 patients, were included. The rate of treatment-related deaths was 0.0% (95% CI, 0.0 to 0.1), while 13.2% of patients (9.5 to 17.3) experienced a grade 3 or 4 treatment-related toxicity. The combined objective response rate was 6.4% (4.6 to 8.5). Among trials using tumor biomarkers as eligibility criteria, the objective response rate was higher (12.0% [7.3 to 17.6] compared to 4.9% [2.5 to 5.7], P value < .01). The same was true of trials focusing on a single tumor type (13.4% [8.2 to 19.4]) compared to multiple tumor types (3.8% [2.5 to 5.3], P value < .01). CONCLUSION: Reduced grade 5 risk and improved benefit appears to exist in modern phase I oncology trials, particularly in trials that target single tumor types and integrate biomarkers as eligibility criteria. These findings provide information to support informed consent discussions, highlight the need for improved reporting of phase I oncology trials, and provide direction for optimizing their design.
PURPOSE: Phase I trials are a crucial step in the evaluation of new cancer therapies. Historically, low rates of response (5%) and comparably high rates of death from toxicities (0.5%) have contributed to debates on the ethics and orientation of these trials. With the introduction of novel targeted therapies, a contemporary estimate is needed. METHODS: We systematically searched PubMed, Embase, and ClinicalTrials.gov for reports of phase I oncology trials of single-agent targeted immunomodulators, molecularly targeted therapies, and antiangiogenic agents, published between January 2015 and July 2018. Adult and pediatric trials of solid and hematological malignancies were eligible. Treatment-related adverse events (grades 3, 4, and 5) and response rates (objective, complete, and partial) were extracted and analyzed. RESULTS: One hundred and fifty-eight trial reports, covering 6,707 patients, were included. The rate of treatment-related deaths was 0.0% (95% CI, 0.0 to 0.1), while 13.2% of patients (9.5 to 17.3) experienced a grade 3 or 4 treatment-related toxicity. The combined objective response rate was 6.4% (4.6 to 8.5). Among trials using tumor biomarkers as eligibility criteria, the objective response rate was higher (12.0% [7.3 to 17.6] compared to 4.9% [2.5 to 5.7], P value < .01). The same was true of trials focusing on a single tumor type (13.4% [8.2 to 19.4]) compared to multiple tumor types (3.8% [2.5 to 5.3], P value < .01). CONCLUSION: Reduced grade 5 risk and improved benefit appears to exist in modern phase I oncology trials, particularly in trials that target single tumor types and integrate biomarkers as eligibility criteria. These findings provide information to support informed consent discussions, highlight the need for improved reporting of phase I oncology trials, and provide direction for optimizing their design.
Authors: Dai Chihara; Ruitao Lin; Christopher R Flowers; Shanda R Finnigan; Lisa M Cordes; Yoko Fukuda; Erich P Huang; Larry V Rubinstein; Loretta J Nastoupil; S Percy Ivy; James H Doroshow; Naoko Takebe Journal: Lancet Date: 2022-08-13 Impact factor: 202.731
Authors: J Thouvenin; C Van Marcke; L Decoster; G Raicevic; K Punie; M Vandenbulcke; R Salgado; E Van Valckenborgh; B Maes; S Joris; D Vander Steichel; K Vranken; S Jacobs; F Dedeurwaerdere; G Martens; H Devos; F P Duhoux; M Rasschaert; P Pauwels; K Geboes; J Collignon; S Tejpar; J-L Canon; M Peeters; A Rutten; T Van de Mooter; J Vermeij; D Schrijvers; W Demey; W Lybaert; J Van Huysse; J Mebis; A Awada; K B M Claes; A Hebrant; J Van der Meulen; B Delafontaine; I Vanden Bempt; J Maetens; M de Hemptinne; S Rottey; P Aftimos; J De Grève Journal: ESMO Open Date: 2022-08-12