A Doussau1, R Thiébaut2, B Geoerger3, P Schöffski4, A Floquet5, M C Le Deley6, S Mathoulin-Pélissier7, E Rizzo8, P Fumoleau9, C Le Tourneau10, X Paoletti11. 1. Department of Biostatistics, Institut Curie, Paris U900, INSERM, Paris CIC1401-Clinical Epidemiology, INSERM U897, Bordeaux Division of Public Health, University Hospital, Bordeaux CIC1401-Clinical Epidemiology, Bordeaux University, Bordeaux adelaide.doussau@isped.u-bordeaux2.fr. 2. CIC1401-Clinical Epidemiology, INSERM U897, Bordeaux Division of Public Health, University Hospital, Bordeaux CIC1401-Clinical Epidemiology, Bordeaux University, Bordeaux Labex Vaccine Research Institute, Bordeaux. 3. Pediatric and Adolescent Oncology, Institut Gustave Roussy, Villejuif CNRS UMR8203, University Paris-Sud 11, Villejuif, France. 4. Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium. 5. CIC1401-Clinical Epidemiology, Institut Bergonié, Bordeaux. 6. Biostatistics and Epidemiology Unit, Institut Gustave Roussy, University Paris-Sud 11, Villejuif, France. 7. CIC1401-Clinical Epidemiology, Bordeaux University, Bordeaux CIC1401-Clinical Epidemiology, Institut Bergonié, Bordeaux. 8. EORTC-Headquarter, Brussels, Belgium. 9. Comprehensive Cancer Center, Centre Georges-François Leclerc, Dijon. 10. U900, INSERM, Paris Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France. 11. Department of Biostatistics, Institut Curie, Paris U900, INSERM, Paris.
Abstract
BACKGROUND: Safety assessment beyond the dose-limiting toxicity evaluation period provides relevant information to define the recommended phase II dose (RP2D) of a new treatment. We retrospectively analyzed three phase I trials to illustrate two indicators: per-cycle probability of graded toxicity and cumulative probability of severe toxicity over the treatment period. PATIENTS AND METHODS: Data were collected from two continual reassessment method (CRM) trials (T1: aviscumine in solid tumors with short time on treatment; T2: erlotinib + radiotherapy in brainstem gliomas with longer time on treatment) and one 3 + 3 design (T3: liposomal doxorubicin + cyclophosphamide combination in ovarian carcinoma). The probability of severe and moderate or severe toxicity per cycle was estimated at each dose level with mixed proportional odds model. The cumulative probability of severe toxicity was also estimated with the time-to-event CRM. RESULTS: Eighty-three patients were included in the three trials; 94, 96 and 72 treatment cycles were administered, in T1, T2 and T3, respectively. Moderate toxicities were at least twice as frequent as severe toxicities. An increased probability of toxicity over time was detected in T3 [P = 0.04; per-cycle probability of severe toxicity: 27% (cycle 1) to 59% (cycle 6) at the RP2D]. At the RP2D, 37% of patients experienced at least one severe toxicity over the first six cycles in T2, and 78% in T3. CONCLUSIONS: Dedicated methods can be used to analyze toxicities from all cycles of treatment. They do not delay accrual and should be integrated in the analysis and reporting of phase I dose-finding trials.
BACKGROUND: Safety assessment beyond the dose-limiting toxicity evaluation period provides relevant information to define the recommended phase II dose (RP2D) of a new treatment. We retrospectively analyzed three phase I trials to illustrate two indicators: per-cycle probability of graded toxicity and cumulative probability of severe toxicity over the treatment period. PATIENTS AND METHODS: Data were collected from two continual reassessment method (CRM) trials (T1: aviscumine in solid tumors with short time on treatment; T2: erlotinib + radiotherapy in brainstem gliomas with longer time on treatment) and one 3 + 3 design (T3: liposomal doxorubicin + cyclophosphamide combination in ovarian carcinoma). The probability of severe and moderate or severe toxicity per cycle was estimated at each dose level with mixed proportional odds model. The cumulative probability of severe toxicity was also estimated with the time-to-event CRM. RESULTS: Eighty-three patients were included in the three trials; 94, 96 and 72 treatment cycles were administered, in T1, T2 and T3, respectively. Moderate toxicities were at least twice as frequent as severe toxicities. An increased probability of toxicity over time was detected in T3 [P = 0.04; per-cycle probability of severe toxicity: 27% (cycle 1) to 59% (cycle 6) at the RP2D]. At the RP2D, 37% of patients experienced at least one severe toxicity over the first six cycles in T2, and 78% in T3. CONCLUSIONS: Dedicated methods can be used to analyze toxicities from all cycles of treatment. They do not delay accrual and should be integrated in the analysis and reporting of phase I dose-finding trials.
Authors: Alexander Drilon; Anne A Eaton; Katja Schindler; Mrinal M Gounder; David R Spriggs; Pamela Harris; S Percy Ivy; Alexia Iasonos; Mario E Lacouture; David M Hyman Journal: Cancer Date: 2016-02-24 Impact factor: 6.860
Authors: Sharon B Love; Sarah Brown; Christopher J Weir; Chris Harbron; Christina Yap; Birgit Gaschler-Markefski; James Matcham; Louise Caffrey; Christopher McKevitt; Sally Clive; Charlie Craddock; James Spicer; Victoria Cornelius Journal: Br J Cancer Date: 2017-06-29 Impact factor: 7.640