A new approach to integrate toxicity grade and repeated treatment cycles 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.


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.
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.
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Doussau
CIC1401-Clinical Epidemiology, INSERM U897, Bordeaux Division of Public Health, University Hospital, Bordeaux CIC1401-Clinical Epidemiology, Bordeaux University, Bordeaux Labex Vaccine Research Institute, Bordeaux.
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Thiébaut
Pediatric and Adolescent Oncology, Institut Gustave Roussy, Villejuif CNRS UMR8203, University Paris-Sud 11, Villejuif, France.
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Geoerger
Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven Laboratory of Experimental Oncology, Department of Oncology, KU Leuven, Leuven, Belgium.
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Schöffski
CIC1401-Clinical Epidemiology, Institut Bergonié, Bordeaux.
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Floquet
Biostatistics and Epidemiology Unit, Institut Gustave Roussy, University Paris-Sud 11, Villejuif, France.
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Le Deley
CIC1401-Clinical Epidemiology, Bordeaux University, Bordeaux CIC1401-Clinical Epidemiology, Institut Bergonié, Bordeaux.
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Mathoulin-Pélissier
EORTC-Headquarter, Brussels, Belgium.
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Rizzo
Comprehensive Cancer Center, Centre Georges-François Leclerc, Dijon.
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Fumoleau
U900, INSERM, Paris Department of Medical Oncology, Institut Curie, Paris and Saint-Cloud, France.
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Le Tourneau
Department of Biostatistics, Institut Curie, Paris U900, INSERM, Paris.
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Paoletti
D000970:Antineoplastic Agents / Q000009:adverse effects*; D017321:Clinical Trials, Phase I as Topic / Q000592:standards*; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy*
D000970:Antineoplastic Agents
cumulative toxicity; dose-finding trials; dose-limiting toxicity; longitudinal studies; phase I; statistical analysis