Comparison of Two Mitotane Starting Dose Regimens in Patients with Advanced Adrenocortical Carcinoma

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 1-36-Adrenal Incidentaloma & Carcinoma
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-23
Thomas Kerkhofs*1, Eric Baudin2, Massimo Terzolo*3, Bruno Allolio4, Rita Chadarevian5, Sophie Leboulleux2, Franco Mantero6, Harm Haak1 and Martin Fassnacht7
1Máxima Medical Center, Eindhoven, Netherlands, 2Institut Gustave-Roussy, Paris, France, 3University of Turin, Orbassano, Italy, 4University of Wuerzburg, Wuerzburg, Germany, 5HRA Pharma, Paris, France, 6University of Padova, Padova, Italy, 7University of Munich, Munich, Germany
Introduction: Current medical treatment of adrenocortical carcinoma (ACC) is based on mitotane alone or in combination with cytotoxic chemotherapy. However, very little is known about the pharmacokinetic properties of mitotane and dosing schedules are based on clinical experience only. The aim of this study was to investigate the relationship between mitotane dose and plasma concentration comparing two pre-defined treatment regimens. Secondary objectives were to evaluate safety and tolerability of mitotane treatment and to study its impact on various hormonal parameters. Time to reach mitotane plasma level of 14 mg/L was determined as a post-hoc endpoint.
Methods: In this prospective open-label multicenter trial, forty mitotane-naïve patients with locally advanced or metastatic ACC were enrolled. Assignment to one of the two dosing regimens (high-dose and low-dose) was done on a case by case basis by the respective local investigator. The predefined study duration was twelve weeks. Adverse events were monitored throughout the study.
Results: Ten out of 20 patients on the high-dose regimen reached plasma concentrations ≥ 14mg/L after a median of 46 days (18-81 days) compared to 4 of 12 patients on the low-dose regimen after a median of 55 days (46-74 days, p=0.286). Mean cumulative mitotane dose was significantly higher in the high-dose group (440 ± 142g versus 272 ± 121g, p=0.013). Median maximum plasma level was 14.3 mg/L (6.3-29.7) in the high-dose group (n=20) and 11.3 mg/L (5.5-20.0) in the low-dose group (n=12, p=0.235). There was no significant difference between the two groups in the incidence and severity of adverse events.
Conclusions: The high-dose start-up regimen did not result in significantly higher mitotane levels or shorter time to reach therapeutic levels, but did result in higher cumulative doses. Toxicity in the high dose regimen was not observed to be greater than in the low-dose regimen. Hormonal changes should be expected and may need additional treatment.

Disclosure: MT: Ad Hoc Consultant, HRA Pharma. RC: Employee, HRA Pharma. Nothing to Disclose: TK, EB, BA, SL, FM, HH, MF

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