Phase I study of daily and weekly regimens of the orally administered MDM2 antagonist idasanutlin in patients with advanced tumors.

Autor: Italiano A; Institut Bergonié, Bordeaux, France.; Gustave Roussy, Villejuif, France.; Faculty of Medicine, University of Bordeaux, Bordeaux, France., Miller WH Jr; Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada., Blay JY; Centre Léon Bérard, Lyon, France., Gietema JA; University Medical Center Groningen, University of Groningen, Groningen, the Netherlands., Bang YJ; Seoul National University College of Medicine, Seoul, South Korea., Mileshkin LR; Peter MacCallum Cancer Center, Melbourne, Australia., Hirte HW; Juravinski Cancer Centre, Hamilton, ON, Canada., Higgins B; Roche Innovation Center, Hoffmann-La Roche, New York, NY, USA., Blotner S; Roche Innovation Center, Hoffmann-La Roche, New York, NY, USA., Nichols GL; Roche Innovation Center, Hoffmann-La Roche, New York, NY, USA., Chen LC; Roche Innovation Center, Hoffmann-La Roche, New York, NY, USA., Petry C; Roche Innovation Center, Basel, Switzerland., Yang QJ; Certara, Montréal, QC, Canada., Schmitt C; Roche Innovation Center, Basel, Switzerland., Jamois C; Roche Innovation Center, Basel, Switzerland., Siu LL; Princess Margaret Cancer Centre, Toronto, ON, Canada. lillian.siu@uhn.ca.
Jazyk: angličtina
Zdroj: Investigational new drugs [Invest New Drugs] 2021 Dec; Vol. 39 (6), pp. 1587-1597. Date of Electronic Publication: 2021 Jun 28.
DOI: 10.1007/s10637-021-01141-2
Abstrakt: Aim The oral MDM2 antagonist idasanutlin inhibits the p53-MDM2 interaction, enabling p53 activation, tumor growth inhibition, and increased survival in xenograft models. Methods We conducted a Phase I study of idasanutlin (microprecipitate bulk powder formulation) to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, food effect, and clinical activity in patients with advanced malignancies. Schedules investigated were once weekly for 3 weeks (QW × 3), once daily for 3 days (QD × 3), or QD × 5 every 28 days. We also analyzed p53 activation and the anti-proliferative effects of idasanutlin. Results The dose-escalation phase included 85 patients (QW × 3, n = 36; QD × 3, n = 15; QD × 5, n = 34). Daily MTD was 3200 mg (QW × 3), 1000 mg (QD × 3), and 500 mg (QD × 5). Most common adverse events were diarrhea, nausea/vomiting, decreased appetite, and thrombocytopenia. Dose-limiting toxicities were nausea/vomiting and myelosuppression; myelosuppression was more frequent with QD dosing and associated with pharmacokinetic exposure. Idasanutlin exposure was approximately dose proportional at low doses, but less than dose proportional at > 600 mg. Although inter-patient variability in exposure was high with all regimens, cumulative idasanutlin exposure over the whole 28-day cycle was greatest with a QD × 5 regimen. No major food effect on pharmacokinetic exposure occurred. MIC-1 levels were higher with QD dosing, increasing in an exposure-dependent manner. Best response was stable disease in 30.6% of patients, prolonged (> 600 days) in 2 patients with sarcoma. Conclusions Idasanutlin demonstrated dose- and schedule-dependent p53 activation with durable disease stabilization in some patients. Based on these findings, the QD × 5 schedule was selected for further development. TRIAL REGISTRATION: NCT01462175 (ClinicalTrials.gov), October 31, 2011.
(© 2021. The Author(s).)
Databáze: MEDLINE
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