Summary
Purpose MDM2 is a negative regulator of the tumor suppressor p53. RO6839921 is an inactive pegylated prodrug of idasanutlin, an MDM2 antagonist, developed for intravenous administration. On cleavage by plasma esterases, the active principle (AP = idasanutlin) is released. This phase 1 study investigated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with advanced solid tumors (NCT02098967). Methods Patients were evaluated on a 5-day dosing schedule every 28 days. Dose escalation used the Bayesian new continual reassessment model. Accelerated dose titration was permitted until grade ≥2 drug-related AEs were observed. The target DLT rate to define the MTD was 16–25%. p53 activation was assessed by measuring macrophage inhibitory cytokine-1 (MIC-1). Results Forty-one patients received 14–120 mg AP; 39 were DLT evaluable. The MTD was 110-mg AP (8% DLT rate), whereas 120-mg AP had a 44% DLT rate. DLTs were neutropenia, thrombocytopenia, and stridor. The most common treatment-related AEs (≥30%) were nausea, fatigue, vomiting, and thrombocytopenia. Pharmacokinetic analyses indicated rapid conversion of prodrug to AP and an approximately linear and dose-proportional dose-exposure relationship, with a 2-fold increase in exposure between Days 1 and 5 of AP. MIC-1 increases were exposure dependent. Stable disease was observed in 14 patients (34%). Conclusions RO6839921 showed reduced pharmacokinetic exposure variability and a safety profile comparable with that of oral idasanutlin. Although this study indicated that RO6839921 could be administered to patients, the results did not provide sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development.
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Acknowledgements
We thank the participants of the study. Special thanks to Steven Middleton, Gwen Nichols, William Pierceall, Jianguo Zhi, Lori Jukofsky, Patricia Delora, David Stephen Ward, and Ene Kelly and in the memory of Zoran Filipovic.
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This study was funded by F. Hoffmann-La Roche Ltd. The sponsor was responsible for the clinical operations oversight, data management, medical monitoring, drug supply, statistical analysis, drug safety process, medical writing, and journal article processing charges. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.
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All authors report support of the parent study and funding of editorial support from F. Hoffmann-La Roche. SB, A-MY, BH, and L-CC are employees of Roche. ARR has received research funding from Genentech/Roche. WHM has served as a consultant for Amgen, BMS, GSK, Merck, Novartis and Roche; has received research funding to his institution from Amgen, AstraZeneca, BMS, MedImmune, Merck, MethylGene, Novartis, Pfizer and Roche; and has received honoraria from BMS, GSK, Merck, Novartis and Roche. LG has served as a consultant for Amgen, Genentech/Roche and Novartis; has stock with Amgen, Anchiano, Blueprint Medicines, Celgene, Clovis, Mirati and Sanofi; and has a spouse employed with Anchiano.
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Abdul Razak, A.R., Miller, W.H., Uy, G.L. et al. A phase 1 study of the MDM2 antagonist RO6839921, a pegylated prodrug of idasanutlin, in patients with advanced solid tumors. Invest New Drugs 38, 1156–1165 (2020). https://doi.org/10.1007/s10637-019-00869-2
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DOI: https://doi.org/10.1007/s10637-019-00869-2