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Invest New Drugs. 2019 Nov 16. doi: 10.1007/s10637-019-00869-2. [Epub ahead of print]

A phase 1 study of the MDM2 antagonist RO6839921, a pegylated prodrug of idasanutlin, in patients with advanced solid tumors.

Author information

1
Princess Margaret Cancer Centre and Mount Sinai Hospital, Toronto, ON, Canada. Albiruni.Razak@uhn.ca.
2
Division of Oncology and Hematology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. Albiruni.Razak@uhn.ca.
3
Jewish General Hospital, Rossy Cancer Network and McGill University, Montreal, Quebec, Canada.
4
Washington University School of Medicine, St. Louis, MO, USA.
5
Pharma Research and Early Development, Roche Innovation Center, New York, NY, USA.
6
Pharma Research and Early Development, Roche Innovation Center, Welwyn Garden City, UK.
7
University of Colorado, Aurora, CO, USA.

Abstract

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.

KEYWORDS:

Idasanutlin; MDM2 antagonist; Prodrug; Solid tumors

PMID:
31734832
DOI:
10.1007/s10637-019-00869-2

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