Abstract
SummaryAim 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 registrationNCT01462175 (ClinicalTrials.gov), October 31, 2011.
Highlights
The p53 tumor suppressor protein is a powerful pro-apoptotic factor that plays a central role in inhibiting tumor development [1]
Following the accelerated dose-escalation phase using an escalation with overdose control (EWOC) design [16], additional patients were recruited to food-effect and apoptosis-imaging cohorts
Dose-escalation cohorts included those on the QW × 3 (n = 36), QD × 3 (n = 15), and QD × 5 (n = 34) regimens; 10 and 4 patients were included in the food-effect and apoptosis-imaging cohorts, respectively (Fig. 1)
Summary
The p53 tumor suppressor protein is a powerful pro-apoptotic factor that plays a central role in inhibiting tumor development [1]. MDM2, a negative regulator of the p53 tumor suppressor, functions as an E3 ubiquitin ligase, targeting p53 for proteasomal degradation [2]. A class of imidazoline compounds, termed “Nutlins,” has been identified as potent and selective inhibitors of the p53–MDM2 interaction, interacting with the p53 binding pocket of MDM2 and releasing p53 from negative control [3,4,5]. Using Nutlins to treat cancer cells that express functional p53 stabilizes p53 and activates its pathway, leading to activation of p53-target genes, cell cycle arrest, apoptosis, and/or senescence [4]. RG7112, the first Nutlin compound to enter the clinic, established clinical proof of mechanism in MDM2-amplified liposarcoma [6, 7]. Patients had difficulty tolerating treatment on the requisite daily RG7112 schedule [6, 8]
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