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

• Published in: Investigational new drugs Vol. 39; no. 6; pp. 1587 - 1597
• Main Authors: Italiano, Antoine, Miller, Wilson H., Blay, Jean-Yves, Gietema, Jourik A., Bang, Yung-Jue, Mileshkin, Linda R., Hirte, Hal W., Higgins, Brian, Blotner, Steven, Nichols, Gwen L., Chen, Lin Chi, Petry, Claire, Yang, Qi Joy, Schmitt, Christophe, Jamois, Candice, Siu, Lillian L.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.12.2021; Springer Nature B.V
• Subjects: Adult; Adverse events; Aged; Antineoplastic Agents - adverse effects; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Appetite loss; Diarrhea; Dosage; Dose-Response Relationship, Drug; Drug Administration Schedule; Exposure; Female; Food; Food safety; Humans; Male; Maximum Tolerated Dose; MDM2 protein; Medicine; Medicine & Public Health; Middle Aged; Myelosuppression; Nausea; Neoplasms - drug therapy; Neoplasms - pathology; Oncology; Oral administration; para-Aminobenzoates - adverse effects; para-Aminobenzoates - pharmacokinetics; para-Aminobenzoates - pharmacology; para-Aminobenzoates - therapeutic use; Patients; Pharmacodynamics; Pharmacokinetics; Pharmacology; Pharmacology/Toxicology; Phase I Studies; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Pyrrolidines - adverse effects; Pyrrolidines - pharmacokinetics; Pyrrolidines - pharmacology; Pyrrolidines - therapeutic use; Sarcoma; Schedules; Thrombocytopenia; Toxicity; Tumors; Vomiting; Xenografts; Xenotransplantation; MIC-1; Cis-imidazoline analog; p53 activation; Nutlin; Idasanutlin; MDM2 antagonist
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-021-01141-2

Summary 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.