Background <p>MDM2 regulates the P53 pathway and is a promising therapeutic target, particularly in pediatric cancers with wild-type (WT) <i>TP53</i>. Idasanutlin is an investigational MDM2 inhibitor that is highly selective and orally bioavailable. The combination of MDM2 inhibition with cytotoxic chemotherapy or Bcl-2 inhibition has been shown to improve activity in preclinical models.</p> Objective <p>iMATRIX idasa was designed to assess the safety, pharmacokinetics, and antitumor activity of idasanutlin in children and young adults with relapsed/refractory solid tumors.</p> Patients and Methods <p>This multicenter phase I/II study enrolled patients aged &lt; 30&#xa0;years with extracranial solid tumors. Patients received idasanutlin on days 1–5 of a 28-day cycle as a single agent or in combination with venetoclax or chemotherapy. The single-agent dose escalation utilized a modified continual reassessment method. The primary endpoints included the safety and determination of the maximum tolerated dose, characterization of the pharmacokinetics, and preliminary efficacy.</p> Results <p>Of 38 patients (median age 9 years [range: 2–23]), 26 with solid tumors received idasanutlin alone, and 12 with neuroblastoma received it in combination: six with venetoclax and six with chemotherapy (cyclophosphamide/topotecan). In total, 5 of 26 patients (19.2%) treated with single-agent idasanutlin experienced dose-limiting toxicities (including thrombocytopenia, neutropenia, and febrile neutropenia), which established a pediatric recommended phase II dose for idasanutlin of 4.5 mg/kg/day on days 1–5 of each 28-day cycle. The most frequently reported treatment-related adverse events were thrombocytopenia and neutropenia. Tolerable exposures were similar to what has been observed in adults<b>.</b> The objective response rate for patients with WT <i>TP53</i> neuroblastoma who were treated with idasanutlin in combination with venetoclax or chemotherapy (primary efficacy endpoint) was 11.1% (<i>N</i> = 9; 95% confidence intervals, CI 0.28, 48.25) with one patient having a complete response. No other patients in the overall study population had an objective response.</p> Conclusions <p>The safety profile and tolerable exposure of idasanutlin in pediatrics was similar to that reported in adults. Limited clinical activity was observed in patients with solid tumors. On the basis of the negative benefit–risk assessment, the study was terminated, and the overall pediatric development program for idasanutlin was discontinued.</p> Clinical Trial Registration <p>ClinicalTrials.gov NCT04029688, registered 19 July 2019.</p>