Phase 1 dose escalation, food effect, and biomarker study of RG7388, a more potent second-generation MDM2 antagonist, in patients (pts) with solid tumors.

Preclinical evaluation of the first intravenous small molecule MDM2 antagonist alone and in combination with temozolomide in neuroblastoma

“…However, interim data from the advanced solid tumour arm of the trial show that RO6839921 was generally well tolerated and main dose limiting toxicities observed were thrombocytopenia and neutropenia, in line with adult trial data for oral idasanutlin, as well as other MDM2 inhibitors . Gastrointestinal toxicity was reported but not dose limiting as previously reported with oral Idasanutlin . The current emphasis is on the development of the oral formulation of idasanutlin, which in comparison to the IV formulation, is at a later stage of development (Phase 3 in AML).…”

“…16,[41][42][43] Gastrointestinal toxicity was reported but not dose limiting as previously reported with oral Idasanutlin. 15,16 The current emphasis is on the development of the oral formulation of idasanutlin, which in comparison to the IV formulation, is at a later stage of development (Phase 3 in AML). Temozolomide is currently used as standard backbone chemotherapy regimens for relapsed and refractory neuroblastoma and has been shown to be generally well tolerated.…”

“…To extend our original in vitro observations, our study assessed RO6839921 the IV prodrug of idasanutlin, alone and in combination with temozolomide, equivalent to one cycle of treatment, in 2 orthotopic models of neuroblastoma. RO6839921 (RG7775) is a pegylated IV prodrug of idasanutlin, which is rapidly metabolised by blood esterases to release active idasanutlin after administration, and was developed to reduce the variability in exposure and dose‐limiting gastrointestinal toxicity observed with oral idasanutlin, and for patients unable to tolerate capsules . Temozolomide is an alkylating agent which is part of standard backbone chemotherapy regimens for relapsed and refractory neuroblastoma .…”

“…RO6839921 (RG7775) is a pegylated IV prodrug of idasanutlin, which is rapidly metabolised by blood esterases to release active idasanutlin after administration, and was developed to reduce the variability in exposure and dose-limiting gastrointestinal toxicity observed with oral idasanutlin, and for patients unable to tolerate capsules. 4,15,16 Temozolomide is an alkylating agent which is part of standard backbone chemotherapy regimens for relapsed and refractory neuroblastoma. 17 The current BEACON trial (ClinicalTrials.gov: NCT02308527) aims to test whether temozolomide and irinotecan is superior to temozolomide alone in the management of relapsed or refractory neuroblastoma.…”

Medicinal Chemistry Strategies to Disrupt the p53–MDM2/MDMX Interaction

“…Phase I studies were carried out in patients with advanced malignancies, excluding leukemia to evaluate the safety, efficacy, and PK and PD properties of 14 when administered as single agent . Compound 14 caused p53 activation in a dose‐ and schedule‐dependent manner; however, serious adverse effects, in particular nausea/vomiting and myelosuppression, were frequent in the daily dosing schedule and associated with PK exposure . Several reported clinical studies for 14 are still undergoing when administered as single agent and in combination with drugs used in therapeutics in patients with a wide range of cancers…”