Results of the Phase I Trial of RG7112, a Small-Molecule MDM2 Antagonist in Leukemia

Abstract

Purpose RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a Phase I study of RG7112 in patients with hematologic malignancies was conducted. Experimental Design Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics, pharmacodynamics, such as TP53-mutation status and MDM2 expression, and preliminary clinical activity. Patients were divided into 2 cohorts: Stratum A (relapsed/refractory AML (except APL), ALL, and CML) and Stratum B (relapsed/refractory CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity. Results RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 DLTs were reported. PK analysis indicated that twice-daily dosing enhanced daily exposure. Anti-leukemia activity was observed in the 30 patients with AML assessed at the MTD included 5 patients who met IWG criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response. Conclusions RG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies.

Dysfunction of the MDM2/p53 axis is linked to premature aging

“…It therefore seems logical that upregulation of WT p53 could, in principle, represent an attractive therapeutic approach (34). Indeed, numerous studies report the identification of drugs that specifically target the MDM2/p53 axis for cancer therapy, with clinical trials already underway (35)(36)(37). Since the potential effects of increased p53 activation on an organismal level in humans are still unknown, the detailed elucidation of the possible effects of p53 activation on MDM2 inhibition is of growing biomedical importance.…”

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy

“…7,101 Recognizing the extended repertoire of p53 GOF mutants and dysfunctional wtp53 proteins enables identifying p53-based druggable targets and improving patient-oriented therapeutic decisions. 12,13,102 Targeting mutp53 in AML Mutp53 targeted therapy aims to abolish mutp53 cancer cells or to rescue p53 mutational inactivation.…”

CUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases

“…As a result, this class of molecules has shown promising anti-cancer efficacy in cancer cell line xenograft assays. Examples include Nutlin-3 and its pharmacologically optimized form, RG7112, which are currently undergoing phase I clinical trials for the treatment of retinoblastoma and liposarcomas, and haematological malignancies, respectively [141,142]. Owing to their selective nature, Nutlin-3 and RG7112 are expected to have less deleterious effects on healthy tissues, although the real scenario will only be clear once the results of the clinical trials are published.…”