Phase 1 study of the MDM2 inhibitor AMG 232 in patients with advanced P53 wild-type solid tumors or multiple myeloma

Abstract

Background This open-label, first-inhuman , phase 1 study evaluated AMG 232, an oral selective MDM2 inhibitor in patients with TP53 wild-type (P53WT), advanced solid tumors or multiple myeloma (MM). Methods In the dose escalation (n = 39), patients with P53WT refractory solid tumors enrolled to receive once-daily AMG 232 (15, 30, 60, 120, 240, 480, and 960 mg) for seven days every 3 weeks (Q3W). In the dose expansion (n = 68), patients with MDM2-amplified (well-differentiated and dedifferentiated liposarcomas [WDLPS and DDLPS], glioblastoma multiforme [GBM], or other solid tumors [OST]), MDM2overexpressing ER+ breast cancer (BC), or MM received AMG 232 at the maximum tolerated dose (MTD). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. Results AMG 232 had acceptable safety up to up to 240 mg. Three patients had dose-limiting toxicities of thrombocytopenia (n = 2) and neutropenia (n = 1). Due to these and other delayed cytopenias, AMG 232 240 mg Q3W was determined as the highest tolerable dose assessed in the dose expansion. Adverse events were typically mild/moderate and included diarrhea, nausea, vomiting, fatigue, decreased appetite, and anemia. AMG 232 plasma concentrations increased dose proportionally. Increases in serum macrophage inhibitor cytokine-1 from baseline were generally dose dependent, indicating p53 pathway activation. Per local review, there were no responses. Stable disease (durability in months) was observed in patients with WDLPS (3.9), OST (3.3), DDLPS (2.0), GBM (1.8), and BC (1.4-2.0). Conclusions In patients with P53WT advanced solid tumors or MM, AMG 232 showed acceptable safety and dose-proportional pharmacokinetics, and stable disease was observed.

Prognostic Assessment in High-Grade Soft-Tissue Sarcoma Patients: A Comparison of Semantic Image Analysis and Radiomics

“…Regarding the high mutational burden of some STS entities, immunotherapeutic checkpoint inhibition may be a further option for a systemic therapy modification, which is currently being tested in the phase-II Sarc032 trial using Pembrolizumab (NCT03092323) [ 55 ]. Other molecular targeted agents, such as the MDM-2 inhibitor AMG 232 (NRG DT001 trial, NCT03217266) or trabectedin (TRASTS trial, NCT02275286), are given as a supplement to neoadjuvant RT [ 56 , 57 ]. Imaging-defined high-risk patients could benefit from such additional therapies, whereas low-risk patients could be spared unnecessary toxicities.…”

Meta-Analysis of Hematological Biomarkers as Reliable Indicators of Soft Tissue Sarcoma Prognosis

“…A number of clinical trials targeting MDM2 gene drugs have recently been conducted. Unfortunately, a meta-analysis shows that the MDM2 gene has a very limited role in prognosis (42,43). Moreover, molecular detection technology must be improved to allow for reduced costs associated with evaluation (44,45).…”

Phase 1 Concentration‐QTc and Cardiac Safety Analysis of the MDM2 Antagonist KRT‐232 in Patients With Advanced Solid Tumors, Multiple Myeloma, or Acute Myeloid Leukemia

“…A total of 1427 post-baseline time-matched concentration-QTc pairs from 130 patients (104 in Study A 9 and 26 in Study B 3 ) were included in the concentration-QTc analysis, after exclusions for QT and PK measurements that were missing or taken more than 30 minutes apart. Among these patients, 50% were female in Study A, and 35% were female in Study B.…”