Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia

Abstract

This open-label, phase 1 study evaluated the safety, pharmacokinetics, and maximum tolerated dose of AMG 232, an investigational oral, selective mouse double minute 2 homolog inhibitor in relapsed/refractory acute myeloid leukemia (AML). AMG 232 was administered orally once daily for 7 days every 2 weeks (7 on/off) at 60, 120, 240, 360, 480, or 960 mg as monotherapy (arm 1) or at 60 mg with trametinib 2 mg (arm 2). Dose-limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics, clinical and pharmacodynamic response, and expression of p53 target genes were assessed. All 36 patients received AMG 232. No DLTs occurred in arm 1, and 360 mg was the highest test dose; dose escalation was halted due to gastrointestinal AEs at higher doses. One of ten patients in arm 2 had a DLT (grade 3 fatigue); 60 mg was the highest dose tested with trametinib. Common treatment-related AEs (any grade) included nausea (58%), diarrhea (56%), vomiting (33%), and decreased appetite (25%). AMG 232 exhibited linear pharmacokinetics unaffected by coadministration with trametinib. Serum macrophage inhibitor cytokine-1 and bone marrow expression of BAX, PUMA, P21, and MDM2 increased during treatment. Of 30 evaluable patients, 1 achieved complete remission, 4 had morphologic leukemia-free state, and 1 had partial remission. Four of 13 (31%) TP53-wild-type patients and 0 of 3 (0%) TP53-mutant patients were responders. AMG 232 was associated with gastrointestinal AEs at higher doses but had acceptable pharmacokinetics, on-target effects, and promising clinical activity warranting further investigation in patients with relapsed/refractory AML. This trial was registered at www.clinicaltrials.gov as #NCT02016729.

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

“…Pharmacokinetics Plasma samples for the measurement of AMG 232 pharmacokinetics in Parts 1 and 2 were collected predose and at 1, 3, 5, and 7 h postdose on days 1 and 7 and 24 and 72 h postdose from day 7 of cycle 1; predose on days 1 and 7 of cycle 2; and at the end of study. Plasma AMG 232 levels were measured using a validated high performance liquid chromatography mass spectrometry method [24]. Pharmacokinetic and exposure parameters were estimated, including terminal half-life (t max ), maximum observed plasma concentration (C max ), area under the concentration-versus-time curve at 24 h (AUC 24h ), volume of distribution (V z /F), terminal elimination half-life (t 1/2,z ), and clearance (CL/F).…”

Targeting Mouse Double Minute 2: Current Concepts in DNA Damage Repair and Therapeutic Approaches in Cancer

“…However, the MTD of AMG 232 was not reached. Dose escalation was discontinued because of its unacceptable gastrointestinal AEs at higher doses (Erba et al, 2019).…”

Chemopreventive Agent 3,3′-Diindolylmethane Inhibits MDM2 in Colorectal Cancer Cells

“…Combination with DIM prevented this drawback from happening, as Nutlin-3a-induced increase of MDM2 is blocked by DIM ( Figure 6 C), and a similar result was found in DIM/RG-7388 combination. As a result, DIM can be used to enhance the therapeutic efficacy of MDM2 inhibitors such as AMG 232, which are currently in clinical trials [ 39 , 40 ].…”