Reference Detail

Ref Type

Journal Article

PMID

(31359240)

Authors

Gluck WL, Gounder MM, Frank R, Eskens F, Blay JY, Cassier PA, Soria JC, Chawla S, de Weger V, Wagner AJ, Siegel D, De Vos F, Rasmussen E, Henary HA

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Investigational new drugs			2019 Jul 29	831-843	Invest New Drugs

URL

Abstract Text

Background This open-label, first-in-human, 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 de-differentiated liposarcomas [WDLPS and DDLPS], glioblastoma multiforme [GBM], or other solid tumors [OST]), MDM2-overexpressing 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.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
TP53 wild-type	multiple myeloma	predicted - sensitive	KRT-232	Phase I	Actionable	In a Phase I trial, KRT-232 (AMG 232) demonstrated acceptable safety, and resulted in stable disease in 50% (5/10) of patients with TP53 wild-type multiple myeloma (PMID: 31359240; NCT01723020).	31359240
TP53 wild-type	estrogen-receptor positive breast cancer	predicted - sensitive	KRT-232	Phase I	Actionable	In a Phase I trial, KRT-232 (AMG 232) demonstrated acceptable safety, and resulted in stable disease in 83.3% (10/12) of patients with TP53 wild-type ER-positive breast cancer (BC), with a median duration of 2.0 months in ER-positive, PR-positive BC, 1.4 months in ER-positive, PR-negative BC, and one patient achieved unconfirmed partial response per central evaluation (PMID: 31359240; NCT01723020).	31359240
TP53 wild-type	Advanced Solid Tumor	sensitive	KRT-232	Phase I	Actionable	In a Phase I trial, KRT-232 (AMG 232) demonstrated acceptable safety, and resulted in stable disease in 80% (31/39) of patients with TP53 wild-type advanced solid tumors, with a median duration of 3.1 months (PMID: 31359240; NCT01723020).	31359240
TP53 wild-type	liposarcoma	predicted - sensitive	KRT-232	Phase I	Actionable	In a Phase I trial, KRT-232 (AMG 232) demonstrated acceptable safety, and resulted in stable disease in 100% (10/10) of patients with TP53 wild-type well-differentiated liposarcomas (WDLPS) and 70% (7/10) of patients with TP53 wild-type de-differentiated liposarcomas, with median duration of 3.9 and 2.0 months respectively, and one patient with WDLPS achieved unconfirmed partial response per central evaluation (PMID: 31359240; NCT01723020).	31359240