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Clin Cancer Res. 2019 Apr 15;25(8):2403-2413. doi: 10.1158/1078-0432.CCR-18-1341. Epub 2018 Nov 13.

Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors.

Author information

1
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas. dshong@mdanderson.org.
2
Medical Oncology, Yale Cancer Center, New Haven, Connecticut.
3
Melanoma Center, The Angeles Clinic and Research Institute, Los Angeles, California.
4
Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Hematology/Oncology, Loyola University Chicago Stritch School of Medicine, Chicago, Illinois.
6
Hematology/Oncology, University of Chicago, Chicago, Illinois.
7
Department of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
8
Department of Internal Medicine, Mayo Clinic, Phoenix, Arizona.
9
Thoracic Oncology, Karmanos Cancer Institute, Detroit, Michigan.
10
Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, Michigan.
11
Oncology Biomarkers, Amgen Inc., Thousand Oaks, California.
12
Clinical Pharmacology, Modeling and Simulation, Amgen Inc., South San Francisco, California.
13
Global Biostatistical Sciences, Amgen Inc., Thousand Oaks, California.
14
Early Development, Hematology and Oncology, Amgen Inc., Thousand Oaks, California.
15
Hematology/Oncology, Massachusetts General Hospital Cancer Center, Boston, Massachusetts.

Abstract

PURPOSE:

This first-in-human, open-label phase I study evaluated AMG 337, an oral, highly selective small-molecule inhibitor of MET in advanced solid tumors.Patients and Methods: Patients enrolled into dose-escalation cohorts received AMG 337 up to 400 mg once daily or up to 250 mg twice daily, following a modified 3+3+3 design. Dose expansion was conducted in MET-amplified patients at the maximum tolerated dose (MTD). Primary endpoints included assessment of adverse events (AEs), establishment of the MTD, and pharmacokinetics; clinical response was a secondary endpoint.

RESULTS:

The safety analysis set included 111 patients who received ≥1 dose of AMG 337. Thirteen patients had ≥1 AE qualifying as dose-limiting toxicity. The MTD was determined to be 300 mg once daily; the MTD for twice-daily dosing was not reached. Most frequent treatment-related AEs were headache (63%) and nausea (31%). Grade ≥3 treatment-related AEs occurred in 23 patients (21%), most commonly headache (n = 6) and fatigue (n = 5). Maximum plasma concentration occurred at 3.0 hours following 300-mg once-daily dosing, indicating AMG 337 absorption soon after treatment. Objective response rate was 9.9% (11/111; 95% CI, 5.1%-17.0%) in all patients and 29.6% (8/27; 95% CI, 13.8%-50.2%) in MET-amplified patients; median (range) duration of response was 202 (51-1,430+) days in all patients and 197 (64-1,430+) days in MET-amplified patients.

CONCLUSIONS:

Oral AMG 337 was tolerated with manageable toxicities, with an MTD and recommended phase II dose of 300 mg once daily. The promising response rate observed in patients with heavily pretreated MET-amplified tumors warrants further investigation.See related commentary by Ma, p. 2375.

PMID:
30425090
DOI:
10.1158/1078-0432.CCR-18-1341
[Indexed for MEDLINE]

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