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

David S. Hong, Patricia LoRusso, Omid Hamid, Filip Janku, Muaiad Kittaneh, Daniel V.T. Catenacci, Emily Chan, Tanios Bekaii-Saab, Shirish M. Gadgeel, Robert D. Loberg, Benny M. Amore, Yuying C. Hwang, Rui Tang, Gataree Ngarmchamnanrith, Eunice L. Kwak

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 3þ3þ3 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 ¼ 6) and fatigue (n ¼ 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 (51–1,430þ) days in all patients and 197 (64–1,430þ) 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.

Original languageEnglish (US)
Pages (from-to)2403-2413
Number of pages11
JournalClinical Cancer Research
Volume25
Issue number8
DOIs
StatePublished - Apr 15 2019

Fingerprint

Maximum Tolerated Dose
Neoplasms
Headache
AMG-337
Nausea
Fatigue
Therapeutics
Pharmacokinetics
Safety

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hong, D. S., LoRusso, P., Hamid, O., Janku, F., Kittaneh, M., Catenacci, D. V. T., ... Kwak, E. L. (2019). Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors. Clinical Cancer Research, 25(8), 2403-2413. https://doi.org/10.1158/1078-0432.CCR-18-1341

Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors. / Hong, David S.; LoRusso, Patricia; Hamid, Omid; Janku, Filip; Kittaneh, Muaiad; Catenacci, Daniel V.T.; Chan, Emily; Bekaii-Saab, Tanios; Gadgeel, Shirish M.; Loberg, Robert D.; Amore, Benny M.; Hwang, Yuying C.; Tang, Rui; Ngarmchamnanrith, Gataree; Kwak, Eunice L.

In: Clinical Cancer Research, Vol. 25, No. 8, 15.04.2019, p. 2403-2413.

Research output: Contribution to journalArticle

Hong, DS, LoRusso, P, Hamid, O, Janku, F, Kittaneh, M, Catenacci, DVT, Chan, E, Bekaii-Saab, T, Gadgeel, SM, Loberg, RD, Amore, BM, Hwang, YC, Tang, R, Ngarmchamnanrith, G & Kwak, EL 2019, 'Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors', Clinical Cancer Research, vol. 25, no. 8, pp. 2403-2413. https://doi.org/10.1158/1078-0432.CCR-18-1341
Hong, David S. ; LoRusso, Patricia ; Hamid, Omid ; Janku, Filip ; Kittaneh, Muaiad ; Catenacci, Daniel V.T. ; Chan, Emily ; Bekaii-Saab, Tanios ; Gadgeel, Shirish M. ; Loberg, Robert D. ; Amore, Benny M. ; Hwang, Yuying C. ; Tang, Rui ; Ngarmchamnanrith, Gataree ; Kwak, Eunice L. / Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 8. pp. 2403-2413.
@article{4a4b617927fd411b9f933c11bc098578,
title = "Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors",
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{\th}3{\th}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 ¼ 6) and fatigue (n ¼ 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{\th}) days in all patients and 197 (64–1,430{\th}) 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.",
author = "Hong, {David S.} and Patricia LoRusso and Omid Hamid and Filip Janku and Muaiad Kittaneh and Catenacci, {Daniel V.T.} and Emily Chan and Tanios Bekaii-Saab and Gadgeel, {Shirish M.} and Loberg, {Robert D.} and Amore, {Benny M.} and Hwang, {Yuying C.} and Rui Tang and Gataree Ngarmchamnanrith and Kwak, {Eunice L.}",
year = "2019",
month = "4",
day = "15",
doi = "10.1158/1078-0432.CCR-18-1341",
language = "English (US)",
volume = "25",
pages = "2403--2413",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "8",

}

TY - JOUR

T1 - Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors

AU - Hong, David S.

AU - LoRusso, Patricia

AU - Hamid, Omid

AU - Janku, Filip

AU - Kittaneh, Muaiad

AU - Catenacci, Daniel V.T.

AU - Chan, Emily

AU - Bekaii-Saab, Tanios

AU - Gadgeel, Shirish M.

AU - Loberg, Robert D.

AU - Amore, Benny M.

AU - Hwang, Yuying C.

AU - Tang, Rui

AU - Ngarmchamnanrith, Gataree

AU - Kwak, Eunice L.

PY - 2019/4/15

Y1 - 2019/4/15

N2 - 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 3þ3þ3 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 ¼ 6) and fatigue (n ¼ 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 (51–1,430þ) days in all patients and 197 (64–1,430þ) 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.

AB - 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 3þ3þ3 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 ¼ 6) and fatigue (n ¼ 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 (51–1,430þ) days in all patients and 197 (64–1,430þ) 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.

UR - http://www.scopus.com/inward/record.url?scp=85064768094&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064768094&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-18-1341

DO - 10.1158/1078-0432.CCR-18-1341

M3 - Article

VL - 25

SP - 2403

EP - 2413

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 8

ER -