Dataset Information

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+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.

SUBMITTER: Hong DS

PROVIDER: S-EPMC6892342 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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

Hong David S DS LoRusso Patricia P Hamid Omid O Janku Filip F Kittaneh Muaiad M Catenacci Daniel V T DVT Chan Emily E Bekaii-Saab Tanios T Gadgeel Shirish M SM Loberg Robert D RD Amore Benny M BM Hwang Yuying C YC Tang Rui R Ngarmchamnanrith Gataree G Kwak Eunice L EL

Clinical cancer research : an official journal of the American Association for Cancer Research 20181113 8

<h4>Purpose</h4>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.<b>Patients and Methods:</b> 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 <i>MET</i>-amplified patients at the maximum tolerated dose (MTD). Primary endpoints included assessment of adverse events ...[more]

PMID: 30425090

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Project description:BackgroundFutibatinib is an oral, irreversible, highly selective fibroblast growth factor receptor (FGFR)1-4 inhibitor with potent preclinical activity against tumors harboring FGFR aberrations. This first-in-human, phase I dose-escalation trial (NCT02052778) evaluates the safety and pharmacokinetics/pharmacodynamics of futibatinib in advanced solid tumors.Patients and methodsFollowing a standard 3+3 dose-escalation design, eligible patients with advanced solid tumors refractory to standard therapies received 8-200 mg futibatinib three times a week (t.i.w.) or 4-24 mg once daily (q.d.).ResultsA total of 86 patients were enrolled in the nine t.i.w. (n = 42) and five q.d. cohorts (n = 44); 71 patients (83%) had tumors harboring FGF/FGFR aberrations. Three of nine patients in the 24-mg q.d. cohort experienced dose-limiting toxicities, including grade 3 increases in alanine transaminase, aspartate transaminase, and blood bilirubin (n = 1 each). The maximum tolerated dose (MTD) was determined to be 20 mg q.d.; no MTD was defined for the t.i.w. schedule. Across cohorts (n = 86), the most common treatment-emergent adverse events (TEAEs) were hyperphosphatemia (59%), diarrhea (37%), and constipation (34%); 48% experienced grade 3 TEAEs. TEAEs led to dose interruptions, dose reductions, and treatment discontinuations in 55%, 14%, and 3% of patients, respectively. Pharmacokinetics were dose proportional across all q.d. doses but not all t.i.w. doses evaluated, with saturation observed between 80 and 200 mg t.i.w. Serum phosphorus increased dose dependently with futibatinib on both schedules, but a stronger exposure-response relationship was observed with q.d. dosing, supporting 20 mg q.d. as the recommended phase II dose (RP2D). Overall, partial responses were observed in five patients [FGFR2 fusion-positive intrahepatic cholangiocarcinoma (n = 3) and FGFR1-mutant primary brain tumor (n = 2)], and stable disease in 41 (48%).ConclusionsFutibatinib treatment resulted in manageable safety, pharmacodynamic activity, and preliminary responses in patients with advanced solid tumors. The results of this phase I dose-escalation trial support 20 mg q.d. futibatinib as the RP2D.Clinical trial registrationFOENIX-101 (ClinicalTrials.gov, NCT02052778).

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

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

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