AMG 337 / ImmunityBio, Amgen - LARVOL DELTA

Restraint-Based ECG and Arterial Pressure Assessment Do Not Reliably Detect Drug Induced QTc Prolongation and Hypotension: Evidence From Case Studies. (PubMed, Clin Transl Sci) - "This paper retrospectively analyzed two case studies (AMG 319 and AMG 337) in which proprietary small molecules were evaluated by both non-restraint-based telemetry and restraint-based methods. However, in toxicology studies in which restraint-based ECG and blood pressure methods were used, CV effects were missed, blunted, or directionally wrong. These case studies highlight the need for the utilization of unrestrained telemetry methods over restraint-based methods."

Journal • Cardiovascular • Hypotension

Exploring Ketones in Chrysopogon zizanioides: A Computational Molecular Dynamic Approach to c-Met Modulation. (PubMed, Mol Biotechnol) - "Through rigorous molecular docking simulations utilizing Auto Dock Vina plugin integrated with Chimera software, Ketone (C29H56O) (IMPHY012701) emerged as a standout candidate, exhibiting a lower binding energy compared to the reference molecule, AMG 337 which was used as a control compound...Notably, Ketone (C29H56O) (IMPHY012701) demonstrated superior binding affinity relative to the control compound, underscoring its potential as a lead for further investigation. This study underscores the utility of computational approaches in drug discovery from natural sources and highlights Ketone (C29H56O) (IMPHY012701) as a promising candidate for the modulation of c-Met-mediated signalling pathways, warranting further experimental validation and exploration of its pharmacological properties."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • MET

QUILT-3.031: AMG 337 in Subjects With Advanced or Metastatic Clear Cell Sarcoma (clinicaltrials.gov) - P2 | N=8 | Terminated | Sponsor: NantPharma, LLC | Active, not recruiting ➔ Terminated; Prematurely terminated due to lack of therapeutic effect

Trial termination • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • ATF1 • EWSR1

QUILT-3.031: AMG 337 in Subjects With Advanced or Metastatic Clear Cell Sarcoma (clinicaltrials.gov) - P2; N=8; Active, not recruiting; Sponsor: NantPharma, LLC; Recruiting ➔ Active, not recruiting; N=37 ➔ 8; Trial completion date: Jun 2021 ➔ Dec 2022; Trial primary completion date: Mar 2021 ➔ Jun 2022

Clinical • Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Ewing Sarcoma • Oncology • Sarcoma • Solid Tumor • ATF1 • EWSR1

C-Met Inhibitor AMG 337, Oxaliplatin, Leucovorin Calcium, and Fluorouracil in Treating Patients With Advanced Stomach or Esophageal Cancer (clinicaltrials.gov) - P1/2; N=308; Not yet recruiting; Sponsor: Eastern Cooperative Oncology Group

Clinical • New P1/2 trial • Breast Cancer • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Cancer • Gastrointestinal Disorder • HER2 Breast Cancer • Oncology • Solid Tumor • HER-2 • MET

C-Met Inhibitor AMG 337, Oxaliplatin, Leucovorin Calcium, and Fluorouracil in Treating Patients With Advanced Stomach or Esophageal Cancer (clinicaltrials.gov) - P2; N=0; Withdrawn; Sponsor: Eastern Cooperative Oncology Group; Phase classification: P1/2 ➔ P2; N=308 ➔ 0; Not yet recruiting ➔ Withdrawn; Trial primary completion date: Jun 2016 ➔ Mar 2018

Clinical • Enrollment change • Phase classification • Trial primary completion date • Trial withdrawal • Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastroesophageal Junction Adenocarcinoma • Gastrointestinal Disorder • HER2 Breast Cancer • HER-2 • MET

Cabozantinib can block growth of neuroendocrine prostate cancer patient-derived xenografts by disrupting tumor vasculature. (PubMed, PLoS One) - "In vitro treatment of SCNPC patient-derived xenograft (PDX) cells with the MET inhibitor AMG-337 had no impact on cell viability in LuCaP 93 (MET+/RET+) and LuCaP 173.1 (MET-/RET-), whereas cabozantinib decreased cell viability of LuCaP 93, but not LuCaP 173.1...Our data suggest that the most likely mechanism of cabozantinib-mediated tumor growth suppression in SCNPC PDX models is through disruption of the tumor vasculature. Thus, cabozantinib may represent a potential therapy for patients with metastatic disease in tumor phenotypes that have a significant dependence on the tumor vasculature for survival and proliferation."

Clinical • Journal • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Amgen and Astellas announce Japan alliance (Amgen) - "Amgen and Astellas have entered into a strategic alliance to provide new medicines to help address serious unmet medical needs of Japanese patients...Both companies will collaborate on the development and commercialization in Japan of five Amgen pipeline medicines, AMG 145 for the treatment of hyperlipidemia; romosozumab (AMG 785) for osteoporosis; rilotumumab (AMG 102) and AMG 337 for gastric cancer; and blinatumomab (AMG 103) for ALL and NHL."

Licensing / partnership • Atherosclerosis • Dyslipidemia • Hematological Malignancies • Oncology

AMG 337, a novel, potent and selective MET kinase inhibitor, has robust growth inhibitory activity in MET-dependent cancer models (AACR 2014) - "...in an expanded panel of additional cancer cell lines derived from gastric, NSCLC, and esophageal cancer confirmed that the in-vitro anti-proliferative activity of AMG 337 correlated with amplification of MET...In vivo, oral administration of AMG 337 resulted in robust dose-dependent anti-tumor efficacy in MET amplified gastric cancer xenograft models, with inhibition of tumor growth consistent with the pharmacodynamic modulation of MET signaling."

Preclinical • Esophageal Cancer • Gastric Cancer • Non Small Cell Lung Cancer • Oncology

Five Prime Therapeutics: R&D Day 2015 (Five Prime Therap) - “AMG337: Responses in Patients With MET-Amplified GEJ/Gastric/Esophageal Cancer”; “13 patients with MET-amplified GEJ/gastric/esophageal cancer treated to date; ORR = 8/13 (62%)"

P2 data • Gastric Cancer • Oncology

Astellas: FY 2014 Results (Astellas) - "Removed from the pipeline list for strategic reasons based on discussion with Amgen"

Licensing / partnership • Gastric Cancer • Oncology

Clinical activity of AMG 337, an oral MET kinase inhibitor, in adult patients (pts) with MET-amplified gastroesophageal junction (GEJ), gastric (G), or esophageal (E) cancer (ASCO-GI 2015) - Abstract #1; P1, N=80; NCT01253707; Sponsor: Amgen; "One pt had a complete response (duration 100 wks) and 4 pts had partial responses (durations up to 52 wks). The most common treatment-emergent AEs (in > 20% of all pts) were headache, nausea, fatigue, vomiting, and constipation....QD maximum tolerated dose (MTD) is 300 mg; BID MTD has not been reached."

P1 data • Esophageal Cancer • Gastric Cancer • Oncology

Phase 2 Study of AMG 337 in MET Amplified Gastric/Esophageal Adenocarcinoma or Other Solid Tumors (clinicaltrials.gov) - P2; N=60; Active, not recruiting; Sponsor: Amgen; Trial primary completion date: Aug 2016 ➔ Jan 2017

Trial primary completion date • Biosimilar • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology

QUILT-3.031: AMG 337 in Subjects With Advanced or Metastatic Clear Cell Sarcoma (clinicaltrials.gov) - P2; N=37; Recruiting; Sponsor: NantPharma, LLC; N=10 ➔ 37; Trial completion date: Dec 2020 ➔ Jun 2021; Trial primary completion date: Oct 2020 ➔ Mar 2021

Clinical • Enrollment change • Trial completion date • Trial primary completion date

QUILT-3.036: AMG 337 in Subjects With Advanced or Metastatic Solid Tumors (clinicaltrials.gov) - P2; N=0; Withdrawn; Sponsor: NantPharma, LLC; N=178 ➔ 0; Trial completion date: Dec 2020 ➔ Aug 2019; Recruiting ➔ Withdrawn; Trial primary completion date: Oct 2020 ➔ Aug 2019

Clinical • Enrollment change • Trial completion date • Trial primary completion date • Trial withdrawal

Clinical Implications and Translation of an Off-Target Pharmacology Profiling Hit: Adenosine Uptake Inhibition In Vitro. (PubMed, Transl Oncol) - "When subjects were advised to drink coffee, an AR antagonist, prior to AMG 337, the severity of headaches was reduced, allowing them to continue treatment. These findings demonstrate the importance of carefully evaluating clinical observations during early drug development and the value of translational nonclinical studies to investigate the mechanism of action driving clinical observations."

Journal

A Multicenter Phase 2 Study of AMG 337 in Patients With MET-Amplified Gastric/Gastroesophageal Junction/Esophageal Adenocarcinoma and Other Solid Tumors. (PubMed, Clin Cancer Res) - "AMG 337 showed antitumor activity in MET-amplified G/GEJ/E adenocarcinoma but not in MET-amplified non-small-cell lung cancer.See related commentary by Ma, p. 2375."

Clinical • Journal • P2 data

Phase 1 Study of AMG 337, a Highly Selective Small-Molecule MET Inhibitor, in Patients With Advanced Solid Tumors. (PubMed, Clin Cancer Res) - "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."

Clinical • Journal • P1 data