AMG 193 for Non-Small Cell Lung Cancer
Recruiting in Palo Alto (17 mi)
+42 other locations
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Amgen
Disqualifiers: EGFR, ALK, ROS1, others
No Placebo Group
Prior Safety Data
Trial Summary
What is the purpose of this trial?The main objective of the study is to characterize safety and efficacy of 2 dose levels of AMG 193 by investigator, and to evaluate AMG 193 monotherapy efficacy by Blinded Independent Central Review (BICR).
Will I have to stop taking my current medications?
The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial team or your doctor.
What data supports the effectiveness of the drug AMG 193 for treating non-small cell lung cancer?
AMG 193, a PRMT5 inhibitor, showed partial responses in a phase I trial for patients with advanced MTAP-deleted solid tumors, indicating potential effectiveness in certain cancer types. Additionally, PRMT5 inhibitors have been shown to inhibit the growth of lung cancer cells, suggesting that targeting PRMT5 could be beneficial in treating lung cancer.
12345What safety data exists for AMG 193 in humans?
In a phase I trial of AMG 193, which is a PRMT5 inhibitor, it was tested on 39 patients with advanced solid tumors, but the study primarily focused on its effectiveness rather than detailed safety outcomes.
34567What makes the drug AMG 193 unique for treating non-small cell lung cancer?
AMG 193 is unique because it targets a specific enzyme called PRMT5, which is essential for the growth of lung cancer cells, especially in cases where a gene called MTAP is deleted. This makes it a novel approach compared to other treatments that do not specifically target this enzyme.
23457Eligibility Criteria
This trial is for adults with advanced non-small cell lung cancer (NSCLC) that lacks a gene called MTAP. Participants should have tried at least one treatment before, can live more than 3 months, and may have small, stable brain tumors not needing steroids. They must provide tissue samples from previous biopsies.Inclusion Criteria
My lung cancer cannot be removed by surgery and lacks the MTAP gene.
My cancer returned or worsened after at least one treatment for advanced disease.
I have a tissue sample or block from a previous procedure available.
+3 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Dose Evaluation
Participants will be randomized to receive one of 2 active dose levels of AMG 193 orally daily in 28-day cycles to determine the recommended phase 2 dose
28 days
Dose Expansion
Participants will receive AMG 193 at the recommended phase 2 dose in 28-day cycles
28 days
Follow-up
Participants are monitored for safety and effectiveness after treatment
4 weeks
Participant Groups
The study tests two different doses of AMG 193 to see how safe and effective they are against NSCLC. The drug's performance will be assessed by the researchers and also independently reviewed without knowing which dose was given.
2Treatment groups
Experimental Treatment
Group I: Part 2: Dose ExpansionExperimental Treatment1 Intervention
Participants will receive AMG 193 PO QD in 28-day cycles at the RP2D.
Group II: Part 1: Dose EvaluationExperimental Treatment1 Intervention
Participants will be randomized to receive one of 2 active dose levels of AMG 193 orally (PO) daily (QD) in 28 days cycles. Part 1 of the study will determine the recommended phase 2 dose (RP2D).
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
City of Hope National Medical CenterDuarte, CA
City of Hope Orange County Lennar Foundation Cancer CenterDuarte, CA
Valkyrie Clinical TrialsLos Angeles, CA
University of California Los AngelesLos Angeles, CA
More Trial Locations
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Who Is Running the Clinical Trial?
AmgenLead Sponsor
References
Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity. [2023]The protein arginine methyltransferase 5 (PRMT5) methylates a variety of proteins involved in splicing, multiple signal transduction pathways, epigenetic control of gene expression, and mechanisms leading to protein expression required for cellular proliferation. Dysregulation of PRMT5 is associated with clinical features of several cancers, including lymphomas, lung cancer, and breast cancer. Here, we describe the characterization of JNJ-64619178, a novel, selective, and potent PRMT5 inhibitor, currently in clinical trials for patients with advanced solid tumors, non-Hodgkin's lymphoma, and lower-risk myelodysplastic syndrome. JNJ-64619178 demonstrated a prolonged inhibition of PRMT5 and potent antiproliferative activity in subsets of cancer cell lines derived from various histologies, including lung, breast, pancreatic, and hematological malignancies. In primary acute myelogenous leukemia samples, the presence of splicing factor mutations correlated with a higher ex vivo sensitivity to JNJ-64619178. Furthermore, the potent and unique mechanism of inhibition of JNJ-64619178, combined with highly optimized pharmacological properties, led to efficient tumor growth inhibition and regression in several xenograft models in vivo, with once-daily or intermittent oral-dosing schedules. An increase in splicing burden was observed upon JNJ-64619178 treatment. Overall, these observations support the continued clinical evaluation of JNJ-64619178 in patients with aberrant PRMT5 activity-driven tumors.
Protein arginine methyltransferase 5 is essential for growth of lung cancer cells. [2021]PRMT5 (protein arginine methyltransferase 5) is an enzyme that catalyses transfer of methyl groups from S-adenosyl methionine to the arginine residues of histones or non-histone proteins and is involved in a variety of cellular processes. Although it is highly expressed in some tumours, its direct role in cancer growth has not been fully investigated. In the present study, in human lung tissue samples we found that PRMT5 was highly expressed in lung cancer cells, whereas its expression was not detectable in benign lung tissues. Silencing PRMT5 expression strongly inhibited proliferation of lung adenocarcinoma A549 cells in tissue culture, and silencing PRMT5 expression in A549 cells also abolished growth of lung A549 xenografts in mice. In vitro and in vivo studies showed that the cell growth arrest induced by loss of PRMT5 expression was partially attributable to down-regulation of fibroblast growth factor receptor signalling. These results suggest that PRMT5 and its methyltransferase activity is essential for proliferation of lung cancer cells and may serve as a novel target for the treatment of lung cancer.
Discovery and Biological Characterization of PRMT5:MEP50 Protein-Protein Interaction Inhibitors. [2022]Protein arginine methyltransferase 5 (PRMT5) is a master epigenetic regulator and an extensively validated therapeutic target in multiple cancers. Notably, PRMT5 is the only PRMT that requires an obligate cofactor, methylosome protein 50 (MEP50), to function. We developed compound 17, a novel small-molecule PRMT5:MEP50 protein-protein interaction (PPI) inhibitor, after initial virtual screen hit identification and analogue refinement. Molecular docking indicated that compound 17 targets PRMT5:MEP50 PPI by displacing the MEP50 W54 burial into a hydrophobic pocket of the PRMT5 TIM barrel. In vitro analysis indicates IC50 < 500 nM for prostate and lung cancer cells with selective, specific inhibition of PRMT5:MEP50 substrate methylation and target gene expression, and RNA-seq analysis suggests that compound 17 may dysregulate TGF-β signaling. Compound 17 provides a proof of concept in targeting PRMT5:MEP50 PPI, as opposed to catalytic targeting, as a novel mechanism of action and supports further preclinical development of inhibitors in this class.
AMG 193 Effective in Multiple Tumor Types. [2023]In a phase I trial of the MTA-cooperative PRMT5 inhibitor AMG 193, five of 39 patients with advanced MTAP-deleted solid tumors who had scans following initial treatment experienced partial responses. The responses occurred in five tumor types-esophageal, pancreatic, renal cell, gallbladder, and ovarian Sertoli-Leydig cell cancer.
Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression. [2022]We hypothesized that small molecule transcriptional perturbation could be harnessed to target a cellular dependency involving protein arginine methyltransferase 5 (PRMT5) in the context of methylthioadenosine phosphorylase (MTAP) deletion, seen frequently in malignant pleural mesothelioma (MPM). Here we show, that MTAP deletion is negatively prognostic in MPM. In vitro, the off-patent antibiotic Quinacrine efficiently suppressed PRMT5 transcription, causing chromatin remodelling with reduced global histone H4 symmetrical demethylation. Quinacrine phenocopied PRMT5 RNA interference and small molecule PRMT5 inhibition, reducing clonogenicity in an MTAP-dependent manner. This activity required a functional PRMT5 methyltransferase as MTAP negative cells were rescued by exogenous wild type PRMT5, but not a PRMT5E444Q methyltransferase-dead mutant. We identified c-jun as an essential PRMT5 transcription factor and a probable target for Quinacrine. Our results therefore suggest that small molecule-based transcriptional perturbation of PRMT5 can leverage a mutation-selective vulnerability, that is therapeutically tractable, and has relevance to 9p21 deleted cancers including MPM.
Inhibition of PRMT5 by market drugs as a novel cancer therapeutic avenue. [2023]Market drugs, such as Food and Drug Administration (FDA) or European Medicines Agency (EMA)-approved drugs for specific indications provide opportunities for repurposing for newer therapeutics. This potentially saves resources invested in clinical trials that verify drug safety and tolerance in humans prior to alternative indication approval. Protein arginine methyltransferase 5 (PRMT5) overexpression has been linked to promoting the tumor phenotype in several cancers, including pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and breast cancer (BC), making PRMT5 an important target for cancer therapy. Previously, we showed that PRMT5-mediated methylation of the nuclear factor (NF)-κB, partially contributes to its constitutive activation observed in cancers. In this study, we utilized an AlphaLISA-based high-throughput screening method adapted in our lab, and identified one FDA-approved drug, Candesartan cilexetil (Can, used in hypertension treatment) and one EMA-approved drug, Cloperastine hydrochloride (Clo, used in cough treatment) that had significant PRMT5-inhibitory activity, and their anti-tumor properties were validated using cancer phenotypic assays in vitro. Furthermore, PRMT5 selective inhibition of methyltransferase activity was confirmed by reduction of both NF-κB methylation and its subsequent activation upon drug treatment. Using in silico prediction, we identified critical residues on PRMT5 targeted by these drugs that may interfere with its enzymatic activity. Finally, Clo and Can treatment have exhibited marked reduction in tumor growth in vivo. Overall, we provide basis for pursuing repurposing Clo and Can as anti-PRMT5 cancer therapies. Our study offers potential safe and fast repurposing of previously unknown PRMT5 inhibitors into clinical practice.
Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP-Deleted Cancers. [2022]The PRMT5•MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of MTAP-deleted cancers. Here, we report the discovery of development candidate MRTX1719. MRTX1719 is a potent and selective binder to the PRMT5•MTA complex and selectively inhibits PRMT5 activity in MTAP-deleted cells compared to MTAP-wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine protein modification in MTAP-deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2H)-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5•MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate MRTX1719.