AMG 193 for Non-Small Cell Lung Cancer

Recruiting at 53 trial locations

Overseen By Amgen Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Amgen

Disqualifiers: EGFR, ALK, ROS1, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

200 Participants Needed

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. ^{1 2 3 4 5}

What 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. ^{3 4 5 6 7}

What 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. ^{2 3 4 5 7}

Research Team

MD

Principal Investigator

Amgen

Eligibility 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.

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

Treatment Details

Interventions

• AMG 193

Trial Overview 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.

Participant Groups

Group I: Part 2: Dose Expansion Experimental Treatment 1 Intervention

Participants will receive AMG 193 PO QD in 28-day cycles at the RP2D.

Group II: Part 1: Dose Evaluation Experimental Treatment 1 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).

Who Is Running the Clinical Trial?

Amgen

Lead Sponsor

Trials

1,508

Recruited

1,433,000+

Founded

1980

Headquarters

Thousand Oaks, USA

Known For

Human Therapeutics

Top Products

Enbrel, Prolia, Neulasta, Otezla

Robert A. Bradway

Amgen

Chief Executive Officer since 2012

MBA from Harvard Business School

Paul Burton

Amgen

Chief Medical Officer since 2023

MD from University of London, PhD in Molecular and Cellular Biology from Imperial College London

Findings from Research

JNJ-64619178 is a novel and selective inhibitor of PRMT5 that shows strong potential in treating various cancers, including advanced solid tumors and non-Hodgkin's lymphoma, by effectively inhibiting tumor growth in preclinical models.

The drug demonstrated a unique mechanism of action, with increased sensitivity observed in cancer samples with splicing factor mutations, suggesting it may be particularly effective for certain patient populations with aberrant PRMT5 activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity. Brehmer, D., Beke, L., Wu, T., et al.[2023]

PRMT5 is highly expressed in lung cancer cells but not in benign lung tissues, indicating its potential role as a biomarker for lung cancer.

Silencing PRMT5 significantly inhibited the growth of lung adenocarcinoma cells in culture and in mouse models, suggesting that targeting PRMT5 could be a promising strategy for lung cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protein arginine methyltransferase 5 is essential for growth of lung cancer cells. Gu, Z., Gao, S., Zhang, F., et al.[2021]

Compound 17 is a novel small-molecule inhibitor that specifically disrupts the interaction between PRMT5 and its cofactor MEP50, which is crucial for PRMT5's function in cancer cells.

In vitro studies show that compound 17 effectively inhibits PRMT5 activity in prostate and lung cancer cells with an IC50 of less than 500 nM, suggesting it could be a promising therapeutic strategy for targeting PRMT5 in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discovery and Biological Characterization of PRMT5:MEP50 Protein-Protein Interaction Inhibitors. Asberry, AM., Cai, X., Deng, X., et al.[2022]

In a phase I trial involving 39 patients with advanced solid tumors lacking the MTAP gene, the PRMT5 inhibitor AMG 193 showed promising results, with five patients experiencing partial responses.

These partial responses were observed across various tumor types, including esophageal, pancreatic, renal cell, gallbladder, and ovarian Sertoli-Leydig cell cancers, indicating the potential efficacy of AMG 193 in treating these specific cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AMG 193 Effective in Multiple Tumor Types. [2023]

MTAP deletion in malignant pleural mesothelioma (MPM) is associated with a poor prognosis, highlighting the importance of targeting this cellular dependency.

The antibiotic Quinacrine effectively suppresses PRMT5 transcription in MTAP-deleted cells, leading to reduced cancer cell growth, suggesting a potential therapeutic strategy for treating MPM by exploiting this specific vulnerability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression. Busacca, S., Zhang, Q., Sharkey, A., et al.[2022]

Two FDA and EMA-approved drugs, Candesartan cilexetil and Cloperastine hydrochloride, were identified as effective inhibitors of PRMT5, a target linked to various cancers, suggesting they could be repurposed for cancer therapy.

Both drugs demonstrated significant anti-tumor effects in vitro and reduced tumor growth in vivo, indicating their potential as safe and effective treatments for cancers associated with PRMT5 overexpression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhibition of PRMT5 by market drugs as a novel cancer therapeutic avenue. Prabhu, L., Martin, M., Chen, L., et al.[2023]

MRTX1719 is a newly discovered drug that specifically targets the PRMT5•MTA complex, showing potent inhibition of PRMT5 activity in cancer cells lacking the MTAP gene, which is crucial for certain cancer treatments.

In mouse models with tumors, daily oral administration of MRTX1719 led to a dose-dependent reduction in PRMT5 activity and demonstrated significant antitumor effects, highlighting its potential as a targeted therapy for MTAP-deleted cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP-Deleted Cancers. Smith, CR., Aranda, R., Bobinski, TP., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Discovery and Pharmacological Characterization of JNJ-64619178, a Novel Small-Molecule Inhibitor of PRMT5 with Potent Antitumor Activity. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Protein arginine methyltransferase 5 is essential for growth of lung cancer cells. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Discovery and Biological Characterization of PRMT5:MEP50 Protein-Protein Interaction Inhibitors. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

AMG 193 Effective in Multiple Tumor Types. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Transcriptional perturbation of protein arginine methyltransferase-5 exhibits MTAP-selective oncosuppression. [2022]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Inhibition of PRMT5 by market drugs as a novel cancer therapeutic avenue. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP-Deleted Cancers. [2022]