AMG 193 + Other Therapies for Lung Cancer

Recruiting at 65 trial locations

Overseen By Amgen Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Amgen

Disqualifiers: Organ transplant, Major surgery, Radiation, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to approximately 3 years

500 Participants Needed

Trial Summary

What is the purpose of this trial?

The study aims to determine maximum tolerated dose (MTD) or recommended combination dose of the MTA-cooperative PRMT5 inhibitor AMG 193 administered in combination with other therapies in adult participants with metastatic or locally advanced methylthioadenosine phosphorylase (MTAP)-deleted thoracic tumors. The study also aims to determine the safety profile of AMG 193 administered in combination with other therapies in adult participants with metastatic or locally advanced MTAP-deleted thoracic tumors.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, it does exclude participants who have had major surgery or radiation therapy within 28 days of the first dose, which might suggest a need to discuss your current treatments with the trial team.

What data supports the effectiveness of the drug AMG 193 for lung cancer?

Research shows that PRMT5, an enzyme targeted by AMG 193, is essential for lung cancer cell growth and is often overexpressed in lung tumors. Inhibiting PRMT5 has been shown to reduce lung cancer cell proliferation and metastasis, suggesting that AMG 193, which targets PRMT5, could be effective in treating lung cancer. ^{1 2 3 4 5}

Is AMG 193 safe for use in humans?

In a phase I trial, AMG 193 was tested on 39 patients with advanced solid tumors, and some patients showed positive responses, indicating it was tolerated in humans. However, specific safety data for AMG 193 in lung cancer or other conditions is not detailed in the available research. ^{1 4 6 7 8}

How is the drug AMG 193 different from other lung cancer treatments?

AMG 193 is unique because it targets a specific enzyme called PRMT5, which is essential for the growth of certain cancer cells that have a genetic deletion known as MTAP. This makes it a promising option for treating lung cancer in patients with this specific genetic profile, offering a more targeted approach compared to traditional treatments. ^{1 4 7 9 10}

Research Team

MD

Principal Investigator

Amgen

Eligibility Criteria

This trial is for adults with advanced thoracic tumors, including non-small cell lung cancer, that have a specific genetic change (homozygous MTAP-deletion). Participants must be able to swallow pills and have measurable disease. They need available tumor tissue samples or agree to a biopsy before starting treatment.

Inclusion Criteria

I am eligible for Subprotocol A, B, or C.

I am at least 18 years old or the legal age in my country.

My cancer can be measured by standard health scans.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive AMG 193 alone or in combination with other therapies for advanced thoracic tumors

Up to approximately 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• AMG 193

Trial Overview The study tests the drug AMG 193 alone or combined with other therapies like Paclitaxel, Carboplatin, Pemetrexed, Sotorasib, and Pembrolizumab. It aims to find the highest dose patients can take without serious side effects and assess safety in those with certain thoracic tumors.

Participant Groups

Group I: Subprotocol C: NSCLC With Brain Metastases Experimental Treatment 1 Intervention

Participants with MTAP-deleted NSCLC with brain metastases will receive AMG 193 PO

Group II: Subprotocol B: NSCLC With KRasG12C Mutation Experimental Treatment 2 Interventions

Participants with MTAP-deleted NSCLC and KRasG12C mutation will receive a combination of AMG 193 and sotorasib PO

Group III: Subprotocol A: Non-Small Cell Lung Cancer (NSCLC) Arm A Experimental Treatment 4 Interventions

Participants with MTAP-deleted NSCLC will receive a regimen of AMG 193 orally (PO) and carboplatin, paclitaxel, and pembrolizumab intravenously (IV)

Group IV: Subprotocol A: NSCLC Arm C Experimental Treatment 2 Interventions

Participants with MTAP-deleted NSCLC will receive a combination of AMG 193 PO and pembrolizumab IV

Group V: Subprotocol A: NSCLC Arm B Experimental Treatment 4 Interventions

Participants with MTAP-deleted NSCLC will receive a regimen of AMG 193 PO and carboplatin, pemetrexed, and pembrolizumab IV

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

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]

PRMT5 is frequently overexpressed in lung tumors and is associated with advanced tumor stages, lymphatic metastasis, and poorer patient outcomes, indicating its potential as a prognostic biomarker.

The study reveals that PRMT5 promotes lung cancer metastasis by repressing the miR-99 family, which leads to increased FGFR3 expression and activation of growth pathways, suggesting that targeting PRMT5 could be a therapeutic strategy to inhibit lung cancer progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protein arginine methyltransferase 5 promotes lung cancer metastasis via the epigenetic regulation of miR-99 family/FGFR3 signaling. Jing, P., Zhao, N., Ye, M., et al.[2019]

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]

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]

PRMT5 inhibitors, specifically the compound PF-06939999, have been shown to effectively reduce the proliferation of non-small cell lung cancer (NSCLC) cells by targeting cancer-specific dependencies linked to PRMT5's function, demonstrating potential as a therapeutic option.

The study identified that resistance to PRMT5 inhibitors can occur through specific mutations in the PRMT5 enzyme, but these mutations do not lead to complete resistance, suggesting that PF-06939999 could remain effective even in the presence of some resistance mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance. Jensen-Pergakes, K., Tatlock, J., Maegley, KA., 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]

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]

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]

MRTX1719 is a small-molecule inhibitor that selectively targets PRMT5 in cancers with MTAP deletion, showing over 70-fold greater effectiveness in inhibiting cell viability in MTAP del cells compared to wild-type cells.

In early clinical trials, MRTX1719 demonstrated promising antitumor activity in patients with various MTAP del cancers, including melanoma and lung cancer, indicating its potential as a targeted therapy for this specific cancer subtype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer. Engstrom, LD., Aranda, R., Waters, L., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

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

2. Ireland pubmed.ncbi.nlm.nih.gov

Protein arginine methyltransferase 5 promotes lung cancer metastasis via the epigenetic regulation of miR-99 family/FGFR3 signaling. [2019]

3. 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]

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

AMG 193 Effective in Multiple Tumor Types. [2023]

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

SAM-Competitive PRMT5 Inhibitor PF-06939999 Demonstrates Antitumor Activity in Splicing Dysregulated NSCLC with Decreased Liability of Drug Resistance. [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]

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

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

9. England pubmed.ncbi.nlm.nih.gov

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

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

MRTX1719 Is an MTA-Cooperative PRMT5 Inhibitor That Exhibits Synthetic Lethality in Preclinical Models and Patients with MTAP-Deleted Cancer. [2023]