AMG 193 + Other Therapies for Lung Cancer

Recruiting at 99 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new drug, AMG 193 (an MTA Cooperative PRMT5 inhibitor), combined with other therapies to determine the best dose and assess safety in treating non-small cell lung cancer (NSCLC). It targets individuals whose tumors lack a specific protein due to a genetic change (MTAP-deletion). The trial divides participants into groups to test different combinations of AMG 193 with other drugs, such as pembrolizumab, carboplatin, and paclitaxel. Individuals with NSCLC who have this genetic change, whether with squamous or non-squamous tumor types or brain metastases, might be suitable candidates. Participants must be able to take oral medication and have measurable disease. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new drug.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that AMG 193 was safe in earlier studies, meaning patients with certain types of tumors tolerated it well. Notably, these studies did not report major side effects, such as severe drops in blood cell counts, a common concern with cancer treatments. AMG 193 targets specific tumor cells while sparing normal cells, reducing unwanted side effects.

For those considering joining a trial with AMG 193, this information suggests it has been safe for others in past studies. However, ongoing research will continue to assess its safety when combined with other treatments. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about AMG 193 for lung cancer because it offers a fresh approach compared to standard treatments like chemotherapy, which often include carboplatin and paclitaxel. AMG 193 primarily targets MTAP-deleted non-small cell lung cancer (NSCLC), a specific genetic alteration that not all therapies address. Additionally, in some trial arms, AMG 193 is paired with pembrolizumab, an immunotherapy that helps the body's immune system attack cancer cells more effectively. In another arm, it is combined with sotorasib to specifically target the KRasG12C mutation, showcasing its adaptability to different cancer profiles. This targeted strategy could lead to more personalized and potentially more effective treatment options for patients.

What evidence suggests that this trial's treatments could be effective for lung cancer?

Research shows that AMG 193, a PRMT5 inhibitor, may help treat MTAP-deleted lung cancer. Studies have found that AMG 193 can stop the growth of cancer cells with this deletion while leaving normal cells unharmed. In this trial, participants in different arms will receive AMG 193 with other therapies. One arm will test AMG 193 with pembrolizumab, carboplatin, and paclitaxel, while another will combine AMG 193 with carboplatin, pemetrexed, and pembrolizumab. For patients whose cancer has spread to the brain, AMG 193 will be tested alone. In cases of non-small cell lung cancer (NSCLC) with a KRasG12C mutation, AMG 193 will be combined with sotorasib. Overall, the evidence supporting AMG 193 is promising for treating these specific types of cancer. ^{1 2 3 6 7}

Who Is on the Research Team?

MD

Principal Investigator

Amgen

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. annalsofoncology.org annalsofoncology.org/article/S0923-7534%2824%2903919-X/fulltext

First-in-human study of AMG 193, an MTA-cooperative ... Here, we report results of the completed monotherapy dose exploration evaluating AMG 193 in patients with MTAP-deleted solid tumors.

2. aacrjournals.org aacrjournals.org/cancerdiscovery/article/15/1/139/750846/AMG-193-a-Clinical-Stage-MTA-Cooperative-PRMT5

AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor ... AMG 193 preferentially inhibits the growth of MTAP-deleted tumor cells by inhibiting PRMT5 when in complex with MTA, thus sparing MTAP wild-type normal cells.

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39293516/

First-in-human study of AMG 193, an MTA-cooperative ... AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT05094336

A Study of AMG 193 in Participants With Advanced MTAP- ... The primary objective of Parts 1 and 2 of this study is to evaluate the safety, tolerability, and to determine the maximum tolerated dose (MTD) or ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S092375342403919X

First-in-human study of AMG 193, an MTA-cooperative ... AMG 193 demonstrated a favorable safety profile without clinically significant myelosuppression. Encouraging antitumor activity across a variety of MTAP- ...

6. sciencedirect.com sciencedirect.com/science/article/pii/S1556086424015065

P3.12D.10 Phase 1b Study of AMG 193, An MTA- ... AMG 193 is an oral S-methyl-5'-thioadenosine (MTA)-cooperative protein arginine methyltransferase 5 (PRMT5) inhibitor designed to induce synthetic lethality in ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT05094336

NCT05094336 | A Study of AMG 193 in Participants With ... The primary objective of Part 3 of this study is to evaluate the efficacy of AMG 193 in adult participants with metastatic or locally advanced MTAP-null solid ...