AMG 193 + IDE397 for Solid Cancers

Recruiting at 29 trial locations

Overseen By Amgen Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Amgen

Must not be taking: CYP3A4/5 inducers, inhibitors

Disqualifiers: Brain metastases, Bowel obstruction, others

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

Compensation: Varies

Number of Visits: Unknown

53 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests the safety and best dose of two drugs, AMG 193 and IDE397, in adults with advanced cancers missing the MTAP gene, especially lung cancer. The goal is to see if this combination can effectively fight these cancers.

Do I need to stop my current medications to join the trial?

You may need to stop taking certain medications. Specifically, you cannot use strong CYP3A4/5 inducers or inhibitors within 7 days for inhibitors, 14 days for inducers, or 5 half-lives before starting the trial.

Will I have to stop taking my current medications?

You may need to stop taking certain medications before joining the trial. Specifically, if you are using prescription medications that strongly affect CYP3A4/5 enzymes, you must stop them at least 7 days before starting the trial if they are inhibitors, or 14 days if they are inducers, or wait for 5 half-lives of the drug, whichever is longer.

What data supports the idea that AMG 193 + IDE397 for Solid Cancers is an effective drug?

The available research shows that in a phase I trial, the drug AMG 193 was tested on 39 patients with advanced solid tumors that had a specific genetic deletion. Out of these, five patients showed partial improvement in their cancer, which included different types like esophageal, pancreatic, renal cell, gallbladder, and ovarian Sertoli-Leydig cell cancer. This suggests that AMG 193 can be effective for some patients with these types of cancers. ^{1 2 3 4 5}

What data supports the effectiveness of the drug AMG 193 + IDE397 for solid cancers?

In a study, the drug AMG 193 showed partial responses in five out of 39 patients with advanced solid tumors that had a specific genetic deletion. This suggests that the drug may be effective in certain types of cancer, such as esophageal, pancreatic, renal cell, gallbladder, and ovarian Sertoli-Leydig cell cancer. ^{1 2 3 4 5}

What safety data is available for the AMG 193 + IDE397 treatment for solid cancers?

The available research does not provide specific safety data for the AMG 193 + IDE397 treatment. However, a phase I trial of AMG 193, a PRMT5 inhibitor, showed partial responses in some patients with MTAP-deleted solid tumors, indicating potential efficacy. The challenges in developing PRMT5 and MAT2A inhibitors, like IDE397, are noted, but specific safety outcomes are not detailed in the provided studies. ^{1 2 4 6 7}

Is the AMG 193 + IDE397 treatment generally safe for humans?

In a phase I trial of AMG 193, some patients with advanced solid tumors experienced partial responses, but the study does not provide specific safety data. The combination of MTAP and MAT2A inhibitors, which includes IDE397, showed effectiveness in cancer models without adverse effects on normal tissues, suggesting potential safety, but more research is needed to confirm this in humans. ^{1 2 4 6 7}

Is the drug AMG 193, IDE397 a promising treatment for solid cancers?

Yes, AMG 193, IDE397 is a promising drug for treating solid cancers, especially those with MTAP deletion. It targets a specific weakness in these cancer cells, leading to positive responses in some patients with different types of tumors, such as esophageal and pancreatic cancer. ^{1 2 6 7 8}

What makes the drug AMG 193 + IDE397 unique for treating solid cancers?

AMG 193 + IDE397 is unique because it targets the PRMT5 and MAT2A pathways, which are involved in the growth of MTAP-deleted cancers. This approach exploits a specific vulnerability in these cancer cells, potentially leading to more effective treatments for tumors that lack the MTAP gene. ^{1 2 6 7 8}

Research Team

MD

Principal Investigator

Amgen

Eligibility Criteria

This trial is for adults with advanced solid tumors that can't be cured and have lost MTAP protein function. They should have tried up to two treatments for non-small cell lung cancer (NSCLC) without success, be able to swallow pills, and not have had certain bowel or heart issues recently. People who've taken MAT2A or PRMT5 inhibitors or strong drug modifiers can't join.

Inclusion Criteria

My cancer lacks MTAP and has no standard treatment available.

My NSCLC lacks MTAP and has worsened after 1-2 treatments.

My cancer has spread and cannot be cured with surgery or radiation.

Exclusion Criteria

I do not have a digestive condition that prevents me from taking pills.

I have untreated brain issues or spinal cord compression due to cancer.

I have previously been treated with an MAT2A or PRMT5 inhibitor.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Exploration

Participants receive escalating doses of AMG 193 and IDE397 administered orally in cycles of 21 days

21 days per cycle

Dose Expansion

AMG 193 and IDE397 are administered orally in cycles of 21 days to evaluate the recommended combination dose

21 days per cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to approximately 2.5 years

Treatment Details

Interventions

• AMG 193
• IDE397

Trial Overview The study tests the safety and ideal dose of a new treatment combo: AMG 193 with IDE397 in patients whose tumors lack MTAP protein. It's also looking at how well this combination works against advanced NSCLC that has spread or cannot be removed by surgery.

Participant Groups

Group I: Part 2: Dose Expansion of AMG 193 Combined With IDE397 Experimental Treatment 2 Interventions

AMG 193 and IDE397 will be administered PO in cycles of 21 days.

Group II: Part 1: Dose Exploration of AMG 193 Combined With IDE397 Experimental Treatment 2 Interventions

Participants will receive escalating doses of AMG 193 and IDE397 administered orally (PO) in cycles of 21 days.

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

Loss of the MTAP gene in approximately 15% of cancers leads to increased levels of methylthioadenosine (MTA), which inhibits PRMT5, a key enzyme involved in protein methylation and regulation of gene expression.

Targeting the MAT2A/PRMT5 pathway shows potential for cancer therapy, but challenges remain in understanding the mechanisms of these inhibitors and identifying downstream effectors that could enhance treatment efficacy, suggesting the need for novel combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The potential and challenges of targeting MTAP-negative cancers beyond synthetic lethality. Bray, C., Balcells, C., McNeish, IA., 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]

GSK3368715 is a potent reversible inhibitor of type I PRMTs that shows anti-proliferative effects across various cancer types, indicating its potential as a cancer treatment.

Combining GSK3368715 with PRMT5 inhibitors can enhance anti-tumor activity, but requires a specific reduction in overall arginine methylation to achieve synergistic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

M-TAP Dance: Targeting PRMT1 and PRMT5 Family Members to Push Cancer Cells Over the Edge. Srour, N., Mersaoui, SY., Richard, S.[2020]

The combination of Methylthio-DADMe-immucillin-A (MTDIA) and MAT2a inhibitor AG-270 can effectively mimic synthetic lethality in colorectal cancer (CRC) cell lines that are MTAP+/+, significantly enhancing drug potency by 104-fold without harming normal tissues.

This treatment works by altering the balance of key metabolites in cells, leading to inhibition of PRMT5 activity, which triggers cell arrest and apoptosis, thus expanding therapeutic options for the majority of CRCs that do not have the MTAP-/- genotype.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition. Bedard, GT., Gilaj, N., Peregrina, K., et al.[2023]

A genome-wide CRISPR/Cas9 screen identified TP53 as a key sensitizer and MSI2 as a driver of resistance to the PRMT5 inhibitor GSK-591, suggesting that mutations in TP53 can predict resistance to this treatment.

Combining PRMT5 inhibition with either MSI2 or BCL-2 inhibition shows promise in reducing cell growth and promoting apoptosis in lymphoma, indicating a potential new therapeutic strategy for this cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma. Erazo, T., Evans, CM., Zakheim, D., 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]

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]

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]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

The potential and challenges of targeting MTAP-negative cancers beyond synthetic lethality. [2023]

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

AMG 193 Effective in Multiple Tumor Types. [2023]

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

M-TAP Dance: Targeting PRMT1 and PRMT5 Family Members to Push Cancer Cells Over the Edge. [2020]

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

Combined inhibition of MTAP and MAT2a mimics synthetic lethality in tumor models via PRMT5 inhibition. [2023]

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

TP53 mutations and RNA-binding protein MUSASHI-2 drive resistance to PRMT5-targeted therapy in B-cell lymphoma. [2023]

6. 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]

7. Netherlands pubmed.ncbi.nlm.nih.gov

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

8. England pubmed.ncbi.nlm.nih.gov

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