AMG 193 + IDE397 for Solid Cancers

Not currently recruiting at 34 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combining two drugs, AMG 193 (a PRMT5 inhibitor) and IDE397 (a MAT2A inhibitor), to determine their effectiveness against certain advanced cancers. Researchers aim to find the safest dose and assess whether the treatment can shrink tumors, particularly in individuals with advanced non-small-cell lung cancer (NSCLC) that have a specific genetic trait called MTAP-null. This trial suits those whose cancer has progressed after 1 or 2 other treatments and who have a tumor that current options cannot cure. Participants must be able to take the treatment orally and track their doses. As a Phase 1, Phase 2 trial, this study focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking cancer research.

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.

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

Research shows that AMG 193, when tested alone, has a good safety record and was generally well-tolerated by patients. Importantly, no serious issues, such as a drop in blood cells, occurred, indicating its safety in humans.

Researchers are studying IDE397 in combination with AMG 193 to treat certain solid tumors. The current trial is in its early stages, focusing on safety and determining the right dose. Although the treatment appears promising, more information is needed to confirm its safety.

Overall, both treatments show positive early results. However, as this is a new combination, the study is still assessing its safety when used together. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike traditional treatments for solid cancers, which often involve chemotherapy or radiation, AMG 193 and IDE397 are targeted therapies that aim to disrupt specific cancer cell processes. AMG 193 works by inhibiting a protein called PRMT5, which is essential for cancer cell survival, while IDE397 targets MAT2A, another key enzyme in cancer cell growth. This dual-targeted approach is what excites researchers, as it could potentially lead to more effective treatments with fewer side effects compared to existing options.

What evidence suggests that this trial's treatments could be effective for MTAP-null solid tumors?

Research shows that combining the drugs AMG 193 and IDE397 may help treat certain solid tumors lacking the MTAP gene. Earlier studies have shown promising results in patients with these genetic changes. In this trial, participants will receive AMG 193 and IDE397 together to assess their effectiveness. These treatments target specific pathways that aid tumor growth. Lab tests have demonstrated strong and lasting effects against tumors when using these drugs together. This combination is currently being tested for its effectiveness against MTAP-null Non-Small-Cell Lung Cancer (NSCLC). The ongoing research aims to confirm these early positive results. ^{1 4 5 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 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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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.

media.ideayabio.com

media.ideayabio.com/2023-05-22-IDEAYA-Announces-IND-Clearance-Enabling-Phase-1-2-Clinical-Trial-for-Combination-of-IDE397-and-AMG-193-in-MTAP-Deletion-Solid-Tumors

News Releases

IDE397 (MAT2A) and AMG 193 (PRMT5) combination being evaluated in an Amgen-sponsored Phase 1/2 clinical trial in MTAP-deletion solid tumors ...

3.

pubmed.ncbi.nlm.nih.gov

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

First-in-human study of AMG 193, an MTA-cooperative ...

Encouraging antitumor activity across a variety of MTAP-deleted solid tumors was observed based on objective response rate and circulating tumor ...

4.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05975073

NCT05975073 | A Phase 1/2 Study of AMG 193 in ...

The main aims of this study are to evaluate the safety and tolerability, and to determine the maximum tolerated dose (MTD) or the recommended combination dose.

5.

ir.ideayabio.com

ir.ideayabio.com/2023-06-12-IDEAYA-Announces-Selection-of-IDE397-Phase-2-Monotherapy-Expansion-Dose-For-Global-Enrollment-Targeting-High-Priority-MTAP-Deletion-Solid-Tumor-Types

IDEAYA Announces Selection of IDE397 Phase 2 ...

IDEAYA and Amgen co-presented preclinical data at AACR 2023 demonstrating deep and durable anti-tumor efficacy for the IDE397 and AMG 193 ...

6.

ir.ideayabio.com

ir.ideayabio.com/2023-05-22-IDEAYA-Announces-IND-Clearance-Enabling-Phase-1-2-Clinical-Trial-for-Combination-of-IDE397-and-AMG-193-in-MTAP-Deletion-Solid-Tumors

News Releases

The proposed clinical study may proceed to evaluate IDE397 in combination with AMG 193 in solid tumors having MTAP deletion.

7.

onclive.com

onclive.com/view/amg-193-shows-preliminary-clinical-activity-in-mtap-deleted-solid-tumors

AMG 193 Shows Preliminary Clinical Activity in MTAP ...

AMG 193, an MTA-cooperative PRMT5 inhibitor, demonstrated responses and an acceptable safety profile across patients with MTAP-deleted solid tumors.