AMG 193 + Other Therapies for Pancreatic Cancer

(MTAPESTRY 103 Trial)

Recruiting at 86 trial locations

Overseen By Amgen Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Amgen

Must not be taking: MAT2A inhibitors, PRMT5 inhibitors

Disqualifiers: Radiation therapy, Major surgery, Transplantation, 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 2 years

350 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment approach for individuals with pancreatic cancer that has spread or cannot be surgically removed. It evaluates the effectiveness of the drug AMG 193 (a PRMT5 inhibitor) when combined with other cancer therapies, aiming to determine the safest and most effective dose. Individuals with pancreatic cancer and a specific genetic change (MTAP deletion) who have experienced cancer spreading or growing might be suitable candidates. The trial is divided into parts, testing different treatment combinations to identify the most effective one. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, and participants could be among the first to receive this new drug.

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

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

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

Research has shown that AMG 193, a potential cancer treatment, has a promising safety record when used with other therapies. When combined with gemcitabine and nab-paclitaxel, studies found that AMG 193 specifically targets cancer cells and proved effective in early trials for various cancers, including pancreatic cancer.

Similarly, when used with mFOLFIRINOX—a mix of cancer drugs—AMG 193 maintained a good safety record. Early data suggests it is generally well-tolerated and has shown positive effects in patients with certain tumors.

For the combination of AMG 193 with RMC-6236, early findings indicate a favorable safety profile, meaning it did not cause significant harmful side effects in patients tested so far. It also showed promising results in reducing tumor size in some cases.

Since the current trial is in an early phase, it mainly focuses on safety and dosage. This phase is crucial to confirm the treatment's safety before further testing. Overall, existing data suggests that AMG 193 is well-tolerated in different combinations, but ongoing trials will provide more detailed insights. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they target pancreatic ductal adenocarcinoma (PDAC) with a new approach. AMG 193 is being tested in combination with both gemcitabine and nab-paclitaxel, as well as with mFOLFIRINOX, which are standard chemotherapy regimens for PDAC. The novelty lies in AMG 193's potential to specifically target tumors with MTAP deletions, a genetic feature found in some PDAC cases, potentially enhancing the effectiveness of these combinations. Additionally, AMG 193 is being explored alongside RMC-6236, which could further refine its action against specific tumor types. This targeted strategy could offer more personalized treatment options and improve outcomes for patients with this aggressive cancer.

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

Research shows that AMG 193 targets a specific enzyme called PRMT5, linked to several cancers, including pancreatic cancer. Studies have shown that AMG 193 works in tumors missing a gene called MTAP. This is significant because about 22% of pancreatic cancer cases lack this gene. In this trial, one group of participants will receive AMG 193 combined with the chemotherapy drugs gemcitabine and nab-paclitaxel, which has shown promise in fighting these specific cancer cells. Another group will test AMG 193 in combination with mFOLFIRINOX, a mix of four chemotherapy drugs. Additionally, researchers are evaluating AMG 193 with RMC-6236 in a separate group, and early studies suggest it could be effective. These combinations aim to offer new hope for treating pancreatic cancer with specific genetic features. ^{1 2 3 4 6}

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 gastrointestinal, biliary tract, or pancreatic cancers that have a specific genetic deletion (MTAP-deletion). Participants should be able to receive chemotherapy and must not have had certain treatments before. Full eligibility depends on additional criteria not provided here.

Inclusion Criteria

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

I can provide a sample of my tumor for the study, either from previous surgery or through a biopsy.

My pancreatic cancer is advanced and cannot be removed by surgery.

Exclusion Criteria

Subprotocol B: History of solid organ transplantation

Subprotocol B: Cardiovascular and pulmonary exclusion criteria as defined in the protocol

I have not had major surgery within the last 28 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive escalating doses of AMG 193 in combination with gemcitabine and nab-paclitaxel or mFOLFIRINOX

Up to approximately 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4-8 weeks

What Are the Treatments Tested in This Trial?

Interventions

• AMG 193

Trial Overview The study tests the highest dose of AMG 193 that's safe when given with other cancer therapies like Cisplatin, Gemcitabine, Modified FOLFIRINOX, Nab-paclitaxel, and Pembrolizumab in patients with MTAP-deleted cancers.

How Is the Trial Designed?

Group I: Subprotocol C: Dose Exploration Experimental Treatment 2 Interventions

Part 1: Participants with MTAP-deleted PDAC will receive oral doses of AMG 193 and RMC-6236.

Group II: Subprotocol C: Dose Expansion Experimental Treatment 2 Interventions

Part 2: Participants with MTAP-deleted PDAC will receive oral doses of AMG 193 andRMC-6236.

Group III: Subprotocol B: Pancreatic Ductal Adenocarcinoma (PDAC) Arm A Experimental Treatment 3 Interventions

Part 1: Participants with MTAP-deleted PDAC will receive doses of AMG 193 orally in combination with gemcitabine and nab-paclitaxel IV. Part 2: Participants with MTAP-deleted PDAC will receive the recommended dose of AMG 193 in combination with gemcitabine and nab-paclitaxel.

Group IV: Subprotocol B: PDAC Arm B Experimental Treatment 2 Interventions

Part 1: Participants with MTAP-deleted PDAC will receive doses of AMG 193 orally in combination with mFOLFIRINOX (irinotecan, fluorouracil, leucovorin calcium, oxaliplatin) IV. Part 2: Participants with MTAP-deleted PDAC will receive the recommended dose of AMG 193 in combination with mFOLFIRINOX.

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

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]

In pancreatic ductal adenocarcinoma (PDAC), targeting protein arginine N-methyltransferase 5 (PRMT5) shows promise, especially in tumors with high MYC expression, indicating a potential new therapeutic approach.

PRMT5 inhibitors not only induce DNA damage and cell cycle arrest in PDAC cells but also lead to increased cell death in MYC-deregulated tumors, suggesting that these inhibitors could be effective in specific subtypes of PDAC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epigenetic drug screening defines a PRMT5 inhibitor-sensitive pancreatic cancer subtype. Orben, F., Lankes, K., Schneeweis, C., et al.[2023]

PRMT5 is found to be up-regulated in pancreatic cancer, promoting cell proliferation, migration, and invasion, which contributes to tumor growth.

Silencing PRMT5 enhances the expression of the epithelial marker E-cadherin while reducing mesenchymal markers, indicating that PRMT5 facilitates epithelial-mesenchymal transition (EMT) through the EGFR/AKT/β-catenin signaling pathway, suggesting it could be a target for pancreatic cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PRMT5 promotes epithelial-mesenchymal transition via EGFR-β-catenin axis in pancreatic cancer cells. Ge, L., Wang, H., Xu, X., 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]

Inhibition of PRMT5 using the selective inhibitor T1-44, when combined with the TGF-β1 signaling inhibitor Vactosertib, significantly reduced tumor size and improved long-term survival in pancreatic cancer models, indicating a promising therapeutic strategy.

The combination treatment altered gene expression related to cancer progression, notably increasing the expression of the tumor suppressor Btg2, which inhibited cell migration and promoted cancer cell death, highlighting the potential mechanism of action for this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination treatment of T1-44, a PRMT5 inhibitor with Vactosertib, an inhibitor of TGF-β signaling, inhibits invasion and prolongs survival in a mouse model of pancreatic tumors. Hong, E., Barczak, W., Park, S., et al.[2023]

PRMT5 is highly expressed in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC), and its overexpression promotes cancer progression, making it a potential therapeutic target.

The newly discovered compound PR5-LL-CM01 effectively inhibits PRMT5 and shows greater anti-tumor efficacy than the existing PRMT5 inhibitor EPZ015666, suggesting it could be a promising candidate for future drug development against these challenging cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adapting AlphaLISA high throughput screen to discover a novel small-molecule inhibitor targeting protein arginine methyltransferase 5 in pancreatic and colorectal cancers. Prabhu, L., Wei, H., Chen, L., et al.[2022]

Researchers developed 30 patient-derived organoid lines from pancreatic and distal bile duct tumors, which accurately mimic the tumor's structure and genetic features, providing a valuable model for studying pancreatic cancer.

In testing 76 therapeutic agents, the PRMT5 inhibitor EZP015556 was found to be effective not only in MTAP-negative tumors but also in some MTAP-positive tumors, highlighting the potential for personalized cancer treatments based on individual tumor characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pancreatic cancer organoids recapitulate disease and allow personalized drug screening. Driehuis, E., van Hoeck, A., Moore, K., et al.[2023]

The study identifies protein arginine methyltransferase 1 (PRMT1) as a crucial factor for the growth and maintenance of pancreatic ductal adenocarcinoma (PDAC), based on an RNAi-based functional genomics approach using patient-derived models.

Inhibition of PRMT1 disrupts RNA metabolism processes, leading to genomic instability and reduced tumor growth, suggesting that targeting PRMT1 could be a promising strategy for developing new therapies for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma. Giuliani, V., Miller, MA., Liu, CY., et al.[2022]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06360354

NCT06360354 | A Study Evaluating AMG 193 in ... The study aims to determine maximum tolerated dose (MTD) or recommended combination dose of the MTA-cooperative PRMT5 inhibitor AMG 193 administered in ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11726016/

AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor ... In this study, we demonstrate the selectivity and activity of AMG 193 in a variety of MTAP-deleted tumor indications, including pancreatic, lung, and lymphoma.

3. amgentrials.com amgentrials.com/study/?id=20230223

A Study Evaluating AMG 193 in Combination With other ... The study aims to determine maximum tolerated dose (MTD) or recommended combination dose of the MTA-cooperative PRMT5 inhibitor AMG 193 administered in ...

4. mskcc.org mskcc.org/cancer-care/clinical-trials/24-248

A Phase 1b Study of AMG 193 Plus mFOLFIRINOX or With ... Researchers want to learn if AMG 193 in combination with standard treatment is safe for people with advanced pancreatic cancer.

5. aacrjournals.org aacrjournals.org/cancerdiscovery/article-pdf/doi/10.1158/2159-8290.CD-24-0887/3503088/cd-24-0887.pdf

1 AMG 193, a Clinical Stage MTA-Cooperative PRMT5 ... pancreatectomy, splenectomy and adjuvant FOLFIRINOX, gemcitabine/nab-paclitaxel ... pancreatic ductal adenocarcinoma; PRMT5, protein arginine methyltransferase 5; ...

6. ctv.veeva.com ctv.veeva.com/study/a-study-evaluating-amg-193-in-combination-with-other-therapies-in-participants-with-advanced-gastroi

A Study Evaluating AMG 193 in Combination With Other ... The study also aims to determine the safety profile of AMG 193 administered in combination with other therapies in adult participants with ...