AMG 193 + Other Therapies for Pancreatic Cancer

Recruiting at 72 trial locations

Overseen By Amgen Call Center

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Amgen

Must not be taking: MAT2A inhibitors, PRMT5 inhibitors

Disqualifiers: Radiation therapy, Major surgery, Transplantation, others

No Placebo Group

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 gastrointestinal, biliary tract, or pancreatic cancers. 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 gastrointestinal, biliary tract, or pancreatic cancers.

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.

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

Research shows that targeting PRMT5, which AMG 193 inhibits, can slow down the growth and spread of pancreatic cancer cells. Studies have found that PRMT5 inhibitors can be particularly effective in certain subtypes of pancreatic cancer, suggesting potential benefits of AMG 193 in treating this disease. ^{1 2 3 4 5}

Is AMG 193 safe for humans?

In a phase I trial, AMG 193 was tested on 39 patients with advanced solid tumors, and some patients showed partial responses, indicating it was generally tolerated, but specific safety data was not detailed in the available research. ^{3 4 6 7 8}

What makes the drug AMG 193 unique for treating pancreatic cancer?

AMG 193 is unique because it targets the PRMT5 enzyme, which is involved in cancer progression, particularly in pancreatic cancers with specific genetic deletions (MTAP-deleted tumors). This drug works by inhibiting PRMT5, potentially offering a new treatment option for patients with these specific tumor types. ^{1 3 4 8 9}

Research Team

MD

Principal Investigator

Amgen

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• AMG 193 (Anti-tumor antibiotic)

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.

Participant Groups

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

Part 1: Participants with MTAP-deleted PDAC will receive escalating 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 II: Subprotocol B: PDAC Arm B Experimental Treatment 2 Interventions

Part 1: Participants with MTAP-deleted PDAC will receive escalating 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

Findings from Research

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]

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]

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]

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]

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]

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]

References

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

Pancreatic cancer organoids recapitulate disease and allow personalized drug screening. [2023]

2. England 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. [2023]

3. United States 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. [2022]

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

Epigenetic drug screening defines a PRMT5 inhibitor-sensitive pancreatic cancer subtype. [2023]

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

PRMT5 promotes epithelial-mesenchymal transition via EGFR-β-catenin axis in pancreatic cancer cells. [2023]

6. England pubmed.ncbi.nlm.nih.gov

PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma. [2022]

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

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

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

AMG 193 Effective in Multiple Tumor Types. [2023]

9. 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]