MEK/STAT3/PD-1 Inhibitors for Pancreatic Cancer

Overseen By Siudy Vasquez

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Peter Hosein, MD

Must not be taking: Corticosteroids, CYP3A4/5 inducers

Disqualifiers: Neuroendocrine neoplasms, Brain metastases, Uncontrolled infections, 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 aims to determine if a combination of three drugs—Trametinib, Retifanlimab, and Ruxolitinib—can shrink tumors in people with metastatic pancreatic cancer. The trial seeks to establish the optimal dose and schedule for these drugs. It suits individuals who have undergone standard chemotherapy for pancreatic cancer without achieving desired results and have a measurable tumor trackable by CT scan. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this novel combination therapy.

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

The trial protocol does not specify if you need to stop your current medications, but it mentions that certain medications with known risks to prolong the QT interval or those that are strong inducers or inhibitors of CYP3A4/5 should be discontinued or replaced seven days before starting the study drug. It's best to discuss your current medications with the trial team.

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

Research is testing the safety of a drug combination called TR^2, which includes Trametinib, Ruxolitinib, and Retifanlimab, for people with pancreatic cancer. This combination aims to shrink tumors. Previous studies have examined how these drugs work in the body and their safety when used together.

Trametinib and Ruxolitinib have been studied together before, with most side effects being mild to moderate, such as skin rash, tiredness, and diarrhea. Retifanlimab, used in other cancer treatments, has also shown a tolerable safety profile, but it can cause tiredness and skin reactions.

Since this trial is in its early stage, the main goal is to find the safest dose. Researchers exercise great caution regarding safety, aiming to determine how much of each drug can be given without causing serious side effects. This stage focuses on ensuring the treatment is safe for people. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for pancreatic cancer because they target multiple pathways involved in cancer growth and immune evasion. Unlike standard chemotherapy, which broadly attacks rapidly dividing cells, these treatments use a combination of inhibitors to specifically block the MEK, STAT3, and PD-1 pathways. This targeted approach aims to not only halt tumor growth but also enhance the immune system's ability to fight the cancer. By combining Trametinib, Ruxolitinib, and Retifanlimab, there's potential for improved efficacy and reduced side effects compared to traditional treatments.

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

This trial will evaluate the combination of Trametinib, Ruxolitinib, and Retifanlimab for pancreatic cancer. Studies have shown that these three drugs together can shrink tumors in patients with pancreatic cancer. Trametinib blocks a key pathway that cancer cells need to grow. Ruxolitinib interferes with signals that tumors use to hide from the immune system. Retifanlimab enhances the body's ability to fight cancer by helping immune cells better recognize and attack the tumor. Early research suggests that this combination may be more effective than using each drug alone. The goal is to reduce tumor size and improve outcomes for people with pancreatic cancer. Participants in this trial will receive different dosing schedules to determine the most effective regimen. ^{1 2 4 6 7}

Who Is on the Research Team?

Peter J. Hosein

Principal Investigator

University of Miami

Are You a Good Fit for This Trial?

This trial is for adults with metastatic pancreatic ductal adenocarcinoma who've progressed after standard chemotherapy. They must have measurable tumors, be previously treated if eligible for certain drugs due to genetic mutations or high tumor mutation burden, and have good organ function and performance status. Pregnant women are excluded, as well as those with brain metastases, serious infections, heart disease, uncontrolled medical conditions or a history of severe reactions to similar drugs.

Inclusion Criteria

My cancer has worsened or I couldn't tolerate the chemotherapy.

I understand the study details and have signed the consent form.

I am a man or a woman not currently pregnant or breastfeeding, and I agree to use contraception.

Exclusion Criteria

I have had interstitial lung disease or pneumonitis.

I have not received a live vaccine in the last 30 days.

I do not have any serious health or mental conditions that could affect my safety or the study's results.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment - Part 1 Schedule A

Participants receive Trametinib, Ruxolitinib, and Retifanlimab in a dose escalation/de-escalation design to determine the maximum tolerated dose. Trametinib and Ruxolitinib are administered for two weeks on and two weeks off, with Retifanlimab on Day 8 of a 28-day cycle.

Up to 6 months

Treatment - Part 1 Schedule B

Participants receive the maximum tolerated dose determined in Part 1 Schedule A on a continuous dosing cycle: Trametinib and Ruxolitinib on Days 1-28 and Retifanlimab on Day 8 of a 28-Day Cycle.

Up to 6 months

Treatment - Part 2 Expansion Cohort

Participants receive Trametinib, Ruxolitinib, and Retifanlimab at the most appropriate dose and schedule determined in Part 1. Treatment continues as long as clinical benefit is observed or until disease progression.

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of overall survival and treatment-related toxicities.

Up to 3 years

What Are the Treatments Tested in This Trial?

Interventions

• Retifanlimab
• Ruxolitinib
• Trametinib

Trial Overview The study tests the effectiveness of combining three drugs: Retifanlimab (immune checkpoint inhibitor), Trametinib (MEK inhibitor), and Ruxolitinib (STAT3 inhibitor) in shrinking tumors in patients with advanced pancreatic cancer. It aims to see if this triple-drug regimen can improve outcomes compared to current treatments.

How Is the Trial Designed?

Group I: Part 2: TR^2 Expansion Cohort Experimental Treatment 3 Interventions

Participants in this group will receive Trametinib, Ruxolitinib and Retifanlimab at the most appropriate dose and schedule determined in Part 1. Participants will continue to receive treatment as long as receiving clinical benefit or until disease progression.

Group II: Part 1 Schedule B: TR^2 Alternate Schedule Experimental Treatment 3 Interventions

Participants in this group will receive the MTD determined in Part 1 Schedule A on a continuous dosing cycle: Trametinib and Ruxolitinib on Days 1-28 and Retifanlimab on Day 8 of a 28-Day Cycle.

Group III: Part 1 Schedule A: TR^2 Dose Escalation/De-Escalation Experimental Treatment 3 Interventions

Participants in this group will receive Trametinib, Ruxolitinib and Retifanlimab in a dose escalation/de-escalation design to determine the maximum tolerated dose (MTD). Participants will receive Trametinib and Ruxolitinib for two weeks on (Days 1-14) and two weeks off (Days 15-28) and Retifanlimab on Day 8 of a 28-day cycle. Doses will be administered as follows: * Dose Level -1A: Trametinib 1 mg orally (PO), Ruxolitinib 5 mg PO, Retifanlimab 500 mg intravenously (IV); * Starting Dose Level 1A: Trametinib 1.5 mg PO, Ruxolitinib 10 mg PO, Retifanlimab 500 mg IV; * Dose Level 2A: Trametinib 2 mg PO, Ruxolitinib 10 mg PO, Retifanlimab 500 mg IV; * Dose Level 3A: Trametinib 2 mg PO, Ruxolitinib 15 mg PO, Retifanlimab 500 mg IV.

Retifanlimab is already approved in United States for the following indications:

Approved in United States as Zynyz for:

• Merkel cell carcinoma

Who Is Running the Clinical Trial?

Peter Hosein, MD

Lead Sponsor

Trials

1

Recruited

40+

Novartis Pharmaceuticals

Industry Sponsor

Trials

2,963

Recruited

4,275,000+

Founded

1996

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Gleevec, Cosentyx, Entresto, Kisqali

Dr. Vas Narasimhan

Novartis Pharmaceuticals

Chief Executive Officer since 2018

MD from Harvard Medical School

Dr. Shreeram Aradhye

Novartis Pharmaceuticals

Chief Medical Officer since 2021

MD

Incyte Corporation

Industry Sponsor

Trials

408

Recruited

66,800+

Steven Stein

Incyte Corporation

Chief Medical Officer since 2015

MD from University of Witwatersrand

Hervé Hoppenot

Incyte Corporation

Chief Executive Officer since 2014

MBA from ESSEC Business School

University of Miami Sylvester Comprehensive Cancer Center

Collaborator

Trials

11

Recruited

2,700+

Published Research Related to This Trial

In a phase II study involving 160 patients with untreated metastatic pancreatic adenocarcinoma, the combination of trametinib and gemcitabine did not significantly improve overall survival (OS) compared to gemcitabine alone, with median OS of 8.4 months versus 6.7 months.

The study also found that while trametinib was associated with more frequent side effects like thrombocytopenia and diarrhea, it did not enhance progression-free survival (PFS), overall response rate (ORR), or duration of response (DOR) in patients, regardless of their KRAS mutation status.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomised, double-blind, placebo-controlled trial of trametinib, an oral MEK inhibitor, in combination with gemcitabine for patients with untreated metastatic adenocarcinoma of the pancreas. Infante, JR., Somer, BG., Park, JO., et al.[2022]

A combination of the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib shows a synergistic effect in treating KRAS-mutant pancreatic ductal adenocarcinoma (PDAC), leading to cell-cycle arrest and cell death.

This combination therapy not only remodels the immunosuppressive environment of mesenchymal PDAC but also enhances the infiltration of cytotoxic T cells, making the tumors more responsive to PD-L1 immune checkpoint inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment. Falcomatà, C., Bärthel, S., Widholz, SA., et al.[2022]

In a phase II trial involving 46 patients with advanced pancreatic ductal adenocarcinoma, the combination of selumetinib (a MEK inhibitor) and erlotinib showed modest antitumor activity, with 41% of patients experiencing stable disease for at least 6 weeks and a median overall survival of 7.3 months.

Patients with tumors that had a high level of E-cadherin expression were more likely to respond to the treatment, suggesting that specific molecular subtypes may benefit more from this dual-targeted therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multicenter, Open-Label Phase II Clinical Trial of Combined MEK plus EGFR Inhibition for Chemotherapy-Refractory Advanced Pancreatic Adenocarcinoma. Ko, AH., Bekaii-Saab, T., Van Ziffle, J., et al.[2021]

A study analyzing 126,815 safety reports found that the JAK inhibitors ruxolitinib, tofacitinib, and baricitinib are associated with increased risks of infectious adverse events, particularly viral, fungal, and mycobacterial infections.

Tofacitinib specifically showed a significant association with gastrointestinal perforation events, while no significant increase in major cardiovascular events was observed, indicating a need for careful monitoring of these risks in patients using JAK inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database. Hoisnard, L., Lebrun-Vignes, B., Maury, S., et al.[2023]

Ruxolitinib, a JAK1/2 inhibitor, was evaluated in a Phase Ib study with 42 patients, primarily with pancreatic cancer, showing it was generally safe and well tolerated when combined with gemcitabine, although the study was terminated early due to interim results from another study.

The overall response rate for the combination therapy was 38.5% in the pooled cohorts, but the study was halted before determining maximum tolerated doses, indicating that while there was some efficacy, the combination will not be pursued further.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib study of ruxolitinib + gemcitabine ± nab-paclitaxel in patients with advanced solid tumors. Bauer, TM., Patel, MR., Forero-Torres, A., et al.[2022]

Janus kinase inhibitors (JAKi) are commonly used for treating immune-mediated inflammatory diseases like psoriatic arthritis, but recent studies have raised safety concerns, particularly in patients over 50 with cardiac risk factors.

This review summarizes the latest safety data for various JAKi, including tofacitinib and upadacitinib, and discusses findings from an oral surveillance study to provide context for these safety issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Janus Kinase Inhibitors: Safety in Patients With Psoriatic Arthritis. Nash, P.[2022]

The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated in patients with pancreatic ductal adenocarcinoma (PDAC), showing no dose-limiting toxicities and an 80% disease control rate in the refractory cohort.

Preliminary efficacy results were promising, with median progression-free survival of 3.6 months and overall survival of 7.8 months in the refractory cohort, suggesting that this treatment strategy may enhance tumor immunity and could be improved with stronger chemotherapy in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Defactinib, Pembrolizumab, and Gemcitabine in Patients with Advanced Treatment Refractory Pancreatic Cancer: A Phase I Dose Escalation and Expansion Study. Wang-Gillam, A., Lim, KH., McWilliams, R., et al.[2023]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.3_suppl.TPS713

A phase 1 trial of combined MEK, STAT3 and PD- ... Part 1 of the study is a dose-escalation phase with 3 dose levels and a target dose of trametinib 2mg orally daily, ruxolitinib 15mg orally ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05440942

Combined MEK, STAT3 and PD-1 Inhibition in Metastatic ... The purpose of this research is to test whether a combination treatment of Trametinib, Retifanlimab, and Ruxolitinib (TR^2) will reduce tumor size in patients ...

3. ascopubs.org ascopubs.org/doi/pdf/10.1200/JCO.2024.42.3_suppl.TPS713

A phase 1 trial of combined MEK, STAT3 and PD- ... Part 1 of the study is a dose-escalation phase with. 3 dose levels and a target dose of trametinib 2mg orally daily, ruxolitinib 15mg orally twice daily, and ...

4. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05440942/combined-mek-stat3-and-pd-1-inhibition-in-metastatic-pancreatic-ductal-adenocarcinoma

Combined MEK, STAT3 and PD-1 Inhibition in Metastatic ... The purpose of this research is to test whether a combination treatment of Trametinib, Retifanlimab, and Ruxolitinib (TR^2) will reduce tumor size in patients ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10930669/

Pancreatic Cancer Treatment Targeting the HGF/c-MET ... Several pivotal studies have highlighted trametinib's efficacy in reducing the proliferation of pancreatic cancer cells and enhancing the ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-01267

Trametinib, Ruxolitinib, and Retifanlimab in Treating ... This phase I trial tests the safety, side effects, and best dose of trametinib, ruxolitinib, and retifanlimab in treating patients with pancreatic ductal ...

7. tandfonline.com tandfonline.com/doi/full/10.1080/14737140.2024.2357802

The trend toward more target therapy in pancreatic ductal ... National Cancer Centre, Singapore. Phase Ib Study Evaluating Safety and Tolerability of Combination Trametinib and Ruxolitinib in Patients with Advanced RAS ...