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

35 Participants Needed

Trial Summary

What is the purpose of this trial?

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 with metastatic pancreatic ductal adenocarcinoma (PDAC).

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.

What data supports the effectiveness of the drug combination including MEK/STAT3/PD-1 inhibitors for pancreatic cancer?

Research shows that combining MEK inhibitors like trametinib with other treatments can help fight pancreatic cancer by stopping cancer cell growth and making the immune system more effective. Additionally, ruxolitinib, which is part of the JAK/STAT pathway inhibitors, has been shown to extend the lives of some pancreatic cancer patients. ^{1 2 3 4 5}

What safety data exists for the treatment involving MEK/STAT3/PD-1 inhibitors for pancreatic cancer?

Ruxolitinib, a drug used in this treatment, has been associated with some safety concerns, including infections (like viral, fungal, and mycobacterial infections), musculoskeletal issues, blood clots, and skin cancers. These findings are based on data from a large number of reports in a global safety database. ^{2 5 6 7 8}

How is the drug combination of Retifanlimab, Ruxolitinib, and Trametinib unique for treating pancreatic cancer?

This drug combination is unique because it targets multiple pathways that contribute to resistance in pancreatic cancer, specifically the MEK and STAT3 pathways, which are often activated in response to each other's inhibition. By combining these inhibitors, the treatment can overcome resistance that typically limits the effectiveness of single-pathway therapies, potentially improving outcomes for patients with pancreatic cancer. ^{1 4 9 10 11}

Research Team

Peter J. Hosein

Principal Investigator

University of Miami

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

References

1. England 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. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment. [2022]

3. United States 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. [2023]

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

Combined MEK and STAT3 Inhibition Uncovers Stromal Plasticity by Enriching for Cancer-Associated Fibroblasts With Mesenchymal Stem Cell-Like Features to Overcome Immunotherapy Resistance in Pancreatic Cancer. [2023]

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

Ruxolitinib Benefits Some with Pancreatic Cancer. [2021]

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

Adverse events associated with JAK inhibitors in 126,815 reports from the WHO pharmacovigilance database. [2023]

7. New Zealand pubmed.ncbi.nlm.nih.gov

A Phase Ib study of ruxolitinib + gemcitabine ± nab-paclitaxel in patients with advanced solid tumors. [2022]

8. Canada pubmed.ncbi.nlm.nih.gov

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

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

Inverse Correlation of STAT3 and MEK Signaling Mediates Resistance to RAS Pathway Inhibition in Pancreatic Cancer. [2022]

10. United States 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. [2021]

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

Rational combination of MEK inhibitor and the STAT3 pathway modulator for the therapy in K-Ras mutated pancreatic and colon cancer cells. [2022]