Combined MEK, STAT3 and PD-1 Inhibition in Metastatic Pancreatic Ductal Adenocarcinoma

NCT05440942 | Completed Phase 1 DMC FDA Drug

• 1 other identifier: 20220171
• Study Type: interventional
• Target: 28
• Locations: 1 country
• Sites: 1

Brief Summary

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).

Conditions

Pancreatic Ductal Adenocarcinoma

Keywords

Pancreatic Cancer

Outcome Measures

Primary Outcomes (1)

• Recommended Phase 2 Dose (RP2D)

  The RP2D of combination therapy of trametinib, ruxolitinib and retifanlimab (TR\^2) therapy will be determined as the maximum tolerated dose of combination treatment (in mg) as assessed by treating physician using the NCI-CTCAE Version 5.0.

  Up to 6 months

Secondary Outcomes (3)

• Incidence of Treatment-Related Toxicity

  Up to 2 years

• Overall Survival (OS)

  Up to 3 years

• Percentage of Participants Achieving Overall Response

  Up to 2 years

Study Arms (3)

Part 1 Schedule A: TR^2 Dose Escalation/De-Escalation

EXPERIMENTAL

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.

Drug: Trametinib; Drug: Ruxolitinib; Drug: Retifanlimab

Part 1 Schedule B: TR^2 Alternate Schedule

EXPERIMENTAL

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.

Drug: Trametinib; Drug: Ruxolitinib; Drug: Retifanlimab

Part 2: TR^2 Expansion Cohort

EXPERIMENTAL

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.

Drug: Trametinib; Drug: Ruxolitinib; Drug: Retifanlimab

Interventions

Trametinib DRUG

Trametinib will be administered orally once daily via tablet.

Also known as: GSK1120212, TMT212-NXA, Mekinist

Part 1 Schedule A: TR^2 Dose Escalation/De-Escalation; Part 1 Schedule B: TR^2 Alternate Schedule; Part 2: TR^2 Expansion Cohort

Ruxolitinib DRUG

Ruxolitinib will be administered orally twice daily (BID) via tablet.

Also known as: INCB018424, INC424

Part 1 Schedule A: TR^2 Dose Escalation/De-Escalation; Part 1 Schedule B: TR^2 Alternate Schedule; Part 2: TR^2 Expansion Cohort

Retifanlimab DRUG

Retifanlimab will be administered intravenously (IV) on Day 8 of a 28-day cycle..

Also known as: INCMGA00012

Part 1 Schedule A: TR^2 Dose Escalation/De-Escalation; Part 1 Schedule B: TR^2 Alternate Schedule; Part 2: TR^2 Expansion Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed, metastatic pancreatic adenocarcinoma. Patients with adenosquamous carcinoma and mixed adenocarcinoma/neuroendocrine carcinoma (MANEC) of the pancreas are eligible, but pure neuroendocrine neoplasms are excluded.
• Progression of disease or intolerance to at least one standard line of chemotherapy.
• Patients who are candidate for an anti-PD-1 antibody due to Microsatellite instability -High (MSI-H) or tumor mutational burden (TMB)-high status must have been treated with this drug before being eligible for this trial.
• Prior treatment with an anti-PD(L)-1 antibody is allowed unless this therapy was stopped due to an immune-related adverse event.
• Patients who are candidate for a poly (ADP-ribose) polymerase (PARP) inhibitor due to a germline BRCA1/2 mutation must have been treated with this drug before being eligible for this trial.
• At least one tumor measurable by CT scan. Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>20 mm with conventional techniques or \>10 mm with spiral CT scan.
• Adult patients (≥ 18 years of age).
• Male or non-pregnant and non-lactating female. Men and women with intact reproductive potential must agree to use contraception as outlined in Section 4.9.
• Adequate biological parameters as demonstrated by the following blood counts at Screening (obtained ≤ 21 days prior to enrollment) and at Baseline-Day 0:
• Absolute neutrophil count (ANC) ≥ 1.0 × 10\^9 cells/L.
• Platelet count ≥ 100,000 cells/mm3 (100 × 10\^9 cells/L).
• Hemoglobin (Hgb) ≥ 9 g/dL.
• Adequate blood chemistry levels at Screening (obtained ≤ 21 days prior to enrollment) and at Baseline-Day 0:
• Aspartate aminotransferase (AST) - serum glutamic-oxaloacetic transaminase (SGOT); alanine transaminase (ALT) - serum glutamic-pyruvic transaminase (SGPT) ≤ 2.5 × upper limit of normal (ULN) range, unless liver metastases are present, then ≤ 5 × ULN is allowed.
• Total bilirubin ≤ 1.5 × ULN.

You may not qualify if:

• Patients with pure neuroendocrine neoplasms of the pancreas.
• Brain metastases.
• Uncontrolled ascites.
• Increase of ECOG to \> 1 between screening and enrollment.
• Corrected QT interval (QTcF) \> 450 msec.
• Active, uncontrolled bacterial, viral, or fungal infection(s) requiring systemic therapy.
• History of HIV and/or Hepatitis B or C infection.
• History of active autoimmune disease that, in the opinion of the Investigator, could deteriorate upon treatment with an immune checkpoint inhibitor.
• Concurrent use of systemic corticosteroids equivalent to or greater than prednisone 10 mg/day within two weeks of start of study therapy.
• Receipt of a live vaccine within 30 days prior to enrollment.
• Patients who are not up to date on FDA-approved coronavirus disease 2019 (COVID-19) vaccination series will be excluded.
• Any impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive small bowel resection).
• History of interstitial lung disease or pneumonitis.
• History of liver disease as follows:
• Cirrhosis

Sponsors & Collaborators

• Peter Hosein, MD: lead
• Incyte Corporation: collaborator
• Novartis Pharmaceuticals: collaborator
• University of Miami Sylvester Comprehensive Cancer Center: collaborator

Study Sites (1)

University of Miami

Miami, Florida, 33136, United States

Location

Related Links

• Laboratory evidence that led to the development of this clinical trial (currently under peer review)

MeSH Terms

Conditions

Pancreatic Neoplasms

Interventions

trametinib; ruxolitinib

Condition Hierarchy (Ancestors)

Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases

Study Officials

• Peter Hosein, MD

  University of Miami

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Clinical

Model Details: Phase 1 dose escalation/de-escalation and dose expansion design.

Study Record Dates

• First Submitted: June 27, 2022
• First Posted: July 1, 2022
• Study Start: January 19, 2023
• Primary Completion: May 30, 2025
• Study Completion: May 30, 2025
• Last Updated: June 5, 2025

Record last verified: 2025-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)