Gemcitabine and Leflunomide in Patients With Advanced Unresectable Pancreatic Cancer

A Phase 1b Study of Gemcitabine and Leflunomide in Patients With Unresectable Pancreatic Cancer

This phase Ib trial tests the safety, side effects, and best dose of leflunomide in combination with gemcitabine in treating patients with pancreatic cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced) and cannot be removed by surgery (unresectable). Improving the effectiveness of gemcitabine without increasing side effects could lead to a greater impact for pancreatic cancer patients' survival and quality of life. Gemcitabine is commonly used as a first-line chemotherapy treatment for pancreatic cancer. Leflunomide is a drug approved for use against rheumatoid arthritis that is being looked at as a cancer treatment option. It has shown promising results when combined with gemcitabine. Giving gemcitabine in combination with leflunomide may be safe and effective in treating patients with advanced unresectable pancreatic cancer.

Study Overview

• Status: Recruiting
• Conditions: Stage III Pancreatic Cancer AJCC v8; Stage IV Pancreatic Cancer AJCC v8; Advanced Pancreatic Adenocarcinoma; Unresectable Pancreatic Ductal Adenocarcinoma
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Drug: Gemcitabine; Procedure: Computed Tomography; Procedure: Biospecimen Collection; Drug: Leflunomide; Drug: Cholestyramine; Procedure: Diagnostic Imaging

Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate the safety and tolerability of gemcitabine in combination with leflunomide and determine the recommended Phase 2 dose (RP2D) of the combination.

SECONDARY OBJECTIVES:

I. To evaluate the progression-free (PFS) and overall survival (OS). II. To evaluate the overall response rate (ORR), including confirmed and unconfirmed, complete and partial response and stable disease.

III. To describe quality of life utilizing the Functional Assessment of Cancer Therapy: General (FACT-G) questionnaire.

EXPLORATORY OBJECTIVES:

I. To describe the pharmacokinetic profile of leflunomide when given in combination with gemcitabine.

II. To examine the relationship between pharmacokinetics and disease progression.

OUTLINE:

Patients receive gemcitabine intravenously (IV) over 30 minutes on days 1, 8, and 15 of each cycle and leflunomide orally (PO) once daily (QD) on days -3 to -1 prior to cycle 1 and days 1-28 of each cycle thereafter. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive cholestyramine PO three times a day (TID) for 11 days at the end of treatment in the absence of unacceptable toxicity. Patients also undergo computed tomography (CT), magnetic resonance imaging (MRI), or other imaging scans as clinically indicated throughout the study, as well as blood sample collection on study and during follow up.

After completion of study treatment, patients are followed up at 30 days then up to 1 year.

• Study Type: Interventional
• Enrollment (Estimated): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • Recruiting
      • City of Hope Medical Center
      • Contact: Vincent Chung; Phone Number: 626-218-9200; Email: vchung@coh.org
      • Principal Investigator: Vincent Chung

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative.

  • Adult patients lacking capacity to consent may participate if they have a caretaker that could ensure oral medication compliance.

• Agreement to allow the use of archival tissue from diagnostic tumor biopsies.

  • If unavailable, exceptions may be granted with study principal investigator (PI) approval.
• Age: ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) ≤ 1.
• Subjects must have histologically or cytologically confirmed diagnosis of advanced unresectable pancreatic ductal adenocarcinoma (PDA).
• Measurable or evaluable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1
• Potential patients must have plans of receiving single agent gemcitabine.
• Fully recovered from the acute toxic effects (except alopecia or neuropathy) to ≤ grade 1 to prior anti-cancer therapy.
• Without bone marrow involvement: Absolute neutrophil count (ANC) ≥ 1,500/mm^3 NOTE: Growth factor is not permitted within 14 days of ANC assessment unless cytopenia is secondary to disease involvement.
• Without bone marrow involvement: Platelets ≥ 100,000/mm^3 NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement.
• Hemoglobin ≥ 9g/dL NOTE: Red blood cell transfusions are not permitted within 14 days of hemoglobin assessment unless cytopenia is secondary to disease involvement.
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 x ULN (unless has Gilbert's disease total bilirubin ≤ 3 x ULN)
• Aspartate aminotransferase (AST) ≤ 1.5 x ULN OR if liver metastases ≤ 3 x ULN
• Alanine aminotransferase (ALT) ≤ 1.5 x ULN OR if liver metastases ≤ 2 x ULN
• Creatinine ≤ 1.5 x ULN OR creatinine clearance (Cockcroft Gault) of ≥ 50 mL/min for participants with a creatinine level of > 1.5 x ULN.
• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.

• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 months after the last dose of gemcitabine therapy for women and at least 3 months after the last dose of gemcitabine therapy for men, and/or undergo drug elimination of leflunomide at end of treatment until leflunomide is undetectable in the plasma.

  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only).

Exclusion Criteria:

• Chemotherapy, radiation therapy, biological therapy, immunotherapy within 21 days prior to day 1 of protocol therapy.
• Drugs metabolized by CYP2C8, CYP1A2, BCRP, OATP1B1/B3, and OAT3 transporters within 21 days prior to day 1 of protocol therapy.
• Herbal medications (excluding cannabidiol [CBD]).
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent.
• Issues with tolerating oral medication (e.g. inability to swallow pills, malabsorption issues, ongoing nausea or vomiting).
• Positive for tuberculosis or latent tuberculosis (TB).
• Active diarrhea.
• Clinically significant uncontrolled illness.
• Active infection requiring antibiotics.
• Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection. (*If seropositive for HIV, HCV or HBV, nucleic acid quantitation must be performed. Viral load must be undetectable.)
• Diagnosis of Gilbert's disease.
• Prior malignancy other than carcinoma in situ of the cervix, or nonmelanoma skin cancer, unless that prior malignancy was diagnosed and definitively treated 5 or more years prior to study entry with no subsequent evidence of recurrence. Patients with a history of low grade (Gleason score ≤ 6 = Gleason group 1) localized prostate cancer will be eligible even if diagnosed less than 5 years prior to study entry. Other malignancies with low probability of recurrence may be allowed with PI approval.
• Females only: Pregnant or breastfeeding.
• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures.
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (gemcitabine, leflunomide); Patients receive gemcitabine IV over 30 minutes on days 1, 8, and 15 of each cycle and leflunomide PO QD on days -3 to -1 prior to cycle 1 and days 1-28 of each cycle thereafter. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also receive cholestyramine PO TID for 11 days at the end of treatment in the absence of unacceptable toxicity. Patients also undergo CT, MRI, or other imaging scans as clinically indicated throughout the study, as well as blood sample collection on study and during follow up.

Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; Magnetic Resonance Imaging (MRI); sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Drug: Gemcitabine; Given IV; Other Names: dFdCyd; dFdC; Difluorodeoxycytidine; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Computerized Tomography (CT) scan; Procedure: Biospecimen Collection; Undergo blood sample collection; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Drug: Leflunomide; Given PO; Other Names: Arava; SU101; Drug: Cholestyramine; Given PO; Other Names: Questran; Cholybar; Colestyramine; Duolite AP143 Resin; Questran Light; Procedure: Diagnostic Imaging; Undergo imaging scans; Other Names: Medical Imaging

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicities (DLTs)	Toxicities will be graded according to Common Terminology Criteria for Adverse Events version 5.0.	Up to 28 days (cycle 1)
Incidence of adverse events	Toxicities will be graded according to Common Terminology Criteria for Adverse Events version 5.0.	Up to 30 days after completion of study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival (PFS)	PFS will be estimated using the Kaplan-Meier product-limit method.	From start of protocol treatment until progression or death, and if neither event occur, the patient is at the time of last contact, assessed up to 1 year after completion of study treatment
Overall survival (OS)	OS will be estimated using the Kaplan-Meier product limit method.	From start of protocol treatment until death, and if the patient is alive, the patient is censored at time of last contact, assessed up to 1 year after completion of study treatment
Overall response rate (ORR)	ORR will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.	Up to 1 year after completion of study treatment
Change in quality of life (QOL)	Change in QOL will be measured by the Functional Assessment of Cancer Therapy: General (FACT-G) questionnaire.	Baseline to 1 year after completion of study treatment

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Vincent Chung, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2024
• Primary Completion (Estimated): November 13, 2026
• Study Completion (Estimated): November 13, 2026

Study Registration Dates

• First Submitted: June 6, 2024
• First Submitted That Met QC Criteria: June 6, 2024
• First Posted (Actual): June 12, 2024

Study Record Updates

• Last Update Posted (Actual): April 13, 2026
• Last Update Submitted That Met QC Criteria: April 10, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Pancreatic Neoplasms; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Investigative Techniques; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Azoles; Physical Phenomena; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Polymers; Macromolecular Substances; Biomedical and Dental Materials; Manufactured Materials; Technology, Industry, and Agriculture; Chemistry Techniques, Analytical; Spectrum Analysis; Electromagnetic Phenomena; Magnetic Phenomena; Electromagnetic Radiation; Radiation; Radiation, Ionizing; Polystyrenes; Plastics; Isoxazoles; Leflunomide; Gemcitabine; Cholestyramine Resin; Specimen Handling; Magnetic Resonance Spectroscopy; X-Rays
• Other Study ID Numbers: 23540 (Other Identifier: City of Hope Medical Center); P30CA033572 (U.S. NIH Grant/Contract); NCI-2024-04359 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No