Leflunomide in Treating Patients With Steroid Dependent Chronic Graft Versus Host Disease

A Safety and Feasibility Trial of Leflunomide in Patients With Steroid Dependent Chronic Graft-Versus-Host Disease

This phase I trial studies the side effects of leflunomide in treating patients with steroid dependent chronic graft versus host disease (cGVHD). cGVHD is a common complication of bone marrow transplant. GVHD occurs when immune cells transplanted from a donor (the graft) recognize the transplant recipient (the host) as foreign, and cause damage to the skin, gastrointestinal tract or other organs. Steroids are the first line of therapy and benefits are seen in about one-third of patients with cGVHD. Prolonged use of steroids is associated with multiple complications. Leflunomide may decrease the body's immune response and reduce inflammation associated with cGVHD.

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Graft Versus Host Disease; Steroid Refractory Graft Versus Host Disease
• Intervention / Treatment: Drug: Leflunomide

Detailed Description

PRIMARY OBJECTIVE:

I. Evaluate safety and tolerability of leflunomide in hematopoietic cell transplant (HCT) patients with steroid dependent chronic GvHD (cGvHD).

SECONDARY OBJECTIVES:

I. Characterize the toxicity profile of leflunomide in patients with steroid dependent cGVHD.

II. Obtain preliminary evidence of leflunomide activity against GVHD by estimating the response rate (as defined by 2014 National Institutes of Health [NIH] consensus development project on clinical trials in cGVHD) in an expansion cohort of 12 patients with steroid dependent cGVHD.

III. Evaluate changes in cGVHD severity using physician-reported cGVHD activity assessment form.

IV. Evaluate changes in symptom activity using cGVHD activity assessment patient self-report.

V. Evaluate failure-free survival and GVHD free survival. VI. Evaluate changes in steroid doses while on therapy. VII. Evaluate rate of infectious complications during leflunomide administration.

EXPLORATORY OBJECTIVES:

I. Assess the presence and percentage of immune cell subsets (including but not limited to Th17 and Treg cells) in whole blood after leflunomide administration.

II. Assess the changes in the presence and levels of GVHD inflammatory biomarkers and cytokines (including but not limited to IL-17A, IL-21, and IL-2) in plasma after leflunomide administration.

III. Assess the plasma pharmacokinetics of teriflunomide (active metabolite of leflunomide).

OUTLINE:

Patients receive leflunomide orally (PO) once daily (QD) for days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may optionally continue leflunomide for an additional 6 cycles as long as response or stable disease is maintained.

After completion of study treatment, patients are followed up at 30 days, and then periodically thereafter.

• Study Type: Interventional
• Enrollment (Actual): 18
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

  • Assent, when appropriate, will be obtained per institutional guidelines.

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

  • If unavailable, exceptions may be granted with study principal investigator (PI) approval.
• Karnofsky performance status of >= 70 %.
• Ability to read and understand English or Spanish for questionnaires.
• Recipients of allogeneic stem cell transplantation (sibling/unrelated/umbilical cord blood [UCB]/Haplo) with myeloablative or non-myeloablative conditioning regimens.
• Participants must have steroid-dependent cGVHD. Steroid dependent cGVHD is defined as having persistent signs and symptoms of cGVHD despite the use of prednisone for 2 months without complete resolution of signs and symptoms. Both classic cGVHD and overlap syndromes will be allowed to participate.
• Estimated life expectancy greater than 3 months.
• No more than 4 prior lines of treatment. Sirolimus and tacrolimus used for prophylaxis will not be counted as line of therapy.
• Stable dose of corticosteroids for 2 weeks prior to enrollment.
• Able to swallow pills.
• Absolute neutrophil count (ANC) >= 1,000/mm^3 (without myeloid growth factors within 1 week of study entry) (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated).

• Platelets >= 50,000/mm^3 (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated).

  • NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement.

• Total bilirubin =< 2 mg/dl (exception permitted in patients with Gilbert's syndrome; aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2 x upper limit of normal [ULN]), unless hepatic dysfunction is a manifestation of presumed cGVHD (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated).

  • Abnormal liver function tests (LFTs) (liver function panel) in the context of active cGVHD involving other organ systems may also be permitted if the treating physician documents the abnormal LFTs as being consistent with hepatic cGVHD and a liver biopsy will not be mandated in this situation.
• AST =< 2.0 x ULN (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated).
• ALT =< 2.0 x ULN (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated).
• Creatinine clearance of >= 60 mL/min/1.73 m^2 for participants with creatinine levels above institutional normal. or calculated by Cockcroft-Gault equation (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated).

• Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo, hepatitis C virus (HCV)*, active hepatitis B virus (HBV) (surface antigen negative), and syphilis (rapid plasma reagin [RPR]) (performed within 28 days prior to day 1 of protocol therapy).

  • If positive, hepatitis C ribonucleic acid (RNA) quantitation must be performed.

• Meets other institutional and federal requirements for infectious disease titer requirements (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated).

  • Note: Infectious disease testing to be performed within 28 days prior to day 1 of protocol therapy.

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (to be performed within 28 days prior to day 1 of protocol therapy unless otherwise stated).

  • 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 3 months after the last dose of protocol therapy. The effects of study treatment on a developing fetus have the potential for teratogenic or abortifacient effects. Should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately.

  • 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:

• Exposure to any new immunosuppressive medication in the 4 weeks prior to enrollment.
• Donor lymphocyte infusion within 100 days prior to enrollment.
• Patients may not be receiving any other investigational agents concurrently. Oral chemotherapeutic agents or biologics -for example ruxolitinib or rituximab therapy and ibrutinib / imatinib (either past or current exposure) - is allowed.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent.
• Active infection requiring antibiotics. An active uncontrolled infection is defined as hemodynamic instability attributed to sepsis or new symptoms, worsening physical signs, or radiographic findings attributable to infection. Persisting fever without signs or symptoms will not be interpreted as an active uncontrolled infection.
• Uncontrolled cardiac angina or symptomatic congestive heart failure (New York Heart Association [NYHA] class III or IV).
• Pregnant women are excluded from this study. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with leflunomide.
• Patients should not have any uncontrolled illness including ongoing or active infection.
• Active malignant relapse.
• Patients with other active malignancies are ineligible for this study, other than superficial localized skin cancer (basal or squamous cell carcinoma).
• Active diarrhea, not related to cGVHD.
• Clinically significant uncontrolled illness.
• Patients on dialysis.
• Patients requiring ventilator support.
• Patients with acute GvHD
• Known history of immunodeficiency virus (HIV) or hepatitis B or hepatitis C infection.
• 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.
• Inability to comply with protocol therapy and follow up visits.
• 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 (leflunomide); Patients receive leflunomide PO QD for days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients may optionally continue leflunomide for an additional 6 cycles as long as response or stable disease is maintained.	Drug: Leflunomide; Given PO; Other Names: Arava; SU101

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicity	Toxicity will be graded according to the National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v.5.0).	Up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Leflunomide activity	Leflunomide activity in patients with steroid dependent chronic graft versus host disease (cGVHD) and disease status at 24 weeks in terms of partial and complete response will be evaluated as defined by 2014 National Institutes of Health (NIH) consensus development project on clinical trials in cGVHD.	At 24 weeks
Changes in cGVHD severity	Evaluated using physicians-reported cGVHD activity assessment form.	Baseline up to 30 days post treatment
Changes in symptom activity	Evaluated using cGVHD activity assessment patient self-report.	Baseline up to 30 days post treatment
Failure-free survival	Defined by the absence of second line of GVHD treatment, non-relapse mortality, and recurrent malignancy during leflunomide treatment. Failure free survival estimates will be calculated using the Kaplan-Meier method.	At 24 weeks
Failure-free survival	Defined by the absence of second line of GVHD treatment, non-relapse mortality, and recurrent malignancy during leflunomide treatment. Failure free survival estimates will be calculated using the Kaplan-Meier method.	At 28 days follow-up
GVHD-free survival	Defined as the probability of being alive without clinically significant GvHD at any time-point post transplantation.	At 24 weeks
GVHD-free survival	Defined as the probability of being alive without clinically significant GvHD at any time-point post transplantation.	At 28 days follow-up
Changes in steroid doses while on therapy	Will be recorded and assessed at each study visit time-points.	Baseline up to 48 weeks
Rate of infectious complications	Will be evaluated while on therapy.	Up to 48 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence and levels of immune cells (i.e., T and B cells, regulatory T cells [T regs], T cell receptor excision circles [TRECs]) after leflunomide consumption	Will be determined using flow cytometric analysis on freshly thawed peripheral blood mononuclear cells (PBMNCs).	Up to 28 days follow-up
Effect of leflunomide consumption of the presence and levels of GVHD inflammatory biomarkers	Will be assessed by performing enzyme-linked immunosorbent assay (ELISA) assays on freshly thawed serum samples.	Up to 48 weeks
Pharmacokinetics concentration of teriflunomide in patients with chronic GVHD		Up to 28 days follow-up

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): May 12, 2020
• Primary Completion (Estimated): June 22, 2026
• Study Completion (Estimated): June 22, 2026

Study Registration Dates

• First Submitted: July 17, 2019
• First Submitted That Met QC Criteria: December 26, 2019
• First Posted (Actual): December 27, 2019

Study Record Updates

• Last Update Posted (Actual): July 4, 2025
• Last Update Submitted That Met QC Criteria: July 2, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organizing Pneumonia; Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchiolitis Obliterans Syndrome; Graft vs Host Disease; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Leflunomide
• Other Study ID Numbers: 19202 (Other Identifier: City of Hope Comprehensive Cancer Center); NCI-2019-04532 (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
• product manufactured in and exported from the U.S.: No