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

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ClinicalTrials.gov Identifier: NCT04212416
Recruitment Status : Recruiting
First Posted : December 27, 2019
Last Update Posted : May 21, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
City of Hope Medical Center

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Chronic Graft Versus Host Disease Steroid Refractory Graft Versus Host Disease Drug: Leflunomide Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Safety and Feasibility Trial of Leflunomide in Patients With Steroid Dependent Chronic Graft-Versus-Host Disease
Actual Study Start Date : May 12, 2020
Estimated Primary Completion Date : August 2, 2021
Estimated Study Completion Date : August 2, 2021


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




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


Secondary Outcome Measures :
  1. Leflunomide activity [ Time Frame: At 24 weeks ]
    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.

  2. Changes in cGVHD severity [ Time Frame: Baseline up to 30 days post treatment ]
    Evaluated using physicians-reported cGVHD activity assessment form.

  3. Changes in symptom activity [ Time Frame: Baseline up to 30 days post treatment ]
    Evaluated using cGVHD activity assessment patient self-report.

  4. Failure-free survival [ Time Frame: At 24 weeks ]
    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.

  5. Failure-free survival [ Time Frame: At 28 days follow-up ]
    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.

  6. GVHD-free survival [ Time Frame: At 24 weeks ]
    Defined as the probability of being alive without clinically significant GvHD at any time-point post transplantation.

  7. GVHD-free survival [ Time Frame: At 28 days follow-up ]
    Defined as the probability of being alive without clinically significant GvHD at any time-point post transplantation.

  8. Changes in steroid doses while on therapy [ Time Frame: Baseline up to 48 weeks ]
    Will be recorded and assessed at each study visit time-points.

  9. Rate of infectious complications [ Time Frame: Up to 48 weeks ]
    Will be evaluated while on therapy.


Other Outcome Measures:
  1. 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 [ Time Frame: Up to 28 days follow-up ]
    Will be determined using flow cytometric analysis on freshly thawed peripheral blood mononuclear cells (PBMNCs).

  2. Effect of leflunomide consumption of the presence and levels of GVHD inflammatory biomarkers [ Time Frame: Up to 48 weeks ]
    Will be assessed by performing enzyme-linked immunosorbent assay (ELISA) assays on freshly thawed serum samples.

  3. Pharmacokinetics concentration of teriflunomide in patients with chronic GVHD [ Time Frame: Up to 28 days follow-up ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04212416


Locations
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United States, California
City of Hope Medical Center Recruiting
Duarte, California, United States, 91010
Contact: Amandeep Salhotra    626-218-2405    asalhotra@coh.org   
Principal Investigator: Amandeep Salhotra         
Sponsors and Collaborators
City of Hope Medical Center
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Amandeep Salhotra City of Hope Medical Center
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Responsible Party: City of Hope Medical Center
ClinicalTrials.gov Identifier: NCT04212416    
Other Study ID Numbers: 19202
NCI-2019-04532 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
19202 ( Other Identifier: City of Hope Comprehensive Cancer Center )
First Posted: December 27, 2019    Key Record Dates
Last Update Posted: May 21, 2020
Last Verified: January 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Leflunomide
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs