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Ibrutinib Plus Rituximab for cGVHD Following Allo-SCT

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ClinicalTrials.gov Identifier: NCT03689894
Recruitment Status : Recruiting
First Posted : October 1, 2018
Last Update Posted : August 13, 2019
Sponsor:
Information provided by (Responsible Party):
John M. Hill, Jr., MD, Dartmouth-Hitchcock Medical Center

Brief Summary:

Allogeneic stem cell transplant is used to treat a variety of blood cancers. However, graft-versus-host disease (GVHD) is a common condition that may occur after transplant. GVHD happens when the donor cells attack and damage the recipients' tissue.

The standard medication to treat chronic graft-versus-host-disease (cGVHD) is corticosteroids. However, there are long-term side effects of steroid therapy, including risk of infection, bone loss and other health problems. In addition, some patients with cGVHD do not respond to standard steroid therapy. In these cases, medications to suppress the immune system may be used.

The purpose of this study is to learn about the effects, both good and bad, of combining the drugs ibrutinib and rituximab for the treatment of cGVHD.

Ibrutinib is Food and Drug Administration (FDA)-approved for the treatment of cGVHD which has not responded to steroid therapy.

Rituximab is an investigational drug, which means it is not FDA approved for this particular use. Rituximab is currently approved for treatment of Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), and other conditions, but is not FDA approved for the treatment of cGVHD.

However, rituximab has been used in a clinic setting for the treatment of cGVHD in a number of patients over the past few years, and has generally been well tolerated and shown some benefit.

The combination of ibrutinib and rituximab is being studied in the treatment of certain types of lymphoma and chronic leukemia, but it has not yet been combined for patients with cGVHD. Because ibrutinib is not approved for this use when combined with rituximab, it is considered investigational in this study.

In this form, the term "study drug" refers to ibrutinib and rituximab.

This study will involve people who have chronic GVHD, have previously taken corticosteroids, and have either not benefited from treatment with corticosteroids or have been unable to successfully taper off steroids.


Condition or disease Intervention/treatment Phase
Chronic Graft-versus-host-disease Drug: Ibrutinib Drug: Rituximab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Combination Ibrutinib and Rituximab for the Treatment of Chronic Graft-Versus-Host Disease Following Allogeneic Stem Cell Transplant
Actual Study Start Date : April 12, 2019
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : December 2024


Arm Intervention/treatment
Experimental: Ibrutinib plus Rituximab

Rituximab

*375 milligrams (mg) per meter squared intravenous infusion weekly for 4 (may repeat 8 weeks after initial therapy, if suboptimal response)

Ibrutinib

  • 420 mg (140 mg capsule x3) by mouth daily
  • May be given beyond 3-6 months (for maintenance).
Drug: Ibrutinib

Subjects will receive oral (PO) Ibrutinib 140 mg once daily with Rituximab 375 mg per meter squared IV weekly x4 (with pre-medications and infusion procedure as per standard protocol) Rituximab Pre-medications:Acetaminophen 650 mg PO; Diphenhydramine 25 mg PO/IV; Dexamethasone 20 mg IV.

If no adverse events >Grade 3+ are noted after 1 week, the Ibrutinib dose schedule will be increased to 280 mg daily. If no adverse events >Gr3+ are noted after an additional 1 week, the Ibrutinib dose will be increased to 420 mg daily.


Drug: Rituximab
Subject will receive an intravenous infusion of 375mg per meter squared weekly for 4 weeks, which may be repeated 8 weeks after initial therapy if only a suboptimal response is achieved.




Primary Outcome Measures :
  1. Evaluate dose-limiting toxicities experienced in subjects treated with Ibrutinib plus Rituximab [ Time Frame: Start of treatment through Week 4 of treatment ]
    During dose escalation, subjects will be assessed for dose-limiting toxicities at each dose level.


Secondary Outcome Measures :
  1. Assess the response rate of cGVHD to treatment with Ibrutinib plus Rituximab [ Time Frame: 6 weeks, 3 months, and 6 months after initiation of treatment ]
    Response rate of clinically significant GVHD will be assessed using NIH criteria (from 2014 NIH Consensus Development Project).

  2. Identify relevant laboratory correlates underlying clinical response, or lack thereof. [ Time Frame: 6 weeks, 3 months, and 6 months after initiation of treatment ]
    Plasma ST2 and CD4CD25FOXp3 correlates will be measured at identified intervals to determine if either correlate demonstrates an affect on clinical response.



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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:

  1. Men and women ≥18 years old who are recipients of an allogeneic bone marrow, cord blood or peripheral blood stem cell transplant. (There will be no restrictions based upon underlying disease, donor source, degree of human leukocyte antigen (HLA) match, intensity of pre-transplant conditioning regimen or use of prior donor lymphocyte infusion(s).)
  2. Chronic GVHD that is confirmed by clinical assessment and/or biopsy.
  3. Either steroid-refractory or steroid-dependent cGVHD.
  4. Karnofsky performance status ≥ 60.

Exclusion Criteria:

  1. History of treatment with a tyrosine kinase inhibitor (eg, imatinib) or other moderate-to-significant Cyclophilin A4 inhibitor within 2 weeks of enrollment.
  2. Renal insufficiency as follows: creatinine > 2.5 mg/deciliters (dL) or Creatinine Clearance < 30 ml/min.
  3. Hepatic insufficiency as follows: serum bilirubin >3 mg/dL or transaminitis >3x upper limit of normal (ULN) (unless deemed due to GVHD).
  4. History of cardiac dysrhythmias or known cardiovascular disease without formal Cardiology clearance.
  5. History of cerebro-vascular accident or intracranial hemorrhage within 6 months prior to enrollment.
  6. History of non-intracranial hemorrhage and/or coagulopathy without formal Coagulation clearance.
  7. Uncontrolled infections not responsive to antibiotics, anti-viral medicines, or anti-fungal medicines; or infection requiring systemic treatment that was completed ≤14 days before enrollment.
  8. History of other hematologic malignancy.
  9. History of human immunodeficiency virus (HIV).
  10. History of active hepatitis B virus (HBV) or hepatitis C virus (HCV) without formal Infectious Disease clearance.
  11. Patients incapable of complying with routine follow up schedule or unable to be compliant with study therapy.
  12. Active or within 3 months use of prohibited medications or substances (e.g., illicit drugs).

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): NCT03689894


Contacts
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Contact: Research Nurse (800) 639-6918 cancer.research.nurse@dartmouth.edu

Locations
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United States, New Hampshire
Dartmouth-Hitchcock Medical Center Recruiting
Lebanon, New Hampshire, United States, 03756
Contact: John M Hill, MD    603-650-4628    John.M.Hill@hitchcock.org   
Contact: Darcie Findley, BS    603-650-4595    darcie.l.findley@hitchcock.org   
Sponsors and Collaborators
Dartmouth-Hitchcock Medical Center
Investigators
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Principal Investigator: John M Hill, MD Dartmouth-Hitchcock Medical Center

Publications:

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Responsible Party: John M. Hill, Jr., MD, Directory, Allogeneic Transplant Program, Dartmouth-Hitchcock Medical Center
ClinicalTrials.gov Identifier: NCT03689894     History of Changes
Other Study ID Numbers: D17120
First Posted: October 1, 2018    Key Record Dates
Last Update Posted: August 13, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Graft vs Host Disease
Immune System Diseases
Rituximab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents