Ibrutinib Plus Rituximab for cGVHD Following Allo-SCT

NCT03689894 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: D17120
• Study Type: interventional
• Target: 2
• Locations: 1 country
• Sites: 1

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.

Conditions

Chronic Graft-versus-host-disease

Outcome Measures

Primary Outcomes (1)

• Evaluate Dose-limiting Toxicities Experienced in Subjects Treated With Ibrutinib Plus Rituximab

  During dose escalation, subjects will be assessed for dose-limiting toxicities at each dose level.

  Start of treatment through Week 4 of treatment

Secondary Outcomes (2)

• Assess the Response Rate of cGVHD to Treatment With Ibrutinib Plus Rituximab

  6 weeks, 3 months, and 6 months after initiation of treatment

• Identify Relevant Laboratory Correlates Underlying Clinical Response, or Lack Thereof.

  6 weeks, 3 months, and 6 months after initiation of treatment

Study Arms (1)

Ibrutinib plus Rituximab

EXPERIMENTAL

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; Drug: Rituximab

Interventions

Ibrutinib DRUG

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.

Ibrutinib plus Rituximab

Rituximab DRUG

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.

Ibrutinib plus Rituximab

Eligibility Criteria

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

You may qualify if:

• 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).)
• Chronic GVHD that is confirmed by clinical assessment and/or biopsy.
• Either steroid-refractory or steroid-dependent cGVHD.
• Karnofsky performance status ≥ 60.

You may not qualify if:

• History of treatment with a tyrosine kinase inhibitor (eg, imatinib) or other moderate-to-significant Cyclophilin A4 inhibitor within 2 weeks of enrollment.
• Renal insufficiency as follows: creatinine \> 2.5 mg/deciliters (dL) or Creatinine Clearance \< 30 ml/min.
• Hepatic insufficiency as follows: serum bilirubin \>3 mg/dL or transaminitis \>3x upper limit of normal (ULN) (unless deemed due to GVHD).
• History of cardiac dysrhythmias or known cardiovascular disease without formal Cardiology clearance.
• History of cerebro-vascular accident or intracranial hemorrhage within 6 months prior to enrollment.
• History of non-intracranial hemorrhage and/or coagulopathy without formal Coagulation clearance.
• 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.
• History of other hematologic malignancy.
• History of human immunodeficiency virus (HIV).
• History of active hepatitis B virus (HBV) or hepatitis C virus (HCV) without formal Infectious Disease clearance.
• Patients incapable of complying with routine follow up schedule or unable to be compliant with study therapy.
• Active or within 3 months use of prohibited medications or substances (e.g., illicit drugs).

Sponsors & Collaborators

• Dartmouth-Hitchcock Medical Center: lead

Study Sites (1)

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

Related Publications (26)

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MeSH Terms

Conditions

Bronchiolitis Obliterans Syndrome

Interventions

ibrutinib; Rituximab

Condition Hierarchy (Ancestors)

Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Director of Clinical Research
• Organization: Dartmouth Hitchcock Medical Center

sean.hobson@hitchcock.org

2167129120

Study Officials

• John M Hill, MD

  Dartmouth-Hitchcock Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Directory, Allogeneic Transplant Program

Study Record Dates

• First Submitted: September 27, 2018
• First Posted: October 1, 2018
• Study Start: April 11, 2019
• Primary Completion: September 20, 2021
• Study Completion: September 20, 2021
• Last Updated: November 28, 2023
• Results First Posted: November 28, 2023

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)