Ofatumumab as Primary Therapy of Chronic Graft Versus Host Disease

Study Overview
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Brief Summary
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To study the safety and side effects of Ofatumumab in the treatment of chronic graft-versus-host disease (GvHD). This study will also evaluate effectiveness of Ofatumumab when added to standard steroid treatment for chronic graft-versus-host disease

Detailed Description
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This is a phase I-II trial to examine the safety and efficacy of prednisone and escalating dose of ofatumumab for the primary therapy of chronic GVHD.

Official Title
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Ofatumumab in Combination With Glucocorticoids for Primary Therapy of Chronic Graft Versus Host Disease

Conditions
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Chronic Graft Versus Host Disease

Intervention / Treatment
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* Drug: Ofatumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hematopoietic cell transplantation (HCT) recipients newly requiring systemic glucocorticoid therapy (at ≥ 1mg/kg/day prednisone or equivalent) for chronic GVHD Participants can be enrolled and begin study therapy with ofatumumab within 14 days from initiation of 1 mg/kg/day prednisone for therapy of chronic GVHD. Exclusion Criteria: Relapse of primary hematologic malignancy that served as indication for HCT. Previous systemic glucocorticoid therapy (at ≥ 1mg/kg/day prednisone or equivalent) for chronic GVHD Prior systemic glucocorticoid therapy for acute GVHD is permitted Prior or ongoing systemic immune suppressive agents (including, but not limited to common examples such as calcineurin inhibitors, sirolimus, mycophenolate mofetil) provided for either prevention or treatment of acute GVHD are permitted and part of routine standard of care Current active hepatic or biliary disease (with exception of liver disease secondary to chronic GVHD, or patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment). Patients with abnormal liver function tests due to chronic GVHD are specifically not excluded from the study. This is a common manifestation of chronic GVHD, and thus a major target for the study therapy. Treatment with experimental non-FDA approved therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer Other past or current solid tumor malignancy Have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible. Prior treatment with anti-cluster of differentiation antigen 20 (CD20) monoclonal antibody or alemtuzumab within 3 months prior to start of therapy. Uncontrolled infectious complications not responsive to appropriate antimicrobial therapy. History of significant cerebrovascular disease (i.e. stroke or TIA) in the past 6 months or ongoing event with active symptoms or sequelae HIV positivity Uncontrolled, current significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (NYHA III-IV), and arrhythmia unless controlled by therapy, with the exception of extra systoles or minor conduction abnormalities. A history of cardiac disease, such as coronary disease, arrhythmia or congestive heart failure that are on appropriate medical therapy and without evidence of current decompensation are eligible. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient. Those patients with medical conditions that are controlled with medical therapy are eligible. Clinically active Hepatitis B defined as positive HBsAg; or positive HBcAb with detectable hepatitis B virus (HBV) DNA viral load. Patients who are HBcAb with undetectable HBV DNA viremia are eligible. Positive serology for hepatitis C (HC) defined as a positive test and confirmed by HC recombinant immunoblot assay (RIBA) or hepatitis C virus (HCV) RNA viral load Screening laboratory value exclusion criteria: platelets < 50 x 10^9/L (patients with platelet counts > 50 x 10^9/L supported by platelet transfusion are eligible); neutrophils < 1.0 x 10^9/L (patients with an absolute neutrophil count > 1.0 x 10^9/L supported by growth factors are eligible); creatinine > 2.0 times upper normal limit; total bilirubin >1.5 times upper normal limit (unless due to chronic GVHD); alanine transaminase (ALT) > 2.0 times upper normal limit (unless due to chronic GVHD); alkaline phosphatase > 2.5 times upper normal limit (unless due to chronic GVHD). Women who are pregnant or lactating. Women of childbearing potential must have a negative pregnancy test at screening. Women of child bearing potential must undergo pregnancy testing within 7 days of the first dose of study therapy. Women must also undergo pregnancy test at 6 months after the last dose. Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence. Males unable or unwilling to use adequate contraception methods from study start to one year after the last dose of protocol therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ofatumumab<br>Phase I: Escalating dose of ofatumumab Phase II: Maximum tolerated dose (MTD) of Ofatumumab | Drug: Ofatumumab<br>* Phase I: test an escalating dose of ofatumumab at cohorts of 300 mg, 700 mg, and 1000 mg given on day 0 and 14 of study. Phase II: Ofatumumab MTD on day 0 and 14; patients will be followed for total of 24 months (months 1, 3, 6, 12 after therapy, then at 18 and 24 months following therapy)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Ofatumumab | Maximum Tolerated Dose was determined by increasing doses, beginning at 300 mg on day 0 and day 14, then increasing to 700 mg on day 0 and day 14 and finally 1000 mg on day 0 and day 14. | within 21 days of initiation | 
| Participants Response Rates | Overall response rate (ORR) at 6 months following initiation of therapy. ORR is the composite outcome of complete response and partial response | 6 months following initiation of Ofatumumab | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) at 24 Months | Overall Survival is defined as the time period from start of treatment to death. | Up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Graft vs. Host Disease, GVHD, chronic graft versus host disease (cGVHD), Allogeneic Transplant, Ofatumumab