Obinutuzumab in cGVHD After Allogeneic Peripheral Blood Stem Cell Transplantation

Study Overview
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Brief Summary
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This research study is studying a drug called obinutuzumab as a means of preventing chronic Graft vs. Host Disease (cGVHD).

Detailed Description
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This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. The FDA (the U.S. Food and Drug Administration) has not approved Obinutuzumab for prevention of chronic Graft-vs.-Host Disease (cGVHD), but it has been approved for other uses. In this research study, the investigators are aiming to determine the effect of Obinutuzumab on the incidence of corticosteroid-requiring cGVHD after allogeneic Hematopoetic Cell Transplant (aHCT). Chronic GVHD is a medical condition that can occur after bone marrow or stem cells are transplanted from one individual to another. After the transplant, the donor immune system may recognize the recipient body as foreign and may attempt to 'reject' the body. This process is referred to as Graft-vs. -Host Disease and may occur at any time, although generally not earlier than one hundred days after transplantation. The immune system produces two types of lymphocytes (white blood cells), B cells and T cells. B cells are part of the 'memory' for the immune system, and they make antibodies (proteins) when bacteria, viruses or other potentially harmful materials enter the body. Obinutuzumab is an antibody, a molecule that targets certain cells by binding to specific parts of the target cell. In this case, Obinutuzumab will bind to a component of B cells called CD20, resulting in the B cell getting killed. It is thought that reducing the number of B cells will reduce the chances of developing cGVHD after transplant. Previous studies with another antibody targeting CD20 on B cells suggests that there may be a reduced chance of developing cGVHD and the need to prescribe Corticosteroids to treat cGVHD when B cells are killed. This is a randomized, placebo controlled trial. This means that approximately half of the study participants will receive Obinutuzumab, and the other half will receive a placebo (saline solution). A computer will decide which participants will receive Obinutuzumab or placebo, and neither the participant or the study doctor will know which the participant has received until the study is completed. It is important to note that the current standard is to receive no therapy specifically to prevent cGVHD.

Official Title
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A Randomized Phase 2 Study of Obinutuzumab for Prevention of Chronic Graft-vs.-Host Disease After Allogeneic Peripheral Blood Stem Cell Transplantation

Conditions
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Graft vs. Host Disease

Intervention / Treatment
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* Drug: Obinutuzumab
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects deemed potentially eligible by their treating physicians will be screened for enrollment after d+60 from transplantation Patients who have undergone either ablative or non-myeloablative allogeneic stem cell transplantation are eligible. Peripheral blood stem cells must have been used as the stem cell source. Patients must have received transplantation from donors (both related and unrelated) who are identical at 8 HLA loci (A, B, C and DR1), or mismatched at no more than 1 locus (7/8). Among related donors, HLA C typing is not required (6/6 HLA matches). Class I typing is to be performed by PCR-SSP techniques and CDC techniques. Class II typing is performed by PCR-RFLP +/- PCR-SSP techniques. No evidence of relapsed or residual malignancy within 30 days of trial entry. All patients must undergo appropriate staging for their malignancy (i.e. bone marrow aspiration for the Leukemias and PET-CT scanning for the lymphomas). Evidence of a persistent Cytogenetic abnormality will constitute evidence of residual or relapsed disease in the Leukemias, where present. Individuals with CLL are eligible if there is no more than 20% residual leukemia in the bone marrow at the time of study entry. Patients who have undergone a non-myeloablative stem cell transplant must have > 80% donor hematopoiesis within 30 days of study enrollment. Chimerism within 30 days of study entry must be greater than, equal to, or no more than 5% less than the chimerism measured at approximately day+30 (if performed). Age ≥ 18.0 ECOG performance status ≤2 (Karnofsky ≥60%) (See Appendix A) Participants must have normal marrow function as defined by: WBC ≥ 2,500/μL Absolute Neutrophil Count ≥ 1,000/μL Platelets ≥ 50,000/μL Ability to understand and the willingness to sign a written informed consent document. The effects of Obinutuzumab on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of Obinutuzumab administration. Exclusion Criteria: Allogeneic stem cell transplantation using a single or multiple umbilical cord blood units or using bone marrow. Allogeneic stem cell transplantation using in vivo or ex vivo T cell depletion, either by cell manipulation or with T cell depleting antibodies (Any anti-thymocyte globulin preparation or alemtuzumab given within 30 days of transplantation) Participation in a clinical trial evaluating another preventative strategy for chronic GVHD, or ongoing participation in a clinical trial for therapy of acute GVHD. Prior completion of experimental therapy for acute GVHD is permissible if the experimental agent was used > 30 days prior to enrollment. Any evidence of ongoing gastrointestinal or hepatic acute GVHD, or evidence of greater than ongoing Stage I cutaneous acute GVHD. Ongoing, tapering therapy for resolved acute GVHD is permissible. Any evidence of prior active or resolved chronic GVHD. History of severe allergic reaction to Obinutuzumab No Donor Lymphocyte Infusion (DLI) prior to day 100, and no plans for a DLI in the upcoming 30 days. Evidence of any active uncontrolled infection (bacterial, viral or fungal) or evidence of natural exposure to Hepatitis B, Hepatitis C or HIV. Evidence of Hepatitis B exposure includes the presence of Hepatitis B surface antigenemia, a positive serological test for Hepatitis B core antibody or nucleic acid testing (NAT testing) that is positive for Hepatitis B. Vaccination to Hepatitis B is not an exclusion criteria. Pregnancy or lactation. Negative pregnancy test is required within the screening window Active use of any other investigational agents.

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
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Obinutuzumab<br>Obinutuzumab or will be administered at a pre- determine dose, intravenously, at 3, 6, 9 and 12 months from transplantation. Premedication with histamine blockers and acetaminophen will be provided All subjects will undergo allogeneic stem cell transplantation according to locally approved clinical trials | Drug: Obinutuzumab<br>* B cell depletion<br>* Other names: Gazyva;|
| Sham Comparator: Placebo<br>Placebo will be administered at a pre- determine dose, intravenously, at 3, 6, 9 and 12 months from transplantation. Premedication with histamine blockers and acetaminophen will be provided All subjects will undergo allogeneic stem cell transplantation according to locally approved clinical trials | Drug: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Rate Of Corticosteroid-Requiring cGVHD At One Year From HCT | The primary endpoint of this phase II trial is the rate of corticosteroid-requiring cGVHD one year after HCT. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall cGVHD Rate After HCT | A secondary endpoint of this phase II trial is the overall rate cGVHD one and two years after HCT. | at 1 year and at 2 years | 
| Immunosuppression-Free Survival (IFS) Rate | IFS is defined as time from randomization to relapse, institution of systemic immune suppression, or death, whichever occurs first. | at 1 year and at 2 years | 
| The Rate Of NIH Moderate-Severe cGVHD After HCT | A secondary endpoint is the rate of NIH Moderate-Severe cGVHD one and two years after HCT. | at 1 year and at 2 years | 
| Cumulative Incidence Of Non-Relapse Mortality And Relapse | A secondary endpoint is the cumulative incidence of non-relapse mortality and relapse one and two years after HCT. | at 1 year and at 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Graft vs. Host Disease