Graft vs. Host Disease
Conditions
Keywords
Graft vs. Host Disease
Brief summary
This research study is studying a drug called obinutuzumab as a means of preventing chronic Graft vs. Host Disease (cGVHD).
Detailed description
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.
Interventions
DRUGObinutuzumab
B cell depletion
DRUGPlacebo
Placebo
Sponsors
Dana-Farber Cancer Institute
Roche-Genentech
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Corticosteroid-Requiring Chronic Graft-Versus-Host Disease (cGVHD) Rate | 1 year | Corticosteroid-requiring cGVHD is defined as the percentage of participants who develop chronic Graft Versus Host Disease cGVHD requiring treatment with corticosteroids within the first year following Hematopoietic Cell Transplantation HCT. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All Chronic Graft-Versus-Host Disease (cGVHD) Rate | at 1 year and 2 years | All cGVHD rate is defined as the percentage of participants who develop chronic Graft Versus Host Disease cGVHD following Hematopoietic Cell Transplantation HCT. |
| Immunosuppression-Free Survival at 1 Year (IFS1) | 1 year | IFS1 is the percent probability estimate at 1 year based on the Kaplan-Meier method. IFS is defined as time from randomization to relapse, institution of systemic immune suppression, or death, whichever occurs first. Participants who are alive without relapse and who have not initiated systemic immunosuppression will be censored at the date of last disease or survival assessment. |
| Immunosuppression-Free Survival at 2 Years (IFS2) | 2 years | IFS2 is the percent probability estimate at 2 years based on the Kaplan-Meier method. IFS is defined as time from randomization to relapse, institution of systemic immune suppression, or death, whichever occurs first. Participants who are alive without relapse and who have not initiated systemic immunosuppression will be censored at the date of last disease or survival assessment. |
| NIH Moderate-Severe Chronic Graft-Versus-Host Disease (cGVHD) Rate | at 1 year and at 2 years | NIH moderate-severe cGVHD rate is defined as the percentage of participants who developed NIH moderate-severe cGVHD following Hematopoietic Cell Transplantation HCT. |
| Cumulative Incidence Of Non-Relapse Mortality (NRM) | at 1 year and at 2 years | Cumulative incidence of NRM is defined as the probability of death from any cause other than disease relapse or progression following treatment or transplantation. Deaths due to relapse or disease progression are treated as competing events. Participants who are alive without relapse or death are censored at the date of last follow-up. |
| Cumulative Incidence of Relapse | at 1 year and 2 years | Cumulative Incidence of Relapse is defined as the percentage probability of disease relapse following treatment, with death without prior relapse treated as a competing risk. Patients who are alive and relapse-free at last follow-up will be censored. |
| Progression-Free Survival at 1 Year (PFS1) | 1 year | PFS1 is the percent probability estimate at 1 year based on the Kaplan-Meier method. PFS is defined as the time from randomization to disease progression or death from any cause, whichever occurs first. Patients who are alive without disease progression at the time of last disease assessment will be censored at that date. |
| Progression-Free Survival at 2 Years (PFS2) | 2 years | PFS2 is the percent probability estimate at 2 years based on the Kaplan-Meier method. PFS is defined as the time from randomization to disease progression or death from any cause, whichever occurs first. Patients who are alive without disease progression at the time of last disease assessment will be censored at that date. |
| Overall Survival at 1 Year (OS1) | 1 year | OS1 is the percent probability estimate at 1 year based on the Kaplan-Meier method. OS is defined as the time from randomization to death from any cause. Participants who are alive at the time of last follow-up will be censored at the date of last contact. |
| Overall Survival at 2 Years (OS2) | 2 years | OS2 is the percent probability estimate at 2 years based on the Kaplan-Meier method. OS is defined as the time from randomization to death from any cause. Participants who are alive at the time of last follow-up will be censored at the date of last contact. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORCorey Cutler, MD MPH
Dana-Farber Cancer Institute
Participant flow
Recruitment details
Participants were enrolled at 5 clinical sites in the U.S. from November 29, 2016 to January 30, 2023.
Participants by arm
| Arm | Count |
|---|---|
| Obinutuzumab Obinutuzumab 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
Obinutuzumab: B cell depletion | 90 |
| Placebo 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
Placebo: Placebo | 88 |
| Never received treatment Some patients never received any treatment and got randomized after enrollment. | 3 |
| Total | 181 |
Baseline characteristics
| Characteristic | Obinutuzumab | Placebo | Never received treatment | Total |
|---|---|---|---|---|
| Age, Continuous | 63 years | 63 years | 62 years | 63 years |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 2 Participants | 0 Participants | 5 Participants |
| Race/Ethnicity, Customized More Than One Race | 4 Participants | 2 Participants | 1 Participants | 7 Participants |
| Race/Ethnicity, Customized Other | 7 Participants | 3 Participants | 0 Participants | 10 Participants |
| Race/Ethnicity, Customized White | 76 Participants | 79 Participants | 2 Participants | 157 Participants |
| Sex: Female, Male Female | 32 Participants | 33 Participants | 2 Participants | 67 Participants |
| Sex: Female, Male Male | 58 Participants | 55 Participants | 1 Participants | 114 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 29 / 90 | 28 / 88 |
| other Total, other adverse events | 87 / 90 | 81 / 88 |
| serious Total, serious adverse events | 28 / 90 | 12 / 88 |
Outcome results
Primary
Rate Of Corticosteroid-Requiring cGVHD At One Year From HCT
Percentage of participants who develop chronic Graft Versus Host Disease cGVHD requiring treatment with corticosteroids within the first year following Hematopoietic Cell Transplantation HCT.
Time frame: 1 year
Population: The analysis only included patients who started treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Obinutuzumab | Rate Of Corticosteroid-Requiring cGVHD At One Year From HCT | 13.3 percentage of participants |
| Placebo | Rate Of Corticosteroid-Requiring cGVHD At One Year From HCT | 35.2 percentage of participants |
p-value: 0.0008Fisher Exact
Secondary
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.
Time frame: at 1 year and at 2 years
Secondary
Immunosuppression-Free Survival (IFS) Rate
IFS is defined as time from randomization to relapse, institution of systemic immune suppression, or death, whichever occurs first.
Time frame: at 1 year and at 2 years
Secondary
Overall cGVHD Rate After HCT
A secondary endpoint of this phase II trial is the overall rate cGVHD one and two years after HCT.
Time frame: at 1 year and at 2 years
Secondary
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.
Time frame: at 1 year and at 2 years