GVHD, Hematologic Neoplasms
Conditions
Keywords
cancer, Graft-Versus-Host Disease, Hematologic Neoplasms, Abatacept, Cyclophosphamide, GVHD prophylaxis, stem cell transplantation, High risk hematologic malignancy, hematologic malignancy, Allogeneic Hematopoetic Stem Cell Transplantation, GVHD
Brief summary
The purpose of this study is to investigate whether the combination of cyclophosphamide and abatacept versus the treatment used in standard of care will reduce the incidence of moderate and severe chronic graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. GVHD occurs when the cells from your donor (the graft) see your body's cells (the host) as different and attack them.
Detailed description
The experimental GVHD prophylaxis arm consists of cyclophosphamide and abatacept. Cyclophosphamide induces apoptosis of activated T cells and abatacept (CTLA4Ig) blocks activation of T cells by inhibiting the co-stimulatory signal. Compared to the standard-of-care control arm, the experimental arm is much more convenient and expected to be associated with fewer toxicities. In addition there is a great theoretical potential for immunological synergy between cyclophosphamide and abatacept for inducing post-transplant immunologic tolerance that clinically might translate into less GVHD without increase in relapse Patients will be randomized 1:1 to the experimental vs the standard of care arm. Randomization will be done prior to the use of any conditional therapy. The two arms will be stratified by disease (acute leukemia vs others) and donor type (MRD vs MUD/MUD vs Haplo) in an effort to keep them balanced. The conditioning regimen for both arms will be mainly Busulfan/Fludarabine (A Total Body Irradiation based conditioning regimen will be allowed for diseases such as ALL) The GVHD prophylaxis regimen on the experimental arm will consist of high dose Cyclophosphamide on Days +3 and +4 followed by abatacept for 6 months. The GVHD prophylaxis regimen on the standard of care arm will consist of methotrexate on Days +1,+3, +6 and +11 and tacrolimus for patients with a 10/10 matched related or unrelated donor and of high dose cyclophosphamide on Days +3 and +4 followed by tacrolimus and mycophenolate for patients with a haploidentical donor.
Interventions
DRUGCyclophosphamide
Day 3 and day 4 following transplant. Dosing will be based on patients' actual weight up to 120% of ideal body weight, above which it will be based on adjusted ideal body weight (ideal weight plus 50% of the difference between ideal and actual weight).
DRUGabatacept
Abatacept at a dose of 10mg/kg will be administered on days +5, +14 and +28, +56, +84, +112, +140, +168
DRUGMethotrexate
standard of care Methotrexate 5 mg/m2 on Days 1, 3, 6 and 11
DRUGTacrolimus
Tacrolimus per institutional guidelines
Sponsors
Bristol-Myers Squibb
Dimitrios Tzachanis, MD PhD
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* High risk hematologic malignancy justifying the need for an allogeneic hematopoetic stem cell transplantation: AML, ALL, CML in accelerated or blast phase, MDS/MPN, NHL, Hodgkin lymphoma, and multiple myeloma * Creatinine clearance \> 40 * Adequate hepatic function * Normal cardiac function (EF \> 50%)
Exclusion criteria
* Patients with hematologic malignancies for which transplant is not the only curative option, such as AML with good or intermediate cytogenetics or molecular markers in CR1 or CML in chronic phase * Inability to identify an 10/10 HLA-Matched Donor (related or unrelated) or a haploidentical donor * Active malignant disease relapse * Active, uncontrolled infection, uncontrolled cardiac angina, symptomatic congestive heart failure * Life expectancy \<3 months * Pregnancy or lactation * Patients may not be receiving any other investigational agents in the last 28 days * Patients with chronic myeloid leukemia in first chronic phase
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Moderate and Severe Chronic GVHD at One Year Post Transplant | through study completion, an average of 1 year | The occurrence of moderate and severe chronic GVHD at one year post Chronic GVHD will be diagnosed and staged according to the previously published and widely accepted National Institutes of Health consensus criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| GVHD- and Relapse- Free Survival by One Year Post Transplant | through study completion, an average of 1 year | GVHD- and relapse- free survival will be defined as the absence of acute GVHD Grade III or IV or moderate or severe chronic GVHD or relapse or non-relapse mortality by one year post transplant. Acute GVHD will be diagnosed and graded according to Glucksberg criteria |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cyclophosphamide and Abatacept The GVHD prophylaxis regimen on the experimental arm will consist of high dose Cyclophosphamide on Days +3 and +4 followed by abatacept for 6 months. Abatacept at a dose of 10mg/kg will be administered on days +5, +14 and +28, +56, +84, +112, +140, +168
Cyclophosphamide: Day 3 and day 4 following transplant. Dosing will be based on patients' actual weight up to 120% of ideal body weight, above which it will be based on adjusted ideal body weight (ideal weight plus 50% of the difference between ideal and actual weight).
abatacept: Abatacept at a dose of 10mg/kg will be administered on days +5, +14 and +28, +56, +84, +112, +140, +168 | 25 |
| Methotrexate and Tacrolimus The GVHD prophylaxis regimen on the standard of care arm will consist of methotrexate on Days +1,+3, +6 and +11 and tacrolimus
Methotrexate: standard of care Methotrexate 5 mg/m2 on Days 1, 3, 6 and 11
Tacrolimus: Tacrolimus per institutional guidelines | 15 |
| Total | 40 |
Baseline characteristics
| Characteristic | Cyclophosphamide and Abatacept | Methotrexate and Tacrolimus | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 2 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 21 Participants | 13 Participants | 34 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 4 Participants | 6 Participants | 10 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 15 Participants | 8 Participants | 23 Participants |
| Region of Enrollment United States | 25 Participants | 15 Participants | 40 Participants |
| Sex: Female, Male Female | 11 Participants | 4 Participants | 15 Participants |
| Sex: Female, Male Male | 14 Participants | 11 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 25 | 3 / 15 |
| other Total, other adverse events | 5 / 25 | 10 / 15 |
| serious Total, serious adverse events | 9 / 25 | 13 / 15 |
Outcome results
Primary
Occurrence of Moderate and Severe Chronic GVHD at One Year Post Transplant
The occurrence of moderate and severe chronic GVHD at one year post Chronic GVHD will be diagnosed and staged according to the previously published and widely accepted National Institutes of Health consensus criteria
Time frame: through study completion, an average of 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide and Abatacept | Occurrence of Moderate and Severe Chronic GVHD at One Year Post Transplant | 0 Participants |
| Methotrexate and Tacrolimus | Occurrence of Moderate and Severe Chronic GVHD at One Year Post Transplant | 8 Participants |
Secondary
GVHD- and Relapse- Free Survival by One Year Post Transplant
GVHD- and relapse- free survival will be defined as the absence of acute GVHD Grade III or IV or moderate or severe chronic GVHD or relapse or non-relapse mortality by one year post transplant. Acute GVHD will be diagnosed and graded according to Glucksberg criteria
Time frame: through study completion, an average of 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cyclophosphamide and Abatacept | GVHD- and Relapse- Free Survival by One Year Post Transplant | 15 Participants |
| Methotrexate and Tacrolimus | GVHD- and Relapse- Free Survival by One Year Post Transplant | 4 Participants |