Graft-versus-host Disease
Conditions
Brief summary
This is a single arm, open label, optimal 2-stage Simon design phase Ib-II clinical trial. Adult patients with hematological malignancies undergoing allogeneic HSCT from first- or second-degree haploidentical donor are eligible for the study if they meet the standard criteria defined in our institutional standard operation procedures (SOPs), meet all inclusion criteria, and do not satisfy any exclusion criteria. Patients will receive non-myeloablative, reduced-intensity or myeloablative conditioning regimen followed by peripheral blood hematopoietic stem cells. Patients will receive cyclophosphamide, abatacept, and short-duration tacrolimus for GvHD prophylaxis.
Interventions
DRUGCyclophosphamide, Abatacept, and Tacrolimus for GvHD Prevention
Cyclophosphamide 50 mg/kg IV over 2 hours on Day +3 and +4 Abatacept 10 mg/kg IV on days +5, +14, and +28 Tacrolimus 0.02 mg/kg IV by continuous infusion, starting on day +5. May switch to oral when tolerated, adjusted to maintain a drug level between 5-12ng/mL. Treatment is discontinued on day +60 after a 4 week-taper
Sponsors
NYU Langone Health
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Intervention model description
Interventional, non-randomized open label, 2- stage optimal Simon design with interim futility analysis.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥ 18 years 2. Karnofsky score ≥ 70% 3. No evidence of progressive bacterial, viral, or fungal infection 4. Creatinine clearance \> 50 mL/min/1.72m2 5. Total bilirubin, ALT and AST \< 2 x the upper limit of normal (except for diagnosed Gilbert's syndrome) 6. Alkaline phosphatase ≤ 250 IU/L 7. Left Ventricular Ejection Fraction (LVEF) \> 45% 8. Adjusted Carbon Monoxide Diffusing Capacity (DLCO) \> 60% 9. Negative HIV serology 10. Negative pregnancy test: confirmation per negative serum β-human chorionic gonadotropin (β-hCG) for women of childbearing age and potential.
Exclusion criteria
1. Donors are excluded in case of donor-specific HLA antibodies or positive cross-match. 2. Pregnant or nursing females or women of child bearing age or potential, who are unwilling to completely abstain from heterosexual sex or practice 2 effective methods of contraception from the first dose of conditioning regimen through day +180. A woman of reproductive capability is one who has not undergone a hysterectomy (removal of the womb), has not had both ovaries removed, or has not been post-menopausal (stopped menstrual periods) for more than 24 months in a row. 3. Male subjects who refuse to practice effective barrier contraception during the entire study treatment period and through a minimum of 90 days after the last dose of study drug, or completely abstain from heterosexual intercourse. This must be done even if they are surgically sterilized (i.e., post-vasectomy). 4. Inability to provide informed consent. 5. Patient had myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see Appendix E), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at screening must be documented by the investigator as not medically relevant. 6. Known allergies to any of the components of the investigational treatment regimen. 7. Serious medical or psychiatric illness likely to interfere with participation in this clinical study. 8. Participation in clinical trials with other investigational agents not included in this trial, within 14 days of the start of this trial and throughout the duration of this trial. 9. Prisoners
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Grade II-IV Acute GvHD by Day +120 | 120 days | The first day of grade II-IV acute GvHD will be used to calculate the cumulative incidence. The cumulative incidence will be defined as the percentage of participants with grade II-IV acute GvHD. The diagnosis of acute GvHD is based on clinical and pathological evaluation by the principal investigator in collaboration with the treating physician. Overall Grades of Acute GvHD: 0 = none; 1. = mild; 2. = moderate; 3. = severe; 4. = life threatening |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cumulative Incidence of Primary Graft Failure | Day 45 | Graft failure is defined as failure to achieve neutrophil engraftment by day +28 or lack of donor chimerism \> 50% by day 45, not due to the underlying malignancy. |
| Cumulative Incidence of Poor Graft Function | Day 28 | Poor Graft Function defined by at least 2 of the following 3 criteria: Hemoglobin \< 8 g/dL, ANC \< 0.5 x 109/L, and platelets \< 20 x 109/L. The cytopenia must be unexplained (such as by disease relapse) and unresponsive to cytokines and must last at least 4 weeks. |
| Incidence of Secondary Graft Failure | Day 730 | Evaluated following engraftment through day +730. Secondary Graft Failure defined as poor graft function associated with donor chimerism \< 5%. |
| Cumulative Incidence of Chronic GvHD | Day 365 | The first day of chronic GvHD will be used to calculate the cumulative incidence of chronic GvHD. This endpoint will be evaluated through day +365 post-transplant. |
| Relapse Rate | Day 730 | Evaluated to day +730 and defined as the percentage of patients in whom the disease for which transplant is performed becomes evident by methods of disease detection after the transplant. |
| GvHD and Relapse-Free Survival (GRFS) | Day 730 | Evaluated to day +730 and defined as the percentage of participants who are without reported grade III-IV acute GvHD, without chronic GvHD requiring systemic therapy, and have not experienced relapse or death. |
| Overall Survival | Day 730 | Evaluated to day +730 and defined as percentage of participants alive at the end of the study's evaluation period. |
| Number of Treatment-Related Deaths | Day 730 | Number of participant deaths not attributable to disease relapse or progression. Will be evaluated to day +730. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| HSCT Patients Adult patients with hematological malignancies undergoing HLA-haploidentical HSCT from first-or second-degree family donors.
Cyclophosphamide, Abatacept, and Tacrolimus for GvHD Prevention: Cyclophosphamide 50 mg/kg IV over 2 hours on Day +3 and +4 Abatacept 10 mg/kg IV on days +5, +14, and +28 Tacrolimus 0.02 mg/kg IV by continuous infusion, starting on day +5. May switch to oral when tolerated, adjusted to maintain a drug level between 5-12ng/mL. Treatment is discontinued on day +60 after a 4 week-taper | 46 |
| Total | 46 |
Baseline characteristics
| Characteristic | HSCT Patients |
|---|---|
| Age, Continuous | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 12 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 34 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 39 Participants |
| Region of Enrollment United States | 46 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 46 |
| other Total, other adverse events | 24 / 46 |
| serious Total, serious adverse events | 19 / 46 |
Outcome results
Primary
Percentage of Participants With Grade II-IV Acute GvHD by Day +120
The first day of grade II-IV acute GvHD will be used to calculate the cumulative incidence. The cumulative incidence will be defined as the percentage of participants with grade II-IV acute GvHD. The diagnosis of acute GvHD is based on clinical and pathological evaluation by the principal investigator in collaboration with the treating physician. Overall Grades of Acute GvHD: 0 = none; 1. = mild; 2. = moderate; 3. = severe; 4. = life threatening
Time frame: 120 days
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| HSCT Patients | Percentage of Participants With Grade II-IV Acute GvHD by Day +120 | 17.4 Percentage of participants |
Secondary
Cumulative Incidence of Chronic GvHD
The first day of chronic GvHD will be used to calculate the cumulative incidence of chronic GvHD. This endpoint will be evaluated through day +365 post-transplant.
Time frame: Day 365
Secondary
Cumulative Incidence of Poor Graft Function
Poor Graft Function defined by at least 2 of the following 3 criteria: Hemoglobin \< 8 g/dL, ANC \< 0.5 x 109/L, and platelets \< 20 x 109/L. The cytopenia must be unexplained (such as by disease relapse) and unresponsive to cytokines and must last at least 4 weeks.
Time frame: Day 28
Secondary
Cumulative Incidence of Primary Graft Failure
Graft failure is defined as failure to achieve neutrophil engraftment by day +28 or lack of donor chimerism \> 50% by day 45, not due to the underlying malignancy.
Time frame: Day 45
Secondary
GvHD and Relapse-Free Survival (GRFS)
Evaluated to day +730 and defined as the percentage of participants who are without reported grade III-IV acute GvHD, without chronic GvHD requiring systemic therapy, and have not experienced relapse or death.
Time frame: Day 730
Secondary
Incidence of Secondary Graft Failure
Evaluated following engraftment through day +730. Secondary Graft Failure defined as poor graft function associated with donor chimerism \< 5%.
Time frame: Day 730
Secondary
Number of Treatment-Related Deaths
Number of participant deaths not attributable to disease relapse or progression. Will be evaluated to day +730.
Time frame: Day 730
Secondary
Overall Survival
Evaluated to day +730 and defined as percentage of participants alive at the end of the study's evaluation period.
Time frame: Day 730
Secondary
Relapse Rate
Evaluated to day +730 and defined as the percentage of patients in whom the disease for which transplant is performed becomes evident by methods of disease detection after the transplant.
Time frame: Day 730