Cyclophosphamide, Abatacept, and Tacrolimus for the Prevention of GvHD

Study Overview
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Brief Summary
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This is a single arm, open label, phase 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 dosed reduced cyclophosphamide, abatacept, and short-duration tacrolimus for GvHD prophylaxis.

Official Title
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Phase II Single-Arm Open-Label Study Of Reduced-Dose Post-Transplant Cyclophosphamide, Abatacept, and Short-Duration Tacrolimus for the Prevention of Graft-Versus-Host Disease (GVHD) Following Haploidentical Hematopoietic Stem Cell Transplantation (HSCT)

Conditions
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Graft Vs Host Disease

Intervention / Treatment
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* Drug: Cyclophosphamide
* Drug: Abatacept
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Karnofsky score ≥ 70% No evidence of progressive bacterial, viral, or fungal infection Creatinine clearance > 50 mL/min/1.72m2 Total bilirubin, Alanine Aminotransferase and Aspartate Aminotransferase < 2 x the upper limit of normal (except for diagnosed Gilbert's syndrome) Alkaline phosphatase ≤ 250 IU/L Left Ventricular Ejection Fraction (LVEF) > 45% Adjusted Carbon Monoxide Diffusing Capacity (DLCO) > 60% Negative HIV serology Negative pregnancy test: confirmation per negative serum β-human chorionic gonadotropin (β-hCG) for women of childbearing age and potential. Exclusion Criteria: Donors are excluded in case of donor-specific HLA antibodies or positive cross-match. 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. 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). Inability to provide informed consent. 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. Known allergies to any of the components of the investigational treatment regimen. Serious medical or psychiatric illness likely to interfere with participation in this clinical study. 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. Prisoners

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: Prevention
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reduced-Dose Post-Transplant Cyclophosphamide, Abatacept, and Short-Duration Tacrolimus<br>Participants to receive: Cyclophosphamide 25 mg/kg IV over 1 hour on Day 3 and Day 4 following transplant Abatacept 10 mg/kg IV on Day 5, Day 14, Day 28, and Day 56 following transplant Tacrolimus 0.02 mg/kg IV by continuous infusion, starting on Day 5 following transplant. May switch to oral administration when tolerated, adjusted to maintain a drug level between 5-12ng/mL. Tacrolimus treatment is continued until Day 60 and then tapered over a period of 4 weeks in the absence of GvHD. | Drug: Cyclophosphamide<br>* Nitrogen mustard alkylating agent produced by Bristol-Myers Squibb.<br>* Other names: Cytoxan;Drug: Abatacept<br>* Calcineurin-inhibitor produced by Astellas.<br>* Other names: Prograf;Drug: Tacrolimus<br>* Selective T cell co-stimulation modulator produced by Bristol-Myers Squibb.<br>* Other names: Orencia;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of Grades II-IV Acute GvHD | The first day of acute GvHD of any grade is used to calculate the cumulative incidence for that grade. The diagnosis of acute GvHD is based on clinical and pathological evaluation by the principal investigator in collaboration with the treating physician. | Up to Day 120 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Incidence of Chronic GvHD | The first day of chronic GvHD is used to calculate the cumulative incidence of chronic GvHD. The diagnosis of chronic GvHD is based on clinical and pathological evaluation by the principal investigator in collaboration with the treating physician. | Up to Day 365 | 
| Number of Participants Presenting with Primary Graft Failure | Primary graft failure is defined as failure to achieve neutrophil engraftment by Day 28 after transplant or lack of donor chimerism greater than 50% by Day 45, not due to the underlying malignancy. | Up to Day 45 | 
| Number of Participants Presenting with Poor Graft Function | Poor graft function is defined by at least 2 of the following 3 criteria: Hemoglobin less than 8 g/dL, absolute neutrophil count less than 0.5 x 109/L, and platelets less than 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. | Up to Day 30 | 
| Number of Participants Presenting with Secondary Graft Failure | Secondary graft failure is defined as poor graft function associated with donor chimerism less than 5%. | Up to Day 730 | 
| Treatment-Related Mortality (TRM) Rate | The proportion of participant deaths not attributable to disease relapse or progression. | Up to Day 730 | 
| Relapse Rate (RR) | The proportion of participants in whom the disease for which transplant was performed is evident by methods of disease detection. | Up to Day 730 | 
| GvHD and Relapse-Free Survival (GRFS) Rate | The proportion of participants who are without reported grade III-IV acute GvHD, chronic GvHD requiring systemic therapy and have not experienced relapse or death. | Up to Day 730 | 
| Overall Survival (OS) Rate | The proportion of participants who are alive at the end of the study's evaluation period. | Up to Day 730 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Haploidentical Hematopoietic Stem Cell Transplantation