High-Dose Post-Transplant Cyclophosphamide and Bortezomib (CyBor) for the Prevention of Graft-versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

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 matched-related or unrelated donor are eligible for the study if they meet the standard criteria defined in the investigator's institutional standard operation procedures (SOPs), meet all inclusion criteria, and do not satisfy any exclusion criteria. Patients will receive reduced-intensity or myeloablative conditioning regimen of fludarabine, busulfan, and rabbit anti-thymocyte globulin (rATG). Patients will receive PTCyBor as GvHD prophylaxis.

Official Title
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A Phase II Study of High-Dose Post-Transplant Cyclophosphamide and Bortezomib (CyBor) for the Prevention of Graft-versus-Host Disease Following Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Conditions
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GVHD

Intervention / Treatment
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* Drug: Bortezomib
* Drug: Cyclophosphamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Karnofsky score ≥ 70% No evidence of progressive bacterial, viral, or fungal infection Creatinine clearance > 50 mL/min/1.72m2 Total bilirubin, ALT and AST < 2 x the upper limit of normal (except for 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) Exclusion Criteria: Pregnant or nursing females or women of reproductive capability who are unwilling to completely abstain from heterosexual sex or practice 2 effective methods of contraception from the first dose of bortezomib through 90 days after the last dose. 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. Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma, an in-situ malignancy, or low-risk prostate cancer after curative therapy. 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

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cyclophosphamide and Bortezomib<br> | Drug: Bortezomib<br>* 1.3 mg/m2 IV 6 hours after graft infusion and 72 hours thereafter.<br>Drug: Cyclophosphamide<br>* 50 mg/kg IV over 2 hours on Day +3 and +4<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experience Acute GvHD | Rate of acute GvHD post-transplant. All participants that received a transplant and received any prophylactic treatment will be included in the analysis. | Day 120 Post-Transplant | 
| Percentage of Participants Who Experience Moderate to Severe Chronic GvHD | Rate of chronic GvHD post-transplant. All participants that received a transplant and received any prophylactic treatment will be included in the analysis. | Day 365 Post-Transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Primary Graft Failure | Incidence of graft failure will be calculated from date of transplant to failure for all patients who receive a transplant and any prophylactic treatment and from date of completion of prophylactic treatment for all participants that completed treatment. Graft failure is defined as failure to achieve neutrophil engraftment by day 28 post-transplant or lack of donor chimerism > 50% by day 45 post-transplant not due to the underlying malignancy. | Day 45 Post-Transplant | 
| Incidence of Poor Graft Function | Incidence of poor graft function will be calculated from date of transplant to failure for all patients who receive a transplant and any prophylactic treatment and from date of completion of prophylactic treatment for all participants that completed treatment. Poor graft function is defined by at least 2 of the following 3 criteria: Hemoglobin < 8 g/dL, ANC < 0.5 109/L, and platelets < 20 109/L. The cytopenia must be unexplained (such as by disease relapse) and unresponsive to cytokines and must last at least 4 weeks. | Day 30 Post-Transplant | 
| Incidence of Secondary Graft Failure | Incidence of secondary graft failure is evaluated after engraftment is achieved; this outcome is calculated from date of engraftment for all patients with engraftment. Secondary graft failure is defined as poor graft function associated with donor chimerism < 5%. | Day 730 Post-Transplant | 
| Treatment Related Mortality (TRM) | Number of participant deaths not attributable to disease relapse or progression . This outcome is analyzed based on participants that who received a transplant with any prophylactic treatment and for all patients who received a transplant and completed prophylactic treatment. | Day 730 Post-Transplant | 
| Relapse Rate (RR) | Percentage of participants in whom the disease for which transplant is performed is evident by methods of disease detection after transplant. This outcome is analyzed for all patients who received a transplant and for all transplanted patients that completed treatment. | Day 730 Post-Transplant | 
| Graft Versus Host Disease Relapse Free Survival (GRFS) | Percentage of participants who are without reported GvHD III-IV acute GvHD, chronic GvHD requiring systemic therapy and have not experienced relapse or death after transplant. | Day 730 Post-Transplant | 
| Overall Survival (OS) | Percentage of participants alive at the end of the study's evaluation period. | Day 730 Post-Transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cyclophosphamide, Bortezomib