Safety & Efficacy of Atorvastatin for Prophylaxis of Acute Graft Versus Host Disease in Patients With Hematological Malignancies HLA- Donor Hematopoietic Stem Cell Transplantation

Study Overview
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Brief Summary
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Phase II trial evaluating the safety & efficacy of Atorvastatin for prophylaxis of Acute Graft Versus Host Disease (GVHD) in patients with hematological malignances undergoing human leukocyte antigen (HLA)-Matched Related Donor Hematopoietic Stem Cell Transplant (HSCT).

Detailed Description
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The study is a single-arm phase II single institutional trial evaluating the safety and efficacy of atorvastatin for the prophylaxis of acute GVHD in patients with hematological malignancies undergoing HLA matched related donor HSCT. This study will explore a two-pronged acute GVHD prophylaxis strategy, consisting of pre-treating consenting related donors with atorvastatin before stem cell mobilization and collection, followed by atorvastatin plus methotrexate/tacrolimus-based GVHD prophylaxis in transplant recipient patients.

Official Title
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Phase II Trial Evaluating the Safety and Efficacy of Atorvastatin for the Prophylaxis of Acute Graft Versus Host Disease(GVHD) in Patients With Hematological Malignancies Undergoing HLA-Matched Related Donor Hematopoietic Stem Cell Transplantation (HSCT)

Conditions
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Acute Myelogenous Leukemia, Acute Lymphocytic Leukemia, Myelodysplastic Syndrome

Intervention / Treatment
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* Drug: atorvastatin
* Drug: Tacrolimus
* Drug: methotrexate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Donor Eligibility Criteria The donor must be at least 18 years of age, and willing/able to provide informed consent. Complete medication list will be reviewed for potential negative interaction with atorvastatin. The donor must be an HLA-matched sibling or relative. Syngeneic donors are not eligible. Female donors of child-bearing potential should have a negative pregnancy test, and must not be breast feeding. Bilirubin, AST and ALT must be < 2 x normal; and absence of hepatic fibrosis/cirrhosis. Adequate renal function as defined by a serum creatinine clearance of ≥ 40% of normal calculated by Cockcroft-Gault equation. Adequate cardiac function with no history of congestive heart failure, uncontrolled atrial fibrillation or ventricular tachyarrhythmias. Patient Eligibility Criteria Have hematologic malignancy requiring allogeneic HSCT, have adequate organ function, a serologic (or higher resolution) 6/6 class I human leukocyte antigen (HLA)-A and B and molecular class II DRB1 matched related donor, and are able to give informed consent. Patients > 18 and ≤ 65 years with comorbidity score ≤ 3 will be eligible for myeloablative conditioning (MAC), while patients > 65 years of age, those with previous history of autologous transplantation, or high comorbidity index (>3) will be eligible for reduced intensity conditioning (RIC) transplantation . All patients must have at least one 6/6 HLA-matched sibling donor. Patient must provide informed consent Patients must have left ventricular ejection fraction > 30%, no uncontrolled arrhythmias or New York Heart Association class III-IV heart failure. Bilirubin must be < 2 x normal; and absence of hepatic fibrosis/cirrhosis. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must be <2 x normal; and absence of hepatic fibrosis/cirrhosis. Serum creatinine clearance of ≥40% of normal calculated by Cockcroft-Gault equation. Forced expiratory volume in one second (FEV1)and diffusion capacity; corrected for hemoglobin(DLCO) ≥ 50% and 40% of predicted respectively. Karnofsky performance status > 70. A negative pregnancy test will be required for all women of child bearing potential. Breast feeding is not permitted. No HIV infection. Patients with immune dysfunction are at a significantly higher risk of toxicities from intensive immunosuppressive therapies. No evidence of active bacterial, viral or fungal infection at the time of transplant conditioning. No active alcohol or substance abuse within 6 months of study entry. Prior allogeneic transplant is acceptable. No history of intolerance or allergic reactions with atorvastatin or other statins. Patients who have previously been taking atorvastatin or any other statin will be eligible as long as there is no contraindication to switch to atorvastatin 40mg/day in the opinion of the treating physician. Exclusion Criteria: Patients undergoing a T-cell depleted allogeneic transplantation will not be eligible. Patients receiving another investigational drug are not eligible unless cleared by Principal Investigator. Patients with prior malignancies except resected basal cell carcinoma, treated carcinoma in-situ, or other hematologic diseases for which allogeneic HSCT is a treatment strategy, are not eligible. Cancer treated with curative intent < 5 years previously will not be allowed unless approved by the Principal Investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Supportive Care
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Donor<br>Related donors will receive atorvastatin 40 mg/day orally at least 14 days before anticipated first day of stem cell leukapheresis (LP) until successful completion of leukapheresis according to institutional guidelines. Peripheral blood stem cells will not be manipulated or T-depleted prior to administration. | Drug: atorvastatin<br>* donors-will receive atorvastatin 40 mg/day orally at least 14 days before anticipated first day of stem cell leukapheresis (LP) until successful completion of leukapheresis according to institutional guidelines. Patients-will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first.<br>* Other names: Lipitor;|
| Experimental: Patient<br>Patients will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first. Standard post transplant care will be administered. | Drug: atorvastatin<br>* donors-will receive atorvastatin 40 mg/day orally at least 14 days before anticipated first day of stem cell leukapheresis (LP) until successful completion of leukapheresis according to institutional guidelines. Patients-will receive atorvastatin 40 mg starting at least 7 days before initiation of transplant conditioning regimen, to permit a 1 week observation period to rule out any atorvastatin-induced side effects before initiation of transplant conditioning. Patients will continue on atorvastatin with standard GVHD prophylaxis with tacrolimus and methotrexate until end of GVHD prophylaxis according to institutional standard guidelines, or until development of endpoint, which ever should occur first.<br>* Other names: Lipitor;Drug: Tacrolimus<br>* beginning on Day -2 through approximately Day +180 (that is, approximately 6 months after Day 0)<br>* Other names: Prograf;Drug: methotrexate<br>* Day +1, +3, and +6 and +11<br>* Other names: MTX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Grades II to IV aGVHD at Day +100 of Atorvastatin Administration | The incidence of grades II to IV aGVHD at day +100 of atorvastatin administration. The grading of aGVHD and cGVHD were done using the Consensus Conference criteria. | Up through day 100 following transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Atorvastatin in Transplant Recipients in Terms of Adverse Events and Toxicities. | Adverse events and toxicities were monitored in patients using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 criteria. | Patients: Baseline, weekly for 9 weeks and then on days 84, 91-100, 180 and 365. Donors: at apheresis and then 30 days later. | 
| Time to Neutrophil and Platelet Engraftment | Neutrophil engraftment will be defined as first of three consecutive days with ANC ≥ 0.5 x 109/L post-conditioning regimen induced nadir. Similarly platelet engraftment is defined as first day of platelet count ≥ 20,000 x 109/L, without transfusion for 7 consecutive days. | weekly for 12 weeks, 100 days, 6 months, and 12 months | 
| Percentage of Patients With Chronic Graft Versus Host Disease (cGVHD) | cGVHD occurring anytime after day 100 post transplant will be termed chronic GVHD, and evaluated in patients who were followed for at least 100 days without early progression or death. Grading of cGVHD was done using the National Institutes of Health Consensus Development Project Criteria | up 1 year post transplant | 
| Non Relapse Mortality (NRM) at One Year | Cumulative incidence of NRM will be calculated as the time from transplant until death not related to disease, where the competing risk for NRM was death due to disease. Patients who had not died were censored at last follow up. | up to 12 months post transplant | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AML, Leukemia, ALL, MDS