Atorvastatin as GVHD Prophylaxis for Allogeneic Hematopoietic Cell Transplantation

NCT01665677 | Completed Phase 2 Results DMC

• 3 other identifiers: PRO00021090WVU 011012116837-IRG-09-061-01
• Study Type: interventional
• Target: 69
• Locations: 1 country
• Sites: 2

Brief Summary

Hematopoietic stem cell transplantation is a procedure in which a person receives blood forming stem cells from a person called a "donor." The stem cells can be obtained from the hollow part of the hip bone or from blood. A serious problem with this treatment is graft-versus-host disease (GVHD). This happens when stem cells from the donor attack normal cells of the recipient. Currently, there is no universal standard of care in the United States to prevent GVHD. This study is being done to see if a medicine that is used to lower cholesterol can also help in reducing GVHD. Patients will receive atorvastatin daily by mouth starting 14 days before stem cell transplant. They will continue to take atorvastatin until 180 days after transplant. This medicine may be stopped earlier if there is a bad side effect or a severe GVHD. Patients will also receive standard treatment to prevent GVHD. Patients will undergo many tests that are standard for their treatment at West Virginia University (WVU), including blood tests to check blood counts, kidney function and HIV status; blood test to check for pregnancy; Multi Gated Acquisition Scan (MUGA scan)or echocardiogram to test heart function; lung function testing; and bone marrow aspirate or biopsy. Patients will also have the option to provide blood samples for optional research related to the study.

Conditions

Graft vs Host Disease

Keywords

Graft vs Host Disease; GVHD; Allogeneic hematopoietic stem cell transplantation; HSCT; Atorvastatin

Outcome Measures

Primary Outcomes (2)

• Matched Related Transplants Who Develop Grade II-IV Acute Graft Versus Host Disease (GVHD).

  The number of subjects in the matched sibling cohort who develop grades II-IV acute GVHD will be assessed by consensus criteria and graded on Bone Marrow Transplant Clinical Trials Network Manual of Procedures suggested grading sheets. Grade I is mild GVHD involving up to 25% of the subject's skin; Grade II is moderate GVHD. involving 25 to 50% of the subject's skin and can include mild changes in liver and/or mild diarrhea; Grade III is severe GVHD involving over 50% of the subject's skin. Liver involvement is likely as are stomach cramps and diarrhea; and Grade 4 is very severe GvHD. Skin may be blistered and may have broken down in places. Skin may be yellow due to liver injury. Severe diarrhea is common. Subjects in the matched unrelated donors are not included in this analysis.

  Day 100

• Matched Unrelated Donors Transplants Who Develop Grade II-IV Acute GVHD.

  The number of subjects in the matched unrelated donor cohort who develop grade II-IV acute GVHD. Acute GVHD will be assessed by consensus criteria and graded on Bone Marrow Transplant Clinical Trials Network Manual of Procedures suggested grading sheets. Grade I is mild GVHD involving up to 25% of the subject's skin; Grade II is moderate GVHD. involving 25 to 50% of the subject's skin and can include mild changes in liver and/or mild diarrhea; Grade III is severe GVHD involving over 50% of the subject's skin. Liver involvement is likely as are stomach cramps and diarrhea; and Grade 4 is very severe GvHD. Skin may be blistered and may have broken down in places. Skin may be yellow due to liver injury. Severe diarrhea is common. Subjects in the matched related donors are not included in this analysis.

  Day 100

Secondary Outcomes (2)

• Matched Related Transplants Who Develop Grade II-IV Chronic GVHD.

  1 year

• Matched Unrelated Donors Transplants Who Develop Grade II-IV Chronic GVHD.

  1 year

Study Arms (2)

Atorvastatin calcium (Lipitor)

EXPERIMENTAL

Atorvastatin will be administered at a dose of 40 mg orally daily starting on day -14, to permit an approximately 1-week observation period to rule out any acute atorvastatin-induced side effects before the initiation of transplant conditioning. Patients will receive atorvastatin until +180 days or until the patient develops grade II-IV acute GVHD, extensive chronic GVHD, or any grade 3-4 toxicity related to atorvastatin.

Drug: Atorvastatin calcium

Unrelated Donor

EXPERIMENTAL

Atorvastatin will be administered at a dose of 40 mg orally daily starting on day -14, to permit an approximately 1-week observation period to rule out any acute atorvastatin-induced side effects before the initiation of transplant conditioning. Patients will receive atorvastatin until +180 days or until the patient develops grade II-IV acute GVHD, extensive chronic GVHD, or any grade 3-4 toxicity related to atorvastatin.

Drug: Atorvastatin calcium

Interventions

Atorvastatin calcium DRUG

40 mg PO daily

Also known as: Lipitor

Atorvastatin calcium (Lipitor); Unrelated Donor

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with a history of a hematological malignancy or bone marrow failure syndrome suitable for allogeneic stem cell transplantation in the opinion of treating transplant physician.
• Patients aged 18-75 years of age are eligible. Patients with age \> 18 and ≤ 50 years will be eligible for myeloablative conditioning (MAC), while patients \> 50 years of age, or those with previous history of autologous transplantation, high hematopoietic cell transplant comorbidity index (HCT-CI) score (\>2), and baseline diagnosis of hodgkin's lymphoma, chronic lymphocytic leukemia and follicular lymphoma will be suitable for reduced intensity conditioning (RIC) transplantation (however intensity of conditioning regimen will remain at the discretion of treating physician).
• All patients must have at least one suitable human leukocyte antigen (HLA)-matched sibling or unrelated donor according to transplant center's guidelines (for selection of appropriate sibling donor).
• Patient must provide informed consent.
• Left ventricular ejection fraction ≥ 40%.
• Bilirubin ≤ 2 x the upper limit of normal (ULN) and aspartate aminotransferase (AST), and alanine aminotransferase (ALT) ≤ 3 x ULN; and absence of hepatic cirrhosis. For patients with Gilbert's syndrome, bilirubin ≤ 3 x ULN is permitted.
• Adequate renal function as defined by a serum creatinine clearance of ≥ 40% of normal calculated by Cockcroft-Gault equation.
• Carbon monoxide diffusing capacity (DLCOcor) corrected for hemoglobin or forced expiratory volume at one second (FEV1) or DL/VA ≥ 40% of predicted (a pulmonary function test).
• Karnofsky performance status \> 70.
• A negative pregnancy test will be required for all women of child bearing potential. Breast feeding is not permitted.
• Patients with positive HIV serology are eligible.
• Patients who have previously been taking atorvastatin or any other statin drug will be eligible as long as there is no contraindication to switch to atorvastatin (40mg/day) in the opinion of the treating physician.
• Method of stem-cell collection from the sibling donor will be at the discretion of the treating physician. Although it is anticipated that majority of sibling donors will undergo Granulocyte colony-stimulating factor(G-CSF) induced stem cell mobilization; however donors undergoing bone marrow harvest or stem cell mobilization with experimental agents (e.g. plerixafor) will remain eligible for the study.

You may not qualify if:

• Uncontrolled arrhythmias or uncontrolled New York Heart Association class III-IV heart failure.
• Evidence of active bacterial, viral or fungal infection at the time of transplant conditioning.
• History of intolerance or allergic reactions with atorvastatin will not be eligible.
• Undergoing a T-cell depleted allogeneic transplantation
• Receiving conditioning regimens containing anti-thymocyte globulin, and/or campath

Sponsors & Collaborators

• Mehdi Hamadani: lead
• West Virginia University: collaborator

Study Sites (2)

West Virginia University Hospitals Mary Babb Randolph Cancer Center

Morgantown, West Virginia, 26506, United States

Location

Froedtert Hospital and the Medical College of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (7)

• Deeg HJ. How I treat refractory acute GVHD. Blood. 2007 May 15;109(10):4119-26. doi: 10.1182/blood-2006-12-041889. Epub 2007 Jan 18.

  PMID: 17234737 BACKGROUND

• Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, Fay JW, Nademanee A, Antin JH, Christiansen NP, van der Jagt R, Herzig RH, Litzow MR, Wolff SN, Longo WL, Petersen FB, Karanes C, Avalos B, Storb R, Buell DN, Maher RM, Fitzsimmons WE, Wingard JR. Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood. 1998 Oct 1;92(7):2303-14.

  PMID: 9746768 BACKGROUND

• Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM, Przepiorka D, Davies S, Petersen FB, Bartels P, Buell D, Fitzsimmons W, Anasetti C, Storb R, Ratanatharathorn V. Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood. 2000 Sep 15;96(6):2062-8.

  PMID: 10979948 BACKGROUND

• Antin JH, Kim HT, Cutler C, Ho VT, Lee SJ, Miklos DB, Hochberg EP, Wu CJ, Alyea EP, Soiffer RJ. Sirolimus, tacrolimus, and low-dose methotrexate for graft-versus-host disease prophylaxis in mismatched related donor or unrelated donor transplantation. Blood. 2003 Sep 1;102(5):1601-5. doi: 10.1182/blood-2003-02-0489. Epub 2003 May 1.

  PMID: 12730113 BACKGROUND

• Liao JK, Laufs U. Pleiotropic effects of statins. Annu Rev Pharmacol Toxicol. 2005;45:89-118. doi: 10.1146/annurev.pharmtox.45.120403.095748.

  PMID: 15822172 BACKGROUND

• Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995 Jun;15(6):825-8.

  PMID: 7581076 BACKGROUND

• Kanate AS, Hari PN, Pasquini MC, Visotcky A, Ahn KW, Boyd J, Guru Murthy GS, Rizzo JD, Saber W, Drobyski W, Michaelis L, Atallah E, Carlson KS, D'Souza A, Fenske TS, Cumpston A, Bunner P, Craig M, Horowitz MM, Hamadani M. Recipient Immune Modulation with Atorvastatin for Acute Graft-versus-Host Disease Prophylaxis after Allogeneic Transplantation. Biol Blood Marrow Transplant. 2017 Aug;23(8):1295-1302. doi: 10.1016/j.bbmt.2017.04.009. Epub 2017 Apr 12.

  PMID: 28412518 RESULT

MeSH Terms

Conditions

Graft vs Host Disease

Interventions

Atorvastatin

Condition Hierarchy (Ancestors)

Immune System Diseases

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids

Results Point of Contact

• Title: Dr. Medhi Hamadani
• Organization: Medical College of Wisconsin

mhamadani@mcw.edu

414-805-6800

Study Officials

• Michael Craig, MD

  West Virginia University

  PRINCIPAL INVESTIGATOR

• Mehdi Hamadani, MD

  Medical College of Wisconsin

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: August 13, 2012
• First Posted: August 15, 2012
• Study Start: January 20, 2014
• Primary Completion: July 9, 2021
• Study Completion: July 9, 2021
• Last Updated: May 15, 2023
• Results First Posted: May 15, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)