Phase II Study of Atorvastatin, Micro-dose Methotrexate and Tacrolimus Administered Only to Transplant Recipients for the Prophylaxis of Acute Graft-versus-host Disease Following Allogeneic Hematopoietic Cell Transplantation
Phase: PHASE2
Conditions: Graft vs Host Disease
Sponsor: Mehdi Hamadani

Protocol Title:  Phase II Study of Atorvastatin, Micro-Dose Methotrexate and Tacrolimus 
Administered only to Transplant Recipients for the Prophylaxis of Acute Graft-Versus-
Host Disease Following Allogeneic Hematopoietic Cell Transplantation 
 
NCT Number:  NCT01665677 
 
Date:  07/03/2014 

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Phase II study of Atorvastatin, micro-dose 
methotrexate and tacrolimus administered only to 
transplant recipients for the prophylaxis of acute 
graft-versus-host disease following allogeneic 
hematopoietic cell transplantation. 
 
 
 
Principal Investigator: 
Mehdi Hamadani, MD 
 
Associate Professor of Medicine,  
 
 
Division of Hematology and Oncology 
 
Froedtert Hospital and the Medical College of Wisconsin 
 
9200 W. Wisconsin Ave. 
 
Milwaukee, WI 53226 
 
Co-Investigators: 
Parameswaran Hari, MD 
 
Mary M. Horowitz, MD 
 
William Drobyski, MD 
 
Timothy S. Fenske 
 
Douglas Rizzo, MD 
 
Marcelo Pasquini, MD 
 
 
 
Wael Saber, MD 
 
Michael Craig, MD 
 
Abraham Kanate, MD 
 
William Petros, PharmD 
 
Aaron Cumpston, PharmD 
 
Scot C. Remick, MD 
 
 
 
Statistician: 
 
 
Alexis Visotcky, MS 
 
Biostatistician II 
 
Division of Biostatistics 
 
Institute for Health and Society 
 
avisotcky@mcw.edu 
 
 
  
 
 

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Study Coordinator: 
For Medical College of Wisconsin: 
Barbara Davies 
Division of Hematology and Oncology 
Froedtert Hospital and the Medical College of Wisconsin 
9200 W. Wisconsin Ave. 
Milwaukee, WI 53226 
Phone: 414-805-8926  
Fax: 414-805-0596 
Email: bdavies@mcw.edu  
 
For West Virginia University: 
 
Pam Bunner, MT, CRCC 
Clinical Research Specialist 
Osborn Hematopoietic Malignancy and Bone Marrow Transplant Service 
Mary Babb Randolph Cancer Center 
PO Box 8110 
One Medical Center Drive 
Morgantown, WV 26506 
Phone:  (304) 598-4511 
Fax:  (304) 598-4519 
Email:  bunnerp@wvuhealthcare.com  
 
Pharmacists 
 
Angela Urmanski, Pharm D. 
Froedtert Hospital 
Inpatient Pharmacy 
Attn: Senad Novic 
9200 W Wisconsin Ave 
Milwaukee,  WI 53226 
 
 
Lisa-Giblin Sutton, Pharm D.,  
Investigational Drug Pharmacist 
West Virginia University Hospitals Pharmaceutical Services 
PO Box 8045  
One Medical Center Drive 
Morgantown, WV 26506 
Phone:  (304) 598-4000 x73760 
Fax:  (304) 598-4073 
Email:  giblinl@wvuhealthcare.com  
 
 

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Schema 
Phase II study of Atorvastatin, micro-dose methotrexate and 
tacrolimus administered only to transplant recipients for the 
prophylaxis of acute graft-versus-host disease following allogeneic 
hematopoietic cell transplantation. 
 
PRIMARY OBJECTIVES: 
1. Determine the efficacy of an atorvastatin/tacrolimus/methotrexate regimen in preventing 
grade II-IV acute GVHD in patients undergoing allogeneic hematopoietic stem cell 
transplantation (HSCT).  
2. Assess the safety of an atorvastatin/tacrolimus/methotrexate regimen in patients 
undergoing allogeneic HSCT. 
 
SECONDARY OBJECTIVES: 
1. To assess rates of chronic GVHD. 
2. To assess rates of late onset acute GVHD at days +180 and +365. 
3. To assess rates of grade III-IV acute GVHD at days +100, +180 and +365. 
4. To assess non-relapse mortality at 100 days post-HSCT. 
5. To assess time to successful neutrophil engraftment. 
6. To assess time to successful platelet engraftment. 
7. To assess incidence of primary and secondary graft failure. 
8. To assess incidence of primary and secondary graft rejection. 
9. To assess relapse rate of the primary hematological malignancy.  
10. To assess lineage specific chimerism kinetics in patients at days +28, +100, +180 and 
+365. 
11. To assess immune reconstitution following transplantation at days +28, +100, +180, and 
+365. 
12. To assess 1 year progression free survival (PFS) and overall survival (OS) following 
transplantation.  
13. To evaluate biologic and genomic markers potentially associated with GVHD and/or 
atorvastatin. 
 
 
STUDY DESIGN: 
This is a phase II study of atorvastatin for the prophylaxis of acute GVHD in patients undergoing 
allogeneic HSCT. The study will have two separate arms: (a) Matched sibling transplants, and 
(b) Matched unrelated donors transplants. Both arms will be enrolled, and analyzed separately.  
 
 
 
 
 

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PATIENT ELIGIBILITY CRITERIA: 
1. 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. 
2. 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). 
3. All patients must have at least one suitable HLA-matched sibling or unrelated donor 
according to transplant center’s guidelines (for selection of appropriate donor). 
4. Patient must provide informed consent.  
5. Left ventricular ejection fraction ≥ 40%. No uncontrolled arrhythmias or uncontrolled 
New York Heart Association class III-IV heart failure. 
6. Bilirubin ≤ 2 x the ULN and AST, and ALT ≤ 3 x ULN; and absence of hepatic cirrhosis. 
For patients with Gilbert’s syndrome, bilirubin ≤ 3 x ULN is permitted.  
7. Adequate renal function as defined by a serum creatinine clearance of ≥ 40% of normal 
calculated by Cockcroft-Gault equation. 
8. DLCOcor (corrected for hemoglobin) or FEV1 or DL/VA ≥ 40% of predicted.  
9. Karnofsky performance status > 70.  
10. A negative pregnancy test will be required for all women of child bearing potential. 
Breast feeding is not permitted.  
11. Patients with positive HIV serology are eligible.  
12. No evidence of active bacterial, viral or fungal infection at the time of transplant 
conditioning. 
13. Patients with history of intolerance or allergic reactions with atorvastatin will not be 
eligible.  

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14. 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. 
15. Patients undergoing a T-cell depleted allogeneic transplantation will not be eligible. 
16. Patients receiving conditioning regimens containing antithymocyte globulin, and/or 
campath will not be eligible.  
17. Method of stem-cell collection from the donor will be at the discretion of the treating 
physician. Although it is anticipated that majority of donors will undergo 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.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Patient Treatment Plan 
 
 
 
 
 
 
 
 
Step1
•Registration
•Baseline evaluations (H&P, vital signs, CBC+differential, 
chemisteries, β-HCG, HIV, KPS, infectious disease titers, 
LVEF, DLCO, BMBx, chimerism specimens, Correlative 
specimens)
Step2
• Start atorvastatin 40mg/day orally on Day -14
• Acceptable MAC Regimens are BuCy2; CY/TBI; TBI/VP:16
• Acceptable RIC Regimens are Flu/Bu; Flu/Mel, Flu/TBI
Step3
•Continue atorvastatin until: (1) Day +180 or until patient 
is off IST, (2) patient develop grade II-IV acute GVHD, (3) 
patient develops extensive chronic GVHD, or (4) patient 
develops any grade 3-4 toxicity related to atorvastatin
•Follow patient for survival until day +365

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Table of Contents 
 
1. 
INTRODUCTION: ............................................................................................................................................ 9 
1.1. 
Graft versus Host Disease: ......................................................................................................................... 9 
1.2. 
HMG-CoA Reductase Inhibitors: ............................................................................................................... 9 
1.3. 
Immunomodulatory effects of Statins: ....................................................................................................... 9 
1.4. 
Pathophysiology of GVHD: ..................................................................................................................... 10 
1.5. 
Statins and Murine Acute GVHD: ............................................................................................................ 10 
1.6. 
Statins and Clinical GVHD: ..................................................................................................................... 11 
1.7. 
Clinical Trial Data for Statin use for preventing acute GVHD: ............................................................... 13 
1.8. 
Inclusion of Women and Minorities: ........................................................................................................ 14 
2. 
OBJECTIVES: ................................................................................................................................................. 14 
2.1. 
Primary Objectives: .................................................................................................................................. 14 
2.2. 
Secondary Objectives: .............................................................................................................................. 15 
3. 
ELIGIBILITY CRITERIA: ............................................................................................................................ 15 
3.1. 
Patient Eligibility Criteria: ........................................................................................................................ 15 
4. 
REGISTRATION PROCEDURE: ................................................................................................................. 17 
4.1.1. 
Registration for collaborating institution(s): ........................................................................................ 17 
5. 
TREATMENT PLAN: ..................................................................................................................................... 17 
5.1. 
Administration schedule to Patients (Transplant recipients) .................................................................... 18 
5.2. 
Dose modification .................................................................................................................................... 19 
5.3. 
Duration of therapy ................................................................................................................................... 19 
5.4. 
Data Safety Monitoring Plan .................................................................................................................... 20 
6. 
MEASUREMENT OF EFFECT: ................................................................................................................... 20 
6.1. 
Visit Schedule:.......................................................................................................................................... 20 
*After 12months, patients will be followed at least yearly for survival, relapse and cause of death for 5 years post 
transplantation. ........................................................................................................................................................ 21 
6.2. 
GVHD Assessment: .................................................................................................................................. 21 
6.3. 
Engraftment Assessment: ......................................................................................................................... 22 
7. 
STUDY PARAMETERS (STUDY CALENDAR): ....................................................................................... 22 
7.1. 
Patient Study Calendar: ............................................................................................................................ 22 
8. 
DRUG FORMULATION AND PROCUREMENT ...................................................................................... 25 
8.1. 
Atorvastatin (Lipitor® Pfizer) ................................................................................................................... 25 
8.1.1. 
Drug description .................................................................................................................................. 25 
8.1.2. 
Pharmacodynamics .............................................................................................................................. 25 
8.1.3. 
Pharmacokinetics ................................................................................................................................. 26 
8.1.4. 
Contraindications ................................................................................................................................. 26 
8.1.5. 
Drug Interactions ................................................................................................................................. 26 
8.1.6. 
Adverse Events: ................................................................................................................................... 28 
8.2. 
How supplied and Storage/Handling ........................................................................................................ 29 
8.3. 
Methods of procurement ........................................................................................................................... 30 
9. 
STATISTICAL CONSIDERATIONS: .......................................................................................................... 30 
10. 
ADVERSE EVENT REPORTING REQUIREMENTS ............................................................................... 32 
DEFINITIONS ........................................................................................................................................................... 32 

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11. 
PATIENT CONSENT AND PEER REVIEW STATEMENT ..................................................................... 36 
11.1. 
Subject Information and Informed Consent .............................................................................................. 36 
12. 
REFERENCES: ............................................................................................................................................... 38 
13. 
APPENDIX A ASSESSMENT OF ACUTE GVHD...................................................................................... 41 
14. 
APPENDIX B GRADING OF CHRONIC GVHD (NIH CRITERIA) ........................................................ 43 
 
 
 

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1. Introduction:   
 
1.1. Graft versus Host Disease: 
Acute graft-versus-host disease (GVHD) is one of the most frequent complications after 
allogeneic hematopoietic stem cell transplantation (HSCT) (1). It develops in 30-75% of 
recipients of allogeneic HSCT depending on the degree of histocompatibility between the donor 
and the recipient, number of T-cells in the graft, recipient’s age and GVHD prophylactic regimen 
used (2-4). Novel strategies designed to effectively prevent the development of this life 
threatening complication of allogeneic transplantation are urgently needed.  
 
1.2. HMG-CoA Reductase Inhibitors:  
HMG-CoA reductase inhibitors (statins), the cholesterol-lowering drugs that are prescribed 
worldwide to prevent and treat atherosclerosis (5), are increasingly being recognized to exhibit a 
variety of immunomodulatory properties (6). The mechanism of action of statins involves 
binding to HMG-CoA reductase and displacement of its natural substrate, HMG-CoA, leading to 
inhibition of mevalonate and cholesterol biosynthesis (5).  
 
1.3. Immunomodulatory effects of Statins: 
In addition to lowering lipid concentrations, statins have recently been shown to possess 
potent immunomodulatory and anti-inflammatory properties that are relevant not only in the 
context of atherosclerosis-associated inflammation but also in autoimmune diseases such as 
multiple sclerosis and rheumatoid arthritis (7-9). Reduced mevalonate production by statins, not 
only inhibits the synthesis of cholesterol but also that of key isoprenoid intermediate molecules 
required for the isoprenylation of GTP-binding cell signaling proteins such as Ras, Rho and Rac 
(5). By inhibiting this posttranslational modification, statins affect intracellular signaling 
pathways and cellular functions such as differentiation, motility, secretion and proliferation 
(7,10).  Inhibiting Ras leads to a bias towards T helper type 2 (Th-2) cell development, and 
inhibition of pro-inflammatory Th-1 driven responses (7,11). This change in intracellular 
signaling can also affect the development of regulatory T (Treg) cells, as exposure of human 
CD4+ T cells to atorvastatin in vitro increases expression of forkhead box P3 (FOXP3) (12). In 
fact increased numbers of circulating FOXP3+ Treg cells are present in dyslipidemic patients 

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taking statins for 4-6 weeks (12). Mira et al. demonstrated statin mediated increases in the 
migration of Treg cells to inflammatory foci in skin by increased the expression of CCL1, the 
ligand for CCR8, a chemokine receptor that is highly expressed on Th-2 cells and FOXP3+ Treg 
cells (13). In addition to direct effects on T cells, statins can also indirectly decrease T-cell 
activation by inhibiting interferon-γ–induced expression of major histocompatibility complex 
class (MHC) II and by blocking up-regulation of a variety of co-stimulatory molecules and 
cytokines in antigen presenting cells (APCs) (7). Hence statins appear to suppress T cell–
dependent immune responses at many levels and hold promise as a new class of 
immunomodulatory drugs, with potential role in preventing acute GVHD. 
 
 
1.4. Pathophysiology of GVHD: 
Acute GVHD is initiated when donor T cells encounter host APCs in lymphoid tissues and 
become activated (14). This T-cell activation process requires co-stimulation via CD80 and 
CD86, which are up-regulated on APCs during the early phase of  acute GVHD. Activation is 
enhanced by local tissue damage due to the conditioning regimen. Local proinflammatory 
cytokines such as tumor necrosis factor (TNF), interleukin 1 (IL-1), and interferon (IFN)-
gamma, promote Th-1 differentiation of donor-derived T cells and enhance their proliferation 
and reactivity against host tissues (15). Massive cytokine release related to the Th-1 phenotype 
predicts the incidence and severity of acute GVHD in both murine models and humans, whereas 
patients with high IL-10 production are less at risk for GVHD development (16-18).  
 
 
1.5. Statins and Murine Acute GVHD: 
Zeiser and colleagues (19) reported protective effects of atorvastatin against acute GVHD in 
a MHC mismatched mouse model. In a series of elegant experiments, the authors demonstrated 
reduced risk of lethal acute GVHD by pre-treating the donor mice with atorvastatin. T-cells 
derived from these atorvastatin pre-treated mice not only showed reduced proliferation potential, 
but also displayed (both in-vivo and in-vitro) reduced Th-1 cytokine (TNF, IFN-gamma) and 
increased Th-2 cytokine (IL-10, IL-4) production. Zeiser and colleagues also investigated the 
impact of atorvastatin administration to recipient mice. Atorvastatin when given to recipient 

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mice only translated into acute GVHD protection with a long-term survival of 50%, compared 
with 0% survival in control animals. Recipient APCs derived from liver, spleen, and lymph 
nodes of recipient mice getting atorvastatin or PBS were analyzed at different time points after 
transplantation. Surface expression of CD80, CD86, CD40, and MHC class II was decreased in 
animals treated with the atorvastatin as compared with PBS-treated recipients. Interestingly pre-
treating both donor and recipient mice with atorvastatin produced synergistic protective effects, 
when compare with survival of only donor or recipient pre-treated groups. Perhaps the most 
significant finding was that atorvastatin pretreatment did not interfere with perforin-mediated 
cytolysis or Fas–Fas-ligand interaction–mediated killing. In summary these key experiments 
highlight the potential of atorvastatin in protecting against acute GVHD, while preserving the 
graft-versus-leukemia (GVL) effects.  
 
These landmark experiments hold great translational potential for clinical benefit in the 
field of allogeneic SCT. In humans, elevated IL-10 production by peripheral blood mononuclear 
cells before allogeneic SCT is associated with a subsequent low incidence of acute GVHD and 
transplant-related mortality (20,21), whereas low IL-10 promoter activity predicts an increased 
risk for GVHD (19). Shimada and colleagues have shown Th-2 polarization in adult patients with 
acute coronary syndrome after treatment with atorvastatin (22). A number of other publications 
in humans have reported similar findings (23-26)., which highlight the fact that the reduced 
GVHD reported by Zeiser et al (19) by pre-treating donors with atorvastatin in murine models, 
can be translated into real clinical benefit in allogeneic transplant recipients. In humans and 
murine models statins also inhibit the expression of T-bet, a transcription factor critically 
involved in Th-1 cell differentiation (25,27,28). Lastly the down regulation of co-stimulatory 
molecules and MHC-II expression in recipient mice demonstrated by Zeiser et al (19), has also 
been described in humans treated with statin drugs (25,29) 
 
 
1.6. Statins and Clinical GVHD: 
 
Prompted by these tantalizing data, we therefore asked whether statin use at the time of 
allogeneic SCT would result in reduced acute GVHD while sparing GVL activity (30). Sixty-
seven consecutive patients with acute leukemia underwent T-cell replete allogeneic SCT 
between June 2002 and October 2006 at The Ohio State University. Patients taking statins 

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(defined as any HMG-CoA reductase inhibitor) at ≥40mg/day for at least 1month before and 
3months after allogeneic SCT (n=10) were compared to those without a history of statin use 
(n=57). The median age was 43 years (range 20-73yrs). Diagnosis included acute myeloid 
leukemia (AML) (n=49) and acute lymphoblastic leukemia (ALL) (n=18). The two groups had 
similar baseline characteristics. Acute GVHD was scored according to modified consensus 
criteria (31). The rate of grade II-IV acute GVHD was 10% (n=1) in the statin group compared to 
40% (n=23) in the no-statin group (p-value=0.08). 56 patients were evaluable for chronic 
GVHD. No difference in the incidence of chronic GVHD was seen in patients using statins 
(55%) compared to those in no-statin group (57%) (p-value=0.9). No patient in either group 
experience primary or secondary engraftment failure. On subgroup analysis of patients with 
AML only (n=49), a significantly reduced incidence of grade II-IV acute GVHD was seen in 
statin group (0%) compared to 43% (n=18) in the no-statin group (p-value=0.02). Rates of 
chronic GVHD were 43% and 58% in similar order (p-value=0.68). We further explored to see if 
statin use, while reducing acute GVHD, mitigated the GVL effect in patients with AML. Kaplan-
Meier estimates of progression free survival (PFS) at 3years in AML patients with or without 
statin use were 54% and 28% respectively (p-value=0.17) respectively (Figure 1). This non 
significant trend of improved PFS indicates that the GVL is preserved in patients using statins at 
the time of allografting.  
 
 
Figure 1. KM estimates of PFS following allogeneic SCT in patients with AML. 
 

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Rotta et al. retrospectively analyzed outcomes among 567 patients with hematologic 
malignancies who had hematopoietic cell transplantation from human leukocyte antigen-
identical sibling donors between 2001 and 2007 for a correlation between statin use and risk of 
GVHD. Compared to allografts where neither the donor nor recipient was treated with a statin at 
the time of transplantation (n = 464), statin use by the donor was associated with a decreased risk 
of grade 3-4 acute GVHD (multivariate hazard ratio, 0.28; 95% confidence interval, 0.1-0.9). 
Statin use by both donor and recipient (n = 12) was suggestively associated with a decreased risk 
of grade 3 or 4 acute GVHD (multivariate hazard ratio, 0.00; 95% confidence interval, 
undefined). Risks of chronic GVHD, recurrent malignancy, nonrelapse mortality, and overall 
mortality were not significantly affected by donor or recipient statin exposure. Statin-associated 
GVHD protection was restricted to recipients with cyclosporine-based postgrafting 
immunosuppression and was not observed among those given tacrolimus (P = .009). These 
results suggest that donor statin treatment may be a promising strategy to prevent severe acute 
GVHD without compromising immunologic control of the underlying malignancy. 
In summary these limited but encouraging retrospective studies, and the extensive pre-
clinical and clinical data suggest that the observations made by Zeiser and colleagues (19) in a 
murine model may have clinical relevance and hints at the potential of statins in reducing acute 
GVHD.  
 
1.7. Clinical Trial Data for Statin use for preventing acute GVHD: 
Based on these data our group, opened a single-arm phase-II study evaluating the safety 
and efficacy of atorvastatin for the prophylaxis of acute graft-versus-host disease in patients with 
hematological malignancies undergoing HLA-matched sibling donor hematopoietic SCT (WVU 
protocol #11010; study registered www.clinicaltrials.gov NCT01175148). To date (September 
26, 2013) 30 donor/patient pairs have been enrolled on this protocol WVU 11010. All healthy 
donors have tolerated atorvastatin with no significant side effects. No statin related grade 3-5 
toxicity in donors was seen. Similarly all patients so far have tolerated atorvastatin well, with no 
study drug related grade 3-5 toxicity. No liver function abnormalities or cases of myopathy were 
seen. In terms of the primary outcome of WVU11010 (i.e. rates of grade II-IV acute GVHD at 
day +100 post transplantation), only one patient experienced grade II acute GVHD before day 
100. In the current protocol, we will evaluate the role of atorvastatin in addition to methotrexate 

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and tacrolimus for the prophylaxis of acute GVHD when administered to transplant recipient 
alone, to assess if routine administration of atorvastatin to healthy sibling donors is warranted. 
This protocol will also include patients undergoing unrelated donor transplantation to see if 
atorvastatin can maintain GVHD rates, seen in transplants using ATG. While some retrospective 
studies (31), but not all (30), suggest that statin-mediated benefit for preventing acute GVHD is 
limited to patients receiving cyclosporine-based GVHD prophylaxis, in our study use of 
cyclosporine prophylaxis is not permitted for two reasons: 1) Our prior study has shown 
excellent safety and efficacy profile of atorvastatin/tacrolimus/methotrexate combination 
[Hamadani M et al. Journal of Clinical Oncology. Accepted manuscript in press], and 2) strong 
drug interaction between cyclosporine and atorvastatin (please see section 8.1.5). 
 
1.8. Inclusion of Women and Minorities:  
 
It is the policy of the Mary Babb Randolph Cancer Center to strive for gender and 
minority patient participation that represents the population of West Virginia in all clinical 
investigations. Between January 1st 2009 and December 31st 2009, 125 patients were enrolled 
onto Phase I/II/III trials at the Mary Babb Randolph Cancer Center.  Of these patients 73% 
percent were female (n=92) and 2.4 percent were members of minority ethnic groups.  It is 
anticipated that a similar or greater proportion of patients on this study will be female and/or 
members of ethnic minorities.    
 
 
2. Objectives:  
 
2.1. Primary Objectives: 
 
1. Determine the efficacy of an atorvastatin/tacrolimus/methotrexate regimen in preventing 
grade II-IV acute GVHD in patients undergoing allogeneic hematopoietic stem cell 
transplantation (HSCT).  
2. Assess the safety of an atorvastatin/tacrolimus/methotrexate regimen in patients 
undergoing allogeneic HSCT. 
 

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2.2. Secondary Objectives: 
 
1. To assess rates of chronic GVHD. 
2. To assess rates of late onset acute GVHD at days +180 and +365. 
3. To assess rates of grade III-IV acute GVHD at days +100, +180 and +365. 
4. To assess non-relapse mortality at 100 days post-HSCT. 
5. To assess time to successful neutrophil engraftment. 
6. To assess time to successful platelet engraftment. 
7. To assess incidence of primary and secondary graft failure. 
8. To assess incidence of primary and secondary graft rejection. 
9. To assess relapse rate of the primary hematological malignancy.  
10. To assess lineage specific chimerism kinetics in patients at days +28, +100, +180 and 
+365. 
11. To assess immune reconstitution following transplantation at days +28, +100, +180, and 
+365. 
12. To assess 1 year progression free survival (PFS) and overall survival (OS) following 
transplantation.  
13. To evaluate biologic and genomic markers potentially associated with GVHD and/or 
atorvastatin. 
 
3. Eligibility Criteria: 
 
3.1. Patient Eligibility Criteria: 
 
1. 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. 
2. 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 

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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). 
3. All patients must have at least one suitable HLA-matched sibling or unrelated donor 
according to transplant center’s guidelines (for selection of appropriate donor). 
4. Patient must provide informed consent.  
5. Left ventricular ejection fraction ≥ 40%. No uncontrolled arrhythmias or uncontrolled 
New York Heart Association class III-IV heart failure. 
6. Bilirubin ≤ 2 x the ULN and AST, and ALT ≤ 3 x ULN; and absence of hepatic 
cirrhosis. For patients with Gilbert’s syndrome, bilirubin ≤ 3 x ULN is permitted.  
7. Adequate renal function as defined by a serum creatinine clearance of ≥ 40% of normal 
calculated by Cockcroft-Gault equation. 
8. DLCOcor (corrected for hemoglobin) or FEV1 or DL/VA ≥ 40% of predicted.  
9. Karnofsky performance status > 70.  
10. A negative pregnancy test will be required for all women of child bearing potential. 
Breast feeding is not permitted.  
11. Patients with positive HIV serology are eligible.  
12. No evidence of active bacterial, viral or fungal infection at the time of transplant 
conditioning. 
13. Patients with history of intolerance or allergic reactions with atorvastatin will not be 
eligible.  
14. 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. 
15. Patients undergoing a T-cell depleted allogeneic transplantation will not be eligible. 
16. Patients receiving conditioning regimens containing antithymocyte globulin, and/or 
campath will not be eligible.  
17. Method of stem-cell collection from the donor will be at the discretion of the treating 
physician. Although it is anticipated that majority of donors will undergo G-CSF 
induced stem cell mobilization; however donors undergoing bone marrow harvest or 

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stem cell mobilization with experimental agents (e.g. plerixafor) will remain eligible for 
the study.  
 
4. Registration Procedure: 
 
4.1. Registration  
 
• 
All source documents that support eligibility including a signed informed 
consent/HIPAA and signed eligibility checklist, should be available review and 
eligibility verification.   
• 
At the point of registration, the research nurse or data manager will register the patient in 
the electronic database, including demographic, consent and on-study information.  The 
patient will be assigned a unique sequence number for the study. 
4.1.1. 
Registration for collaborating institution(s): 
• 
The collaborating institution (e.g. WVU) must contact Study Coordinator at MCW prior 
to registering a patient.  After speaking with the Study Coordinator, the following 
documents should be faxed to 414-805-9025 to begin the registration process: 
 The dated and signed informed consent 
 A physician signed eligibility checklist 
 All source documents that validate eligibility 
 The demographic form 
• 
Written confirmation (via email to study coordinator at WVU) will be sent to the site 
once the patient has been enrolled into the study to issue the unique patient identifier and 
cohort as applicable. 
 
5. Treatment Plan: 
 
This is a phase II study of atorvastatin for the prophylaxis of acute GVHD in patients undergoing 
allogeneic HSCT. The study will have two separate arms: (a): Matched sibling transplants, and 
(b): Matched unrelated donors transplants. Both arms will be enrolled and analyzed separately. 
 

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5.1. Administration schedule to Patients (Transplant recipients) 
1. Atorvastatin will be administered at dose of 40mg 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.  
2. 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.  
3. Patients undergoing myeloablative conditioning (MAC) matched sibling or unrelated 
donor allogeneic transplantation can receive one of following three conditioning 
regimens: 
a) Busulfan ≥0.8 mg/kg/dose (16 doses given every 6 hours, IV on days –7 to –4), 
and cyclophosphamide 60 mg/kg/dose (2 doses given every 24hours, IV on days –
3 and –2). Monitoring busulfan levels with this regimen, per institutional practice, 
is recommended. Oral busulfan is not permitted.  
b) Total body irradiation (>500cGy) and cyclophosphamide as above.  
c) Total body irradiation (>1200cGy) and etoposide. 
d) Other ablative regimens will be permitted after consultation with study PI. 
4. Patients undergoing reduced-intensity conditioning (RIC) matched sibling or unrelated 
donor allogeneic transplantation will receive one of following three regimens: 
 
a) Fludarabine and IV busulfan-based regimen (Flu/Bu2 or Flu/Bu4).  
b) Fludarabine and low dose total body irradiation (200-400cGy) 
c) Fludarabine and melphalan (<140mg/m2) 
d) Other RIC will be permitted after consultation with study PI. 
In addition to atorvastatin, standard GVHD prophylaxis will consist of:Tacrolimus (0.015 
mg/kg I.V every 12 hours or 0.03 mg/kg/day PO; starting day -2) and mini-dose 
methotrexate (5mg/m2 on days +1, +3, +6 and +11). Tacrolimus will be monitored to keep 
levels between 5-12 ng/ml for matched sibling and between 8-12 ng/ml for unrelated donor 
HCT. In absence of acute GVHD, renal insufficiency and disease relapse/progression it is 
recommended that tacrolimus taper SHOULD NOT commence before day +100. The goal 
of tapering is the complete discontinuation of immunosuppressive medications by (but not 
before) day +180. Tacrolimus should be tapered every two to three weeks. Attempt should be 

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19 
 
made to apply similar reductions in dosages at each tapering event, to allow complete 
discontinuation of immunosuppression by day +180. It is recommended by not required that 
tacrolimus dose be reduced by no more than 25% at each tapering event. 
5. Administration of cyclosporine (because of associated risk of myopathy with 
atorvastatin), mycophenolate mofetil, monoclonal (e.g. campath) or polyclonal antibodies 
(e.g. antithymocyte globulin) will not be permitted for GVHD prophylaxis. 
6. Antibiotic prophylaxis will be given according to institutional guidelines. 
7. Temporary interruption (≤10-14days) of atorvastatin is permitted in patients unable to 
tolerate oral intake secondary to severe nausea, vomiting, mucositis etc. Administration 
of atorvastatin via feeding tubes is permitted. In case atorvastatin therapy is interrupted, 
the time interval should be recorded. 
8. Toxicity will be evaluated according to CTCAE v4.0. 
9. Progression free survival (PFS) and overall survival (OS) following transplantation will 
be recorded. 
 
5.2. Dose modification 
1. Patients experiencing a grade 3-4 hematological or non-hematological toxicity (as 
specified in CTCAE v4.0) thought to be related to atorvastatin will be removed from the 
study permanently. No dose modifications for atorvastatin are permitted. 
2.  Decision to hold atorvastatin in patients developing grade 3-4 liver function 
abnormalities (bilirubin, AST and ALT) post-HSCT will be at the discretion of treating 
physician. In such patients if liver function abnormalities are thought not be related to the 
study drug, then atorvastatin prophylaxis can be restarted at time of resolution of hepatic 
transaminases (to grade 1 or less) after consulting with principal investigator. 
 
5.3. Duration of therapy 
        Atorvastatin will be continued until one of the following criteria is met: 
- 
Patient is no longer on immunosuppressive medications or until day +180 after 
transplantation, whichever occurs first. 
- 
Patient develops grade II-IV acute GVHD.  
- 
Patient develops severe chronic GVHD. 

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20 
 
- 
Patient develops any grade 3-4 toxicity related to atorvastatin use. 
Patients experiencing a disease relapse (before day +180) can continue atorvastatin at the 
discretion of treating physician, provided the patient has not been tapered off of tacrolimus.  
 
5.4. Data Safety Monitoring Plan 
At West Virginia University: This protocol will adhere to the policies of the Mary Babb 
Randolph Cancer Center Data and Safety Monitoring Plan, guidelines in accordance with 
NCI regulations. The Data and Safety Toxicity Committee (DSTC) will review all 
serious adverse events and toxicity reports as well as continuing reviews.  This study is 
designated as a moderate risk level and requires quarterly summary reporting to the 
DSTC. 
 
At Medical College of Wisconsin: The Medical College of Wisconsin Cancer Center 
Data Safety Monitoring Committee (DSMC) is responsible for monitoring data quality 
and subject safety for all cancer center investigator initiated clinical trials.  A six to eight 
member Data and Safety Monitoring Committee will complete a review of protocol-
specific data safety monitoring reports, to provide recommendations on trial continuation, 
suspension or termination.  The DSMC will review these reports no less than bi-annually.  
A summary of the DSMC activities are as follows 
• Review the clinical trials for data integrity and safety 
• Review all adverse events requiring expedited reporting as defined per protocol 
• Review all DSM reports 
• Submit a summary of any recommendations related to study conduct 
• Terminate the study if deemed unsafe for patients 
6. Measurement of Effect: 
 
6.1. Visit Schedule: 
The schedule for the study is shown in the table below. 
Study Visit  
Target Day Post-
Transplant  
1 week  
7 ± 3 days  
2 week  
14 ± 3 days  

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3 week  
21 ± 7 days  
4 week  
28 ± 7 days  
5 week  
35 ± 7 days  
6 week  
42 ± 7 days  
7 week  
49 ± 7 days  
8 week  
56 ± 7 days  
9 week  
63 ± 7 days  
10 week  
70 ± 7 days  
11 week  
77 ± 7 days  
12 week  
84 ± 7 days  
100 day  
100± 7 days  
6 month  
180 ± 28 days  
12 month* 
365 ± 28 days  
 
 
 
*After 12months, patients will be followed at least yearly for survival, relapse and cause of 
death for 5 years post transplantation. 
 
6.2. GVHD Assessment: 
Following neutrophil engraftment, patients will be monitored for development of acute and 
chronic GVHD at once a week until day +100. After Day 100, patients will be assessed at 
each study visit for the presence of GVHD. Diagnosis of acute GVHD will require biopsy 
confirmation in at least one involved organ. When more than one organ is involved, biopsy 
confirmation of all involved organs is recommended but not necessary. Liver-only GVHD 
must be confirmed by biopsy. Acute GVHD will be assessed by consensus criteria 
(Appendix A) (32) and graded on BMT CTN MOP suggested grading sheets (Appendix A). 
Acute GVHD assessment and grading will be performed by treating physicians. Chronic 
GVHD diagnosis and grading will be according to NIH Criteria. Please see Appendix B (33-
34). 
 
Clinical Grading of Chronic GVHD (According to Appendix B) 
None 
Mild chronic GVHD involves only 1 or 2 organs or sites (except the lung: see below ‡), 
with no clinically significant functional impairment (maximum of score 1 in all affected 
organs or sites) 

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Moderate chronic GVHD involves: (1) at least 1 organ or site with clinically significant 
but no major disability (maximum score of 2 in any affected organ or site) or (2) 3 or more 
organs or sites with no clinically significant functional impairment (maximum score of 1 in 
all affected organs or sites). ‡A lung score of 1 will also be considered moderate chronic 
GVHD. 
Severe chronic GVHD indicates major disability caused by chronic GVHD (score of 3 in 
any organ or site). ‡A lung score of 2 or greater will also be considered severe chronic 
GVHD. 
 
 
6.3. Engraftment Assessment: 
Neutrophil engraftment will be defined as first of three consecutive days with ANC ≥ 500 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. 
Lineage specific chimerism analysis (CD3 and CD33 subsets), quantitative 
immunoglobulins and immune reconstitution will be performed on days +28, +100, +180 
and +365. 
 
7. Study Parameters (Study Calendar): 
 
7.1. Patient Study Calendar:  
 
The table below summarizes the patient clinical assessments over the course of the study. 

Version Date 07/03/14 
23 
 
 
Study Assessment 
 
Baseline1 
 
Day-14 
 
Day0 
Days Post-Transplantation 
7 
14 
21 
28 
35 
42 
49 
56 
63 
70 
77 
84 
100 
180 
36515 
Informed consent and H & PE2 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Vital signs3 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Karnofsky performance status 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
CBC/differential & platelet count 
X 
 
X 
X4 
X4 
X4 
X4 
 
 
 
 
X 
 
 
 
X 
X 
X 
Serum chemistries panel5 
X 
 
X 
X 
X 
X 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Infectious disease titer6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LVEF7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DLCO 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV quantitative PCR 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Bone marrow aspirate/biopsy8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Β-HCG serum pregnancy test 9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Quantitative immunoglobulins10 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Peripheral blood for chimerism 
X13 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Immune reconstitution panel11 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
CD34/CD3 cell dose infused 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acute/chronic GVHD assessment 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Toxicity assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research specimens (voluntary)12 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
ANC and platelet recovery14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Notes 
H & PE= history and physical examination 
1Baseline refers to the period prior to conditioning. Assessments should be made within 4 weeks prior to day of conditioning. 
2History is only required at baseline. 
3Vital signs: blood pressure, pulse rate, respiratory rate and temperature. 
4Daily during the post-infusion period while hospitalized (recommended) and once weekly after discharge until Day 28. 
5Serum chemistries panel: electrolytes, BUN, ALT, AST, creatinine, bilirubin, alkaline phosphatase, LDH, albumin. Electrolytes to include 
sodium, potassium, chloride, carbon dioxide, and calcium. 
6Infectious disease titers: Cytomegalovirus (CMV) antibody test, hepatitis panel (Hepatitis B including HBsAg, HBcAb; Hepatitis C Ab), HIV 
including HIV testing, syphilis, Epstein-Barr Virus (EBV) IgG and IgM, herpes simplex virus (HSV) IgG and IgM  
7To be determined by MUGA or echocardiogram. 
8Required at baseline. On Days +100, +180 and +365, bone marrow biopsy will be performed if clinically indicated. Other tests and/or 
imaging studies for response assessment will be performed as clinically indicated. 
9Females of reproductive potential only. 
10IgG, IgM and IgA. 
11Peripheral blood flow cytometry to assess recipient immune reconstitution. 
12Peripheral blood specimens: draw 15 mL in  purple top  (EDTA containing) tubes AND 5 mL in blue top (citrate containing) tubes at 
indicated time points and send to the Biospecimen Processing Core at WVU. At MCW voluntary research specimens will not be collected.  
13Chimersim testing to be performed prior to study from BOTH donor and recipient at any time point. Chimerism testing should be sorted 
(lineage specific) to assess myeloid and lymphoid cell chimerism.  
14Record time to neutrophil engraftment defined as first of three consecutive days with ANC ≥ 500 x 109/L, and platelet engraftment defined 
as first day of platelet count ≥ 20,000 x 109/L, without transfusion for 7 consecutive days. 
15After day 365, patients will be followed at least yearly for survival, relapse and cause of death for a total of 5 years post transplantation.

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8. Drug Formulation and Procurement 
 
8.1. Atorvastatin (Lipitor® Pfizer)  
8.1.1. 
Drug description 
LIPITOR is a synthetic lipid-lowering agent. Atorvastatin is an inhibitor of 3-hydroxy-3-
methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the 
conversion of HMG-CoA to mevalonate, an early and rate-limiting step in cholesterol 
biosynthesis. Atorvastatin calcium is [R-(R*, R*)]-2-(4-fluorophenyl)-β, δ-dihydroxy-5- 
(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoic acid, 
calcium salt (2:1) trihydrate. The empirical formula of atorvastatin calcium is 
(C33H34FN2O5)2Ca•3H2O and its molecular weight is 1209.42. Its structural formula 
is: Atorvastatin calcium is a white to off-white crystalline powder that is insoluble in 
aqueous solutions of pH 4 and below. Atorvastatin calcium is very slightly soluble in 
distilled water, pH 7.4 phosphate buffer, and acetonitrile; slightly soluble in ethanol; and 
freely soluble in methanol. LIPITOR Tablets for oral administration contain 10, 20, 40, 
or 80 mg atorvastatin and the following inactive ingredients: calcium carbonate, USP; 
candelilla wax, FCC; croscarmellose sodium, NF; hydroxypropyl cellulose, cellulose, 
NF; Opadry White YS-1-7040 (hypromellose, polyethylene glycol, talc, titanium 
dioxide); polysorbate 80, NF; simethicone emulsion. 
 
 
8.1.2. 
Pharmacodynamics 
LIPITOR, as well as some of its metabolites, are pharmacologically active in humans. 
The liver is the primary site of action and the principal site of cholesterol synthesis and 

Version Date 07/03/14 
26 
 
LDL clearance. Drug dosage, rather than systemic drug concentration, correlates better 
with LDL-C reduction.  
 
8.1.3. 
Pharmacokinetics 
Absorption: LIPITOR is rapidly absorbed after oral administration; maximum plasma 
concentrations occur within 1 to 2 hours. Extent of absorption increases in proportion to 
LIPITOR dose. The absolute bioavailability of atorvastatin (parent drug) is 
approximately 14% and the systemic availability of HMG-CoA reductase inhibitory 
activity is approximately 30%. The low systemic availability is attributed to presystemic 
clearance in gastrointestinal mucosa and/or hepatic first-pass metabolism. Although food 
decreases the rate and extent of drug absorption by approximately 25% and 9%, 
respectively, as assessed by Cmax and AUC, LDL-C reduction is similar whether 
LIPITOR is given with or without food.  
 
8.1.4. 
 Contraindications  
Active Liver Disease which may include Unexplained Persistent Elevations of Hepatic 
Transaminase Levels 
Hypersensitivity to any Component of this Medication 
Pregnancy 
Nursing Mothers 
 
8.1.5. 
 Drug Interactions 
Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis include 
the following. 
Interacting Agents                                 
Prescribing Recommendations 
Cyclosporine 
Atorvastatin is a substrate of the OATP1B1 
transporter. Inhibitors of the OATP1B1 (e.g., 
cyclosporine) can significantly increase the 
bioavailability of atorvastatin. Concomitant 
administration of atorvastatin and cyclosporine is 
not permitted on the protocol. 
Clarithromycin, itraconazole, HIV protease inhibitors 
Caution when exceeding doses 

Version Date 07/03/14 
27 
 
(ritonavir plus saquinavir or lopinavir plus ritonavir) 
> 20mg atorvastatin daily. The 
lowest dose necessary should be used. 
Atorvastatin is metabolized by cytochrome P450 3A4. 
Concomitant administration of atorvastatin with 
inhibitors of cytochrome P450 3A4 can potentially lead 
to increased plasma atorvastatin concentrations.  
Use of strong inhibitors of cytochrome P450 3A4 
(erythromycin, clarithromycin, protease 
inhibitors, diltiazem, or itraconazole), with 
atorvastatin should be done with caution.  
Grapefruit juice 
: Contains one or more components that inhibit 
CYP 3A4 and can increase plasma concentrations 
of atorvastatin, especially with excessive 
grapefruit juice consumption (>1.2 liters per 
day). 
Gemfibrozil 
Due to an increased risk of 
myopathy/rhabdomyolysis when HMG-CoA 
reductase inhibitors are co-administered with 
gemfibrozil, concomitant administration of 
LIPITOR with gemfibrozil should be avoided 
Digoxin 
Digoxin concentrations are unaffected 
by atorvastatin doses of <80mg/day 
Rifampin or other Inducers of Cytochrome P450 3A4: 
Concomitant administration of LIPITOR with 
inducers of cytochrome P450 3A4 (e.g., 
efavirenz, rifampin) can lead to variable 
reductions in plasma concentrations of 
atorvastatin. Due to the dual interaction 
mechanism of rifampin, simultaneous co-
administration of LIPITOR with rifampin is 
recommended, as delayed administration of 
LIPITOR after administration of rifampin has 
been associated with a significant reduction in 
atorvastatin plasma concentrations. 
                                               
 
 
 
 

Version Date 07/03/14 
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8.1.6. 
 Adverse Events: 
Skeletal Muscle 
Rare cases of rhabdomyolysis with acute renal failure secondary to myoglobinuria have 
been reported with LIPITOR and with other drugs in this class. A history of renal 
impairment may be a risk factor for the development of rhabdomyolysis. Such patients 
merit closer monitoring for skeletal muscle effects. Atorvastatin, like other statins, 
occasionally causes myopathy, defined as muscle aches or muscle weakness in 
conjunction with increases in creatine phosphokinase (CPK) values >10 times ULN. The 
concomitant use of higher doses of atorvastatin with certain drugs such as cyclosporine 
and strong CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, and HIV protease 
inhibitors) increases the risk of myopathy/rhabdomyolysis. Myopathy should be 
considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or 
marked elevation of CPK. Patients should be advised to report promptly unexplained 
muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. 
LIPITOR therapy should be discontinued if markedly elevated CPK levels occur or 
myopathy is diagnosed or suspected. 
Liver Dysfunction 
Statins, like some other lipid-lowering therapies, have been associated with biochemical 
abnormalities of liver function. Persistent elevations (>3 times the upper limit of normal 
[ULN] occurring on 2 or more occasions) in serum transaminases occurred in 0.7% of 
patients who received LIPITOR in clinical trials. The incidence of these abnormalities 
was 0.2%, 0.2%, 0.6%, and 2.3% for 10, 20, 40, and 80 mg, respectively 
Endocrine Function 
Statins interfere with cholesterol synthesis and theoretically might blunt adrenal and/or 
gonadal steroid production. Clinical studies have shown that LIPITOR does not reduce 
basal plasma cortisol concentration or impair adrenal reserve. The effects of statins on 
male fertility have not been studied in adequate numbers of patients. The effects, if any, 
on the pituitary-gonadal axis in premenopausal women are unknown. Caution should be 
exercised if a statin is administered concomitantly with drugs that may decrease the 
levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone, 
and cimetidine. 

Version Date 07/03/14 
29 
 
CNS Toxicity 
Brain hemorrhage was seen in a female dog treated for 3 months at 120 mg/kg/day. Brain 
hemorrhage and optic nerve vacuolation were seen in another female dog that was 
sacrificed in moribund condition after 11 weeks of escalating doses up to 280 mg/kg/day. 
The 120 mg/kg dose resulted in a systemic exposure approximately 16 times the human 
plasma area-under-the-curve (AUC, 0-24 hours) based on the maximum human 
dose of 80 mg/day. A single tonic convulsion was seen in each of 2 male dogs (one 
treated at 10 mg/kg/day and one at 120 mg/kg/day) in a 2-year study. No CNS lesions 
have been observed in mice after chronic treatment for up to 2 years at doses up to 400 
mg/kg/day or in rats at doses up to 100 mg/kg/day. These doses were 6 to 11 times 
(mouse) and 8 to 16 times (rat) the human AUC (0-24) based on the maximum 
recommended human dose of 80 mg/day. 
Other adverse reactions reported in placebo-controlled studies include: Body as a 
whole: malaise, pyrexia; Digestive system: abdominal discomfort, eructation, flatulence, 
hepatitis, cholestasis; Musculoskeletal system: musculoskeletal pain, muscle fatigue, neck 
pain, joint swelling; Metabolic and nutritional system: transaminases increase, liver 
function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase 
increase, hyperglycemia; Nervous system: nightmare; Respiratory system: epistaxis; Skin 
and appendages: urticaria; Special senses: vision blurred, tinnitus; Urogenital system: 
white blood cells urine positive. 
 
8.2. How supplied and Storage/Handling  
 
40 mg tablets: coded “PD 157” on one side and “40” on the other. 
NDC 0071-0157-23 bottles of 90 
NDC 0071-0157-73 bottles of 500 
NDC 0071-0157-88 bottles of 2500 
NDC 0071-0157-40 10 x 10 unit dose blisters  
Stored at controlled room temperature 20 - 25°C (68 - 77°F). 
 
 

Version Date 07/03/14 
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8.3. Methods of procurement         
 
The Medical College of Wisconsin & West Virginia University Hospitals Departments of 
Pharmacy will order Atorvastatin 40mg and receive drug specifically for this study.  The 
CTRU (at WVU) and CTO (at MCW) will be billed for the cost of the drug which will be 
paid for by study funds.  The drug will be dispensed per patient and labeled according to 
more stringent state or federal law.  Drug accountability and inventory records will be 
created and maintained within the Investigational Drug Services. 
 
9. Statistical Considerations: 
 
The study is a single-arm phase II trial evaluating the safety and efficacy of atorvastatin for 
the prophylaxis of acute GVHD in patients with hematological malignancies undergoing 
HLA-matched HSCT. The primary objective of this study is to evaluate the cumulative 
incidence of grade II-IV acute GVHD by day +100 in patients receiving acute GVHD 
prophylaxis with atorvastatin, tacrolimus and methotrexate. The incidence of grade II-IV 
acute GVHD in patients undergoing MAC or RIC matched sibling allogeneic SCT, and 
receiving GVHD prophylaxis with tacrolimus and methotrexate is approximately 30-40%. 
The respective rates for patients undergoing RIC unrelated donor transplantation with ATG 
are 45-55% and without ATG 50-60%. The sibling and unrelated donor arms of this study 
will be analyzed separately, with aim for separate publications. At the time of publication the 
results of unrelated donor arm of the study will be retrospectively compared against patients 
undergoing unrelated transplantation at our center after conditioning with Flu/Bu2 or 
Flu/Bu4 and receiving GVHD prophylaxis with tacrolimus, MTX and ATG. 
 
For this phase II study, we will use an open-label, minimax two-stage design as specified by 
Simon. We will consider the “experimental” acute GVHD prophylactic regimen of 
atorvastatin/tacrolimus/methotrexate to be no more effective than GVHD prophylaxis with 
tacrolimus/methotrexate alone for matched sibling allogeneic HCT, if the true probability of 
developing grade II-IV acute GVHD is more than 35% (p0). We will also assume that the 
new prophylactic regimen is worthy of further study if the true probability of grade II-IV 

Version Date 07/03/14 
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acute GVHD is equal or less than 15% (p1). In statistical terms, we are testing the null 
hypothesis H0: p≥0.35, versus the alternate H1: p≤0.15, where p is probability of grade II_IV 
acute GVHD. These figures result in a two-stage design of 25 and 30 patients during stage 1 
and 2 respectively, with an alpha of 0.05 and beta of 0.20. In the first stage, we will enter 25 
patients undergoing matched sibling transplantation. If 6 or more of these patients develop 
grade II-IV acute GVHD, we will stop and conclude in favor of H0: p≥0.35. If only 5 or less 
of the first 25 patients develop grade II-IV acute GVHD, we will enter an additional 5 
patients, for a total of 30 patients. In the final analysis, if 7 or fewer of the 30 patients 
develop grade II-IV acute GVHD we will reject null hypothesis. 
 
 
For the unrelated donor HCT arm of this study we will consider the “experimental” 
acute GVHD prophylactic regimen of atorvastatin/tacrolimus/methotrexate to be no more 
effective than GVHD prophylaxis with tacrolimus/methotrexate alone, if the true probability 
of developing grade II-IV acute GVHD is more than 55% (p0). We will also assume that the 
new prophylactic regimen is worthy of further study if the true probability of grade II-IV 
acute GVHD is equal or less than 40% (p1). In statistical terms, we are testing the null 
hypothesis H0: p≥0.55, versus the alternate H1: p≤0.35, where p is probability of grade II_IV 
acute GVHD. These figures result in a two-stage design of 30 and 39 patients during stage 1 
and 2 respectively, with an alpha of 0.05 and beta of 0.20. In the first stage, we will enter 30 
patients undergoing unrelated donor transplantation. If 14 or more of these patients develop 
grade II-IV acute GVHD, we will stop and conclude in favor of H0: p≥0.55. If only 13 or 
less of the first 30 patients develop grade II-IV acute GVHD, we will enter an additional 9 
patients, for a total of 39 patients. In the final analysis, if 17 or fewer of the 39 patients 
develop grade II-IV acute GVHD we will reject null hypothesis. 
We anticipate that a maximum of 30 each, matched sibling and unrelated donor patients will 
be accrued to the study provided 10 or less patients develop grade II-IV acute GVHD during 
the first stage of the study. Descriptive statistics (i.e. means, standard deviations, 95% 
confidence intervals for continuous variables, and frequencies for discrete data) will be 
computed for all correlative laboratory parameters.  
 
Safety/Stopping Rules: 

Version Date 07/03/14 
32 
 
1. 
Development of grade 3-4 adverse events deemed to be related to atorvastatin in 6 or 
more transplant recipients, will mandate halting further patient accrual until review by 
DSMB. 
2. 
Cumulative incidence of relapse of >50% (with NRM as competing event) observed 
after enrolling at least 20 patients in each cohort, will mandate halting further patient accrual 
until review by DSMB. 
3. 
In patients complaining of grade II or worse muscle pain, weakness or myopathy, a 
serum CPK level will be checked to rule out development of rhabdomyolysis.  
 
Accrual Estimate: 55-69 patients. Patients experiencing mortality within 100 days of 
transplant due to disease relapse/progression, will be replaced to fully assess late onset acute 
GVHD rates. However, all patients will be included in toxicity and survival analysis. 
Accrual Period :  Approximately 24-36 months 
 
 
Follow-Up Period : One year to evaluate incidence of acute and chronic GVHD and relapse 
pattern. Five years for survival outcomes, relapse, and mortality.  
 
10. Adverse Event Reporting Requirements 
 
Definitions 
 
The following are definitions of adverse events as defined by 21CFR312.32. 
 
Types of Adverse Events 
 
Adverse Event means any untoward medical occurrence associated with the use of a drug in 
humans, whether or not consider drug related. 
 
Life-threatening adverse event or life-threatening suspected adverse reaction:  An adverse 
event or suspected adverse reaction is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It 
does not include an adverse event or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death. 
 

Version Date 07/03/14 
33 
 
Serious adverse event or serious suspected adverse reaction:  An adverse event or suspected 
adverse reaction is considered “serious” if, in the view of the investigator or sponsor, it results in 
any of the following outcomes: 
 
• Death, 
• A life-threatening prolongation of existing hospitalization, 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions, or 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent of the outcomes listed above.   
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event.  “Reasonable possibility” means there is evidence to 
suggest a causal relationship between the drug and the adverse event.  Suspected adverse 
reaction implies a lesser degree of certainty about causality than adverse reaction, which means 
any adverse event caused by a drug. 
 
Unexpected adverse event or unexpected suspected adverse reaction:  An adverse event or 
suspected adverse reaction is considered “unexpected” if it is not listed in the investigator 
brochure or is not listed at the specificity or severity that has been observed; or, if an investigator 
brochure is not required or available, it is not consistent with the risk information currently 
described.   
 
Unexpected also refers to adverse events or suspected adverse reactions that are mentioned in the 
investigator brochure as occurring with a class of drugs or as anticipated from the 
pharmacological properties of the drug, but are not specifically mentioned as occurring with the 
particular drug under investigation. 
 
 

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Adverse Event Grading 
 
Grade 
Description 
 
0 
No AE (or within normal limits). 
 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
 
2 
Moderate; minimal, local or noninvasive intervention (e.g., packing 
cautery) indicated; limiting age-appropriate instrumental activities of 
daily living (ADL). 
 
3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
 
4 
Life-threatening consequences; urgent intervention indicated. 
 
5 
Death related to AE 
 
 
Adverse Event Attribution 
 
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related to the 
intervention 
Unlikely 
The AE is doubtfully related to the 
intervention 
Related to investigationl 
agent/intervention 
Possible 
The AE may be related to the 
intervention 
Probable 
The AE is likely related to the 
intervention 
Definite 
The AE is clearly related to the 
intervention 
 
 
Reporting of Adverse Events 
Because all of the study transplant recipients will be receiving potentially toxic preparative 
therapy, significant regimen related toxicity is expected.  These risks are listed in the consent 
form.  A study specific toxicity CRF will be designed to capture information regarding these 
expected events.  Transplant is also related to a degree of mortality and this will also be captured 
by a study designed CRF.  Unexpected adverse events will be reported throughout the study. 

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The sub-site (i.e. West Virginia University) must report all serious adverse events to the sponsor-
investigator (SAE FAX-414-805-9025 or Froedtert Hospital and the Medical College of 
Wisconsin Cancer Center Clinical Trials Office 9200 W. Wisconsin Ave. Milwaukee, WI) so that 
the sponsor-investigator can meet his/her foregoing reporting obligations to the required 
regulatory agencies, unless otherwise agreed between the sponsor-investigator and sub-
investigator(s).   
Unexpected Adverse Events 
Grades 3-5 (severe, life threatening, disabling, or fatal) require expedited reporting and will be 
submitted to the DSTC within 24 hours of discovery for review.  If the Grade 3-5 event is 
determined to be an unanticipated problem, the event will be forwarded to the WVU IRB for 
review as required by their policy.  Unexpected adverse events, regardless of severity, will be 
reported to the DSTC and reviewed on a quarterly basis. 
 
Expected Adverse Events 
All fatal (grade 5) expected adverse events require expedited reporting and will be reported to 
the DSTC within 24 hours for review.  Expected adverse events that are being captured on the 
study toxicity form will be reported at the time of the form’s scheduled due date.   
 
All DSTC reports and recommendations will be submitted to the IRB for their review. 
 
Adverse Events Occurring after the End of the Study 
 
Follow-up of AEs 
Any unexpected AEs ongoing at the time of study discontinuation will be followed until 
resolution or stable for at least 2 months.  
 
 
FDA Reporting Procedures  
 
Commercial Agents:    Commercial agents are those agents not provided under an IND but 
obtained instead from a commercial source.  In some cases an agent obtained commercially may 

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be used for indications not included in the package label.  The following procedures should be 
followed to determine if an adverse is reportable to the FDA: 
 
Refer to the pharmaceutical section of the protocol to determine if an agent is investigational or 
commercial.   
• 
WHAT TO REPORT:  An unexpected, life-threatening (Grade 4) or unexpected, fatal (Grade 5) 
adverse event with an attribution of possible, probable or definite. 
 
• 
WHEN TO REPORT:  These events should be reported within (7) working days. 
 
 
• 
WHERE TO REPORT:  These adverse events with commercial agents must be reported to the 
FDA using the MedWatch form.  A copy of the MedWatch form can be obtained from theFDA’s 
MedWatch web site at www.fda.gov/medwatch.  You can mail the reports to the address below or 
fax it 1-800-332-0178. 
MedWatch 
 
5600 Fishers Lane 
Rockville, MD 20852-9787 
 
11. Patient Consent and Peer Review Statement 
11.1. 
Subject Information and Informed Consent 
 
Written informed consent must be obtained from the subject prior to study participation. 
 
The informed consent document must be signed and dated by the subject and properly 
witnessed (if applicable) before initiation of any study procedures including any change 
in medication or initiation of study drug dosing.   
 
Subjects must be consented in accordance with all local regulatory and legal 
requirements.  This process must include a verbal explanation of the nature, scope, and 
possible consequences of the study provided in plain language.  The information should 

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be presented by the investigator unless a designee is permitted by local regulations.  The 
potential study subject should be encouraged to ask questions about the study.   
 
The informed consent document must be prepared in accordance with GCP guidelines 
and with local regulatory and legal requirements.  A copy of the signed consent form will 
be given to the subject and the original document must be safely archived by the 
investigator so that the forms can be retrieved at any time for monitoring, auditing, and 
inspection purposes. 
 
The informed consent will be updated as appropriate (e.g., due to protocol amendment or 
if significant new safety information that may be relevant to consent of the subjects 
becomes available).  If the informed consent is revised, it is the investigator’s 
responsibility to ensure that an amended consent form is reviewed and signed by all 
subjects subsequently entered into the study and those currently in the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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13. Appendix A Assessment of Acute GVHD 
 
 
 
 
 
 

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14. Appendix B Grading of Chronic GVHD (NIH Criteria) 
 
 
 
 
 

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