Maraviroc as Graft Versus Host Disease Prophylaxis in Pediatric and Adult Stem Cell Transplant Recipients
Phase: PHASE1
Conditions: Diagnoses That Require Stem Cell Transplant, Graft Versus Host Disease (GVHD)
Sponsor: Children's Hospital Medical Center, Cincinnati

 
 
COVER PAGE FOR CLINICALTRIALS.GOV
 
 
 
Protocol Title: 
Maraviroc as graft versus host disease prophylaxis in 
pediatric and  adult stem cell transplant recip
ients  
 
 
NCT Number: NCT02167451  
 
 
Document Version Date: 
03/23/2018  

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Title of study:  Maraviroc as graft versus host disease prophylaxis in pediatric and 
adult stem cell transplant recipients. 
 
 
Principal Investigator:  Pooja Khandelwal, MD 
 
Co-Investigators:       Stella Davies MBBS, PhD, MRCP 
  
                  Ashish Kumar, MD, PhD 
Sharat Chandra, MD 
Rebecca Marsh, MD 
Parinda Mehta, MD 
Michael Grimley, MD 
Michael Jordan, MD 
Kasiani Myers, MD 
Jacob Bleesing, MD, PhD 
 
 
 
 
Christopher Dandoy, MD 
 
 
 
 
Alexander A. Vinks, PharmD, PhD 
                        Adam Nelson, MBBS 
 
 
 
 
Mary Christa Krupski, DO, MPH 
Statistician:         
Adam Lane, PhD 
 
Pharmacist:  
 
Ashley Teusink, PharmD  
 
 

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Abstract-  
Acute graft versus host disease (GVHD) is the most significant complication of stem cell 
transplant (SCT), with high rates of morbidity and mortality.  In children with GVHD, 
activated donor lymphocytes migrate to target organs and cause characteristic end 
organ damage to skin gut and liver.  Small protein molecules called chemokines 
mediate the process of migration.  CCR5, a chemokine receptor employed by the HIV 
virus to enter CD4 T cells, is also widely implicated in the pathogenesis of visceral 
GVHD, mediating migration of T-cells to target organs. 
  
Maraviroc is an oral CCR5 antagonist that is currently FDA approved as antiretroviral 
therapy for HIV in adults. However, it has also been used to reduce visceral GVHD in 
murine models.  
 
We hypothesize that addition of Maraviroc to our standard GVHD prophylactic regimen 
will reduce the incidence of acute visceral (gut and liver) GVHD in children at day + 100 
after a stem cell transplant without impacting engraftment. Our initial study will 
investigate Maraviroc pharmacokinetics and pharmacodynamics to establish 
appropriate dosing for future studies. In the second stage of the study we will 
investigate efficacy.  Patients will receive Maraviroc orally at the dose established in 
the first step of the study along with standard graft versus host disease prophylaxis from 
day -3 to day +30 after transplant, and will be observed until day + 100 for incidence of 
acute GVHD, infectious complications, relapse and overall survival. This study has high 
relevance as it may alter the rates of GVHD in children and improve overall survival 
after SCT. 
 
Purpose of the Study 
1. To establish the pharmacokinetics and feasibility of oral Maraviroc in children 
undergoing allogeneic stem cell transplantation (SCT). 
2. To evaluate efficacy and adverse events of Maraviroc in prophylaxis of acute 
GVHD in children and young adults undergoing allogeneic SCT. 
3. To describe the impact of Maraviroc on time to engraftment, rate of complications 
early mortality after transplant, chronic GVHD and relapse-free survival. 
 

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Significance of the Study in Relation to Human Health 
Acute GVHD is a serious complication of SCT, associated with significant morbidity and 
mortality[1].  Despite many efforts to reduce the incidence of GVHD, which include 
improved donor selection, preparative regimens that include serotherapy with ATG or 
alemtuzumab, and established graft-versus –host disease prophylactic agents, acute 
GVHD remains a challenging complication. Further strategies to reduce its incidence 
are needed[2].  
 
GVHD can be prevented or decreased with a variety of pharmacologic agents and non-
pharmacologic techniques. Early transplants were done using post-transplant 
methotrexate to prevent GVHD; in the 1980s cyclosporine was demonstrated to be 
superior to methotrexate and in 1986 the combined use of cyclosporine and 
methotrexate was shown to be superior to single agent prophylaxis[3]. Subsequently, 
the immunophillin inhibitor tacrolimus was introduced as an alternative to 
cyclosporine[4].  Large phase III studies comparing tacrolimus and methotrexate 
(Tac/MTX) with cyclosporine and methotrexate (CSA/MTX) have been performed and 
failed to demonstrate a significant difference between the two approaches[5]. In the 
matched, related donor setting, 329 patients were randomized to receive either 
Tac/MTX or CSA/MTX. The incidence of Grade II-IV acute GVHD was 31.9% in the 
Tac/MTX arm and 44.4% in the CSA/MTX arm. Similarly, in the unrelated donor study, 
the incidence of Grade II-IV acute GVHD was 56% among the 46 patients randomized 
to Tac/MTX and was 74% among the 63 patients randomized to receive CSA/MTX[6]. 
Based on these data, both CSA/MTX and Tac/MTX can be considered standard 
prophylactic therapy after SCT.  In small children, methotrexate might be replaced with 
steroids or mycophenolate mofetil to reduce severity of mucositis. Rates of GVHD 
continue to be high despite these “best available” prophylactic agents. In addition, 
current GVHD prophylactic therapy function by reducing donor T cell function, impairing 
immunologic recovery and perhaps limiting the graft versus tumor potential of allogeneic 
SCT[7,8]. GVHD prophylaxis that could prevent target organ recognition and damage, 
without impairing immune reconstitution or tumor specific immunity, would represent a 
major advance in transplantation[9]. 
 
 
 
 

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Background  
The interaction of donor T cells with antigen presenting cells is the first step in the 
induction of acute GVHD[7]. This interaction is regulated positively or negatively by a 
multitude of cellular receptors, cytokines, and chemokines[7].  Chemokines are a group 
of small proteins that act together with their cell surface receptors to direct cells to 
specific locations throughout the body, and function in T cell trafficking[10]. The role of 
T-cell trafficking in acute GVHD is a crucial element in its pathogenesis[11]. Donor T 
cells migrate to secondary lymphoid organs where they recognize alloantigens on either 
donor or recipient antigen presenting cells [12-14]. These cells become activated, exit 
the lymphoid tissues and traffic to the target organs (liver, skin, spleen and lungs) and 
proceed to cause organ damage [15,16]. It is now established that trafficking of donor T 
cells into target GVHD organs is chemokine dependent [17]. There is evidence of 
overexpression of CCL2–5, CXCL2, CXCL9–11, CCL17 and CCL27 in the liver, spleen, 
skin and lungs during acute GVHD, and CXCR3 and CCR5 receptor expression has 
been observed on T cells associated with acute GVHD in the GI tract and liver[18,19].  
CCR5 is a chemokine receptor whose natural ligands are macrophage inflammatory 
protein-1-alpha (MIP-1α = CCL3) and MIP-1β (CCL4) as well as RANTES (CCL5)[10]. 
CCR5 is expressed on a subset of T-cells with a memory cell phenotype and on 
macrophages. It is a G-protein coupled receptor with 7 transmembrane domains. 
Del32 is a large 32-bp deletion in the coding region of the CCR5 gene, resulting in 
deletion and frame-shift and a non-functional receptor. This allele is found at moderately 
high frequency in European-Americans (8%) but absent in Chinese and Yoruba 
populations. Approximately 1% of the population is homozygous for the deletion. The 
allele frequency is around 16% in Northern Europe, 6% in Italy and 4% in Greece. In the 
Baltic region and in Ashkenazi Jews a relatively high allele frequency was found. There 
is very little evidence that Δ32 carriers are more susceptible to infections; mainly 
increased susceptibility to infections with Flaviviruses such as West-Nile virus was 
described. Therefore this mutation in not considered an immune defect[20]. On the 
other hand, evidence exists for immune privileges that accompany this mutation. 
Carriers are less prone to develop severe asthma and other atopic disorders and are 
less likely to suffer severe rheumatoid arthritis or multiple sclerosis[21]. Long-term effect 
of CCR5 inhibition is unknown, but these data suggest that this will not cause severe 
susceptibility to infection, in excess of that normally occurring after SCT.  Patients with 
del32 mutation remain healthy and have a normal life span.   Importantly, CCR5 is a 
major co- receptor for HIV entry into host cells[22]. 
Maraviroc (Selzentry – Pfizer, formerly UK-427, 857) is the first FDA-approved drug in 
its class of CCR5- inhibitors[23]. Maraviroc is approved for 2nd line treatment of CCR5-

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tropic HIV-infected patients and is a specific slowly reversible small molecule antagonist 
of the CCR5 receptor, preventing HIV-1 entry into cells[23]. Two pivotal phase III trials 
(MOTIVATE-1 and MOTIVATE-2) have shown that Maraviroc was able to produce a 
significant decrease in viral load and an increase in CD4 count in HIV patients who 
failed standard regimens.  Doses used were 150 and 300 mg bid. 
Maraviroc is a true antagonist of the CCR5 receptor. It creates an allosteric 
conformational change in the extracellular domain of the receptor and prevents binding 
of all 3 ligands (CCL3-5).  Maraviroc does not cause any calcium influx, meaning that it 
has no agonist activity and does not cause internalization of the receptor. 
Pharmacokinetic data derived from studies in normal volunteers suggest that drug 
absorption is rapid but bioavailability is 23-33% due to a first pass effect in the liver with 
maximum concentrations achieved 1–4 h after dosing. Absorption is decreased with 
food but no efficacy data determined any difference in outcome so the drug is offered 
without food restrictions. 
Maraviroc is extensively metabolized through the CYP3A4 pathway. Renal clearance 
contributes approximately 23% of total clearance. Inducers and suppressors of CYP3A4 
such as rifampin, antiretroviral medications and certain azoles affect its concentration in 
blood. The drug itself is not a significant inhibitor or inducer of any known metabolic 
pathway. 
The recommended dose to HIV patients is determined by concomitant medications and 
the drug was thoroughly investigated in combination with many inducers and inhibitors 
of its metabolic pathway. Adult patients on strong inhibitors of CYP3A should take 
150mg bid, patients on strong inducers of CYP3A should take 600mg bid and all other 
patients should take 300mg bid[23]. In an ongoing pediatric trial, doses of Maraviroc 
have been established based on body surface area and the presence or absence of 
strong inducers or inhibitors by pharmacokinetic analysis[24]. 
The drug is available in oral form only. 
 
Previous Work Done in this Area 
Phase II trials in adults with Maraviroc monotherapy in the antiretroviral setting have 
shown maximum reduction in viral load in 11 days. No effects on blood counts, 
immunoglobulin levels or lymphocyte subset numbers were observed in phase I/II data. 
Phase III studies showed significant improvement in achieving undetectable viral loads 
when used with a background antiviral combination of 1,2 or 3 drugs (43, 53, 61% 

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compared with 29% on a standard 3-drug regimen). CD4 recovery rate was also 
significantly better[23].  
Phase III data showed mild side effects which included nausea, diarrhea, headache and 
fatigue and these were not significantly different from placebo. The drug was well 
tolerated in all trial phases in adults.  Liver enzyme and bilirubin elevation occurred in 
9.2% as opposed to 6.2% in the placebo groups. This finding as well as reports of 
hepatotoxicity with a different CCR5 inhibitor triggered a black box warning for 
hepatotoxicity. Post-marketing surveillance reveals that no significant events were 
registered so far[23,25]. 
In phase 1 congenital HIV trial A4001031, of the 78 children enrolled, 13 patients (17%) 
had 17 treatment-emergent, non-treatment-related serious AEs: infections and 
infestations (11), gastrointestinal disorders (1), hepatobilliary disorders (1), 
investigations (1), musculoskeletal and connective tissue disorders (1), psychiatric 
disorders (1), and skin and subcutaneous tissue disorders (1).  
Fourteen subjects (18%) experienced 32 treatment-related AEs (all mild-to-moderate): 
gastrointestinal disorders (12), nervous system disorders (5), hepatobilliary disorders 
(4), metabolism and nutrition disorders (3), skin and subcutaneous tissue disorders (3), 
reproductive system and breast disorders (2), psychiatric disorders (2), and cardiac 
disorders (1). Enrollment is currently ongoing and thus far, Maraviroc appears to be a 
well-tolerated drug in children[26]. 
The role of CCR5 and its ligands in GVHD have been primarily explored in murine 
models. It has been reported that CCR5+CD8+ T cells mediate hepatic injury in murine 
GVHD and a blocking antibody to CCR5 reduces the damage[27].  
Recently, the functional states of T cells have been characterized by chemokine 
receptor expression pattern in humans. The expression of CCR5 is very low on naıve T 
cells, but is highly up regulated on both CD4+ (Th1) T cells and activated antigen-
specific CD8+ T cells suggesting that the chemokine receptor CCR5 is a marker for 
effector T cells[14,15].  
Palmer et al investigated the role of CCR5 in skin GVHD and demonstrated that CCR5 
expression was present on both CD4+ and CD8+ T cell infiltrates in the skin biopsies of 
human aGVHD. By using an intracellular cytokine assay, it was found that activated 
CD4+ T cells that produce inflammatory cytokines TNFa, IL-2, or IFN-g, were positive 
for CCR5. Thus CCR5 was upregulated upon allostimulation and expressed on 
activated T cells. In addition, the expression of CCR5 was shown to be restricted only to 
the proliferating T lymphocytes in this study[27].  

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Clinical data supporting the role of CCR5 in the allogeneic transplant setting starts with 
investigation of carriers of the Δ32 mutation in the CCR5 gene. In a meta-analysis of 
1227 renal transplant patients, it was shown that homozygous patients had better graft 
survival, in some cases longer than 20 years[28,29]. It was shown in separate studies 
that in both acute and chronic renal rejection there is upregulation of the ligands for 
CCR5. 
In the stem-cell transplantation setting, a retrospective study in Poland, where the 
prevalence of the Δ32 mutation is relatively high, analysis of 186 recipients and 163 
donors of stem-cell transplants revealed that recipient Δ32 was a protective factor for 
acute GVHD of any grade. Δ32 in the donor did not predict outcome but the 
combination of Δ32 in both donor and recipient was highly protective (0/11 patients had 
GVHD) 
It has been observed in vitro that maraviroc effectively and specifically inhibited CCR5 
internalization and reduced RANTES-induced chemotaxis in concentrations achievable 
in humans, recapitulating a defect observed in homozygotes for the del32-CCR5 
polymorphism. Maraviroc had no effect on hematopoietic cell colony formation, T-cell 
mediated cytotoxicity or T-cell proliferation.  
Prevention of GVHD by targeting CCR5 was explored by Reshef et al, who 
hypothesized that CCR5 inhibition early after allogeneic SCT would reduce lymphocyte 
chemotaxis and result in low rates of acute GVHD without impairing engraftment or 
antitumor activity. Thirty eight patients with a median age of 62 years (range 21-74) 
received a reduced intensity stem cell transplant with fludarabine and busulfan as a 
preparative regimen, followed by peripheral blood stem cells for a variety of indications 
(AML, MDS, NHL, myelofibrosis, aplastic anemia, multiple myeloma, CLL, Hodgkin’s 
lymphoma, CML). In addition to standard GVHD prophylaxis of tacrolimus and 
methotrexate, Maraviroc was given from day -2 to +30 after establishing an oral dose of 
300 mg twice daily by initial pharmacokinetic analysis on the first 13 patients.  The 
outcome of incidence of GVHD at day+100 and day + 180 was compared to a cohort of 
well-matched historic controls who had received a reduced intensity conditioning stem 
cell transplant.  A cumulative incidence of grade II-IV GVHD at day +180 was 23.6+/- 
7.4%, which was significantly lower than the author’s institutional GVHD rate of 38.5%. 
Virtually no liver or gastrointestinal GVHD was observed until day +100 and incidences 
of visceral GVHD were low at day +180 (Liver 2.9+/-2.9% Gastrointestinal tract 8.5+/-
5%). There was no significant difference in recovery of lymphocyte counts, infectious 
complications, incidence of relapse of primary malignancy, overall survival and relapse 
free survival in both groups. However, there was a lower incidence of transplant related 
mortality in the Maraviroc cohort [30,31].  

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In the phase 1 study, administration of the drug was briefly suspended in 7 of 13 
patients because of grade 3 abnormalities on liver function testing (n=2) or grade 3 or 4 
mucositis (n=5). Liver-function abnormalities did not recur when the drug was re- 
started. The adverse event profile was similar to the expected toxicity observed in 
patients undergoing reduced intensity conditioned SCT without maraviroc. In addition, 
there were no viral or fungal infections other than asymptomatic reactivation of 
cytomegalovirus. The incidence of bacterial infections was not higher than the expected 
rate for a reduced intensity transplant.  In conclusion, Maraviroc was generally well 
tolerated in this study [30,31].   
 
Research Plan 
The study continues seamlessly from one stage to the next and therefore does not have 
“phases” in the conventional sense. The initial part of the study will be a dose finding 
and feasibility study. The second stage of the study will involve administering the 
appropriate dose of Maraviroc to children as a prophylactic agent against acute graft 
versus host disease. Maraviroc will be added to standard GVHD prophylaxis of a 
calcineurin inhibitor (cyclosporine or tacrolimus), methylprednisolone, mycophenolate 
mofetil (MMF) or methotrexate.  The study plan is described below. 
 
Number of Subjects 
We plan to enroll 65 patients over the course of approximately 5 years. 
 
Selection 
This study will be conducted at Cincinnati Children’s Hospital, in patients 2 years of age-
40 years of age who are undergoing allogeneic stem cell transplant. 
 
Eligibility 
Inclusion Criteria  
1. Ages- 2 years and < 40 years. For Phase I, the dose finding part of the study, 
enrollment will be limited to ages 2-12 years as adult dosing is already available 
and it is likely that a teenager metabolizes the drug similar to adults. 

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2. All diagnoses are eligible 
3. Stem cell source must be marrow, peripheral blood stem cells or cord blood from 
an unrelated or related donor 
4. All conditioning regimens are eligible. 
5. Patient must be planned to receive a calcineurin inhibitor (cyclosporine or 
tacrolimus) together with steroid, methotrexate or mycophenolate mofetil as 
GVHD prophylaxis. 
6. Willingness and ability to provide signed informed consent (including assent, for 
ages 11-17 years) 
 
Exclusion Criteria 
1. Documented anaphylaxis to Maraviroc 
2. Ex vivo T depleted grafts 
3. Abnormal ALT (>/=--5X ULN) on day -3. (This criterion is to be assessed at study 
enrollment, but it will be confirmed again prior to the first dose of maraviroc) 
4. Individuals who are HIV positive will not be enrolled in the study.  
 
Treatment Plan 
Dose and schedule of Maraviroc administration-  
Maraviroc administration will start on day -3 and will end on day +30 after stem cell 
transplant, making the total number of days of drug administration 34 days. Our goal is 
to have steady state Maraviroc concentrations before stem cell infusion (on day 0) and 
continuing during the period of engraftment. The day of planned stem cell infusion will 
be recorded as day zero. If the stem cell infusion is given over 2 days, the first of those 
2 days will be considered as day zero. Maraviroc will be administered twice daily orally 
or via enteral tube. Maraviroc absorption is somewhat reduced with ingestion of a high-
fat meal; however, it can be given with or without food. 
Dosing of Maraviroc will be based on body surface area, which will be assessed prior to 
starting maraviroc. This is based on the current congenital HIV trial using Maraviroc.  
We hypothesize that the optimal dose and exposure (as measured by the area under 
the concentration-time curve; AUC) for GVHD prophylaxis will likely conform to the 
optimal dose for the congenital HIV population (Table1).  However, we recognize that 
stem cell transplant patients are more highly catabolic and have significantly more 

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concomitant medications than HIV patients, so are aware that we may find important PK 
differences. 
BSA (m2) 
Dose of Maraviroc to be administered orally 
<0.22 
40 mg bid 
0.2-0.43 
100 mg bid 
0.44-0.72 
200 mg bid 
0.73-1.19 
300 mg bid 
1.20-1.30 
300 mg bid 
1.31-1.73 
300 mg bid 
>1.73 
300 mg bid 
Table 1. Dosing of Maraviroc based on BSA [32]. 
 
Drug interactions with maraviroc occur with strong CYP3A4 inducers and inhibitors so 
these may not be used during the period of administration of maraviroc. 
 
Enzyme Inducers 
Enzyme Inhibitors 
Carbamazepine 
Amiodarone 
Phenobarbital 
Clarithromycin/Erythromycin 
Phenytoin 
Azoles (Keto/ Itra/ Vori/Posaconazole) 
Rifampin 
Verapamil 
Rifabutin 
Diltiazem 
St. John’s Wart 
Grapefruit Juice 
 
Antiretroviral medications 
Table 2. List of concomitant medications (CYP3A4 inducers and inhibitors) not allowed at enrollment or 
during study treatment 
 

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Adverse effects of Maraviroc  
For a complete list of adverse effects, please see page 18 of protocol [23].  
 
Study design- 
For the first part of the study, where full AUC analysis will be performed to verify the 
dose, we anticipate initially enrolling 12 patients to achieve 12 dose verifications. Any 
patients who do not achieve a complete PK data profile (i.e. due to suboptimal dose or 
incomplete course of study drug) will be replaced to achieve 12 dose verifications. The 
total number of patients will still remain 65 (Phase I and Phase II). The age of 
enrollment for these patients will be limited to 2-12 years old. This age restriction has 
been imposed because adult dosing for maraviroc in the stem cell transplant setting has 
already been established and it is likely that teenagers metabolize the drug similar to 
adults. The second part of the study, where full AUC analysis will not be conducted, will 
enroll the remaining patients between the ages 2-40 years.  
We will enroll eligible patients and maraviroc will be administered as per study rules. 
Area under the concentration-time curve (AUC) determination will be performed on days 
0 +/- 3 days and 10 +/- 3 days to account for weekends, national holidays or clinical 
deterioration not allowing for scheduled blood draws on the specified days. PK analysis 
will be performed after the first 3 patients. As per our study design graph, this is not an 
“interim” analysis , but an analysis to verify PK target attainment which then will drive 
either further observation or dose escalation. See Figure 1. 

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Figure 1. Study design  
 
Pharmacokinetic measurement and analysis- 
 
Blood for PK will be collected on day 0 +/- 3 days and Day 10 +/- 3 days. Complete PK 
profile (full AUC) will be performed on these days (see time points below). Evaluation of 
maraviroc trough levels will also be done routinely on all patients on study on days 
0,7,14 and 21 in order to collect additional PK data, verify compliance and allow for 
additional dose corrections if necessary. 
 
Target AUC/12 hours= >/=100ng/mL (based on HIV data)  
 
PK processing will be performed at University of North Carolina’s Clinical Pharmacology 
and Analytical Chemistry Laboratory using mass spectrometer with HPLC separation. 

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Plasma Maraviroc concentration data will be analyzed by compartmental and non-
compartmental analysis with the help of Dr Alexander Vinks, Director of Pediatric 
Pharmacology Research Unit (PPRU) at CCHMC, and parameter estimates generated 
will include clearance, half-lives, and volume of distribution along with area under the 
curve (AUC).  
While data on Maraviroc blood levels are available from other studies, our patients are 
different from those previously studied, and these first cases will be of great value in 
determining the levels of drug we can achieve in this population 
 
The time points of obtaining drug levels will be as follows: 
 Hour 0- Pre maraviroc administration 
 Hour 1+10 minutes - After maraviroc administration 
 Hour 2+10 minutes- After maraviroc administration 
 Hour 4 +10 minutes- After maraviroc administration 
 Hour 6 + 10 minutes- After Maraviroc administration 
 Hour 8 + 10 minutes- After maraviroc administration 
 Hour 12+ 20 minutes- After Maraviroc administration 
Plasma concentration-time data will be explored graphically and the AUC will be 
estimated by non-compartmental analysis with the software package WinNonlin 
(Version 6.2, Pharsight Corporation, Palo Alto, CA). Full maraviroc PK profile and 
trough concentration data will be analyzed using a PK model-based Bayesian approach 
(MW/Pharm, MediWare, Groningen, the Netherlands).  
Pharmacodynamic analysis will be performed in the laboratory using standard 
techniques. 
Pharmacodynamic assessments will occur on days 0 +/-3 days and one time on day 14 
+/- 3 days after stem cell infusion.  Results will be available in a timely fashion to 
correlate with pharmacokinetic test results. 
 
Dose escalation criteria- 
Dose escalation will take place if all the requirements listed below are met: 
1. The AUC/12 hours of the initial 2/3 patients is below 100 ng/ml 

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2. No more than 0 of 3 or 1/6 patients on the first dose level experience a dose 
limiting toxicity by day 30, defined as either- 
a. Non-engraftment by day 30. Engraftment is defined as the first of three 
consecutive measurements of ANC>500/mcL over 3 or more days. 
b. Grade 4 liver abnormalities, unless clearly related to stem cell transplant 
and not to the study drug, including but not limited to grade 4-5 liver 
toxicity due to hepatic veno-occlusive disease, grade 4-5 organ toxicities 
related to expected infections following stem cell transplant and their 
sequelae, or grade 4-5 toxicities related to graft versus host disease. 
c. Other grade 4-5 toxicity , unless clearly related to stem cell transplant and 
not to study drug, including but not limited to veno-occlusive disease of the 
liver, acute graft versus host disease, autoimmune cytopenias, infectious 
complications due to stem cell transplant, or organ toxicities due to 
conditioning regimens. 
 
BSA 
 Original 
Dose 
Dose 
escalation 
Value 
increment/dose 
<0.22 
40 mg bid 
50 mg bid 
+ 10 mg 
0.2-0.43 
100 mg bid 
120mg bid 
+ 20 mg 
0.44-0.72 
200 mg bid 
250 mg bid 
+ 50 mg 
0.73-1.19 
300 mg bid 
350 mg bid 
+ 50 mg 
1.20-1.30 
300 mg bid 
350 mg bid 
+ 50 mg 
1.31-1.73 
300mg bid 
350 mg bid 
+ 50 mg 
>1.73 
300 mg bid 
350 mg bid 
+ 50 mg 
Table 4. Table showing doses and increments for dose escalation of Maraviroc.  
 
Stopping Rules 
1. If the incidence of Grade 2-4 acute GI or Liver ( visceral) graft versus host 
disease is greater than 50% in the first 20 subjects by day +100, the study will be 
stopped. Enrollment will not stop while the analysis is being conducted. 

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2. If 3 out of 6 subjects experience DLT by day +30 as defined above at the initial 
dose in the first phase (AUC analysis) of the study, the study will be stopped. 
Enrollment will not be suspended while the analysis is being conducted.  
3. The study will be halted for any grade 4 liver toxicity occurring within 30 days of 
study drug administration and without clear attributable alternative cause. 
Enrollment will be suspended while an analysis of the toxicity is being conducted. 
Enrollment will only restart with approval of the Medical Monitor, IRB and FDA. 
(Of note: any grade 3 liver toxicity (ALT> 5xULN or Total Bilirubin > 3xULN), 
regardless of cause, will lead to permanent discontinuation of Maraviroc for that 
specific patient, but enrollment will continue.) 
Primary study end points 
1. Feasibility 
2. GVHD incidence by day +100 (all grades) 
3. pK target >100ng/ml  
Secondary Study end points 
1. Overall survival by day +100 
2. Graft failure by day + 100 
3. Primary disease relapse by day +100 
4. Incidence of toxicities either due to drug or transplant  
5. Infectious complications which include asymptomatic viremias for EBV, 
Adenovirus, CMV, and/or viral disease, bacterial and fungal infections as 
documented by blood cultures. 
6. Time to neutrophil and platelet engraftment 
 
GVHD will be graded according to IBMTR criteria as shown in table 5 [33]- 
 
Stage 0 
Stage 1 
Stage 2 
Stage 3 
Stage 4 
Skin 
No rash 
Rash < 25% 
BSA 
Rash 25-50% 
BSA 
> 50% BSA or 
generalized 
erythroderma 
Bullae or 
desquamation 
GI  
< 500 ml 
diarrhea 
501-1000 ml 
diarrhea/day 
1001-1500 ml 
diarrhea/day 
> 1500 ml 
diarrhea/day 
Abdominal pain 
and ileus 
Liver 
Bilirubin < 
2 mg/dL 
2.1-3 mg/dL 
3.1-6 mg/dL 
6-15 mg/dL 
> 15 mg/dL 

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Grading 
 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Skin 
 
1 
2 
3 
4 
GI 
 
0 
1-2 
3 
4 
Liver 
 
0 
1-2 
3 
4 
Table 5. Grading and staging of GVHD. 
 
Diagnosis of GVHD is mostly clinical and as such will be on the discretion of the treating 
physician. Biopsies may aid the diagnosis whenever clinically indicated but are not 
required in the study.  
 
Clinical Data to be Collected and Reported: 
Patients’ medical information will be systematically and prospectively collected as is 
usual for all SCT patients. The data collected will include, but not be limited to- 
1. Demographics including age, gender, weight, and height.   
2. Underlying diagnosis  
3. Specifics of HCT (preparative regimen, type of graft, cell dose, GVH prophylaxis, 
HLA type and donor relation etc.). 
4. Details of engraftment (timing, failure to engraft, loss of graft) 
5. Adverse effects directly related to maraviroc and transplant course  
6. Onset of GVHD, grade, organ involved and treatments used by day +100 
7. Whole blood donor chimerism  
8. Infectious complications which include asymptomatic viremias for EBV, 
Adenovirus, CMV, and viral disease, bacterial and fungal infections as 
documented by blood cultures or bronchoalveolar lavage cultures/PCRs.  
9. Overall survival at day +100  
   10. Incidence of relapse of primary disease by day +100 
 
Study calendar 
All testing below is part of standard evaluation for all patients undergoing allogeneic 
stem cell transplant and is not dependent on study enrollment, unless marked by “*” 

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Enrollment 
D-3 
D 0 
(± 3 
days) 
D +7 
(± 2 
days) 
D+10 
(± 3 
days) 
D+14 
(± 3 
days) 
D+21 
(+ 3 days) 
D+30  
(+ 7 days) 
Monthly 
after day 
+30 until 
day+ 100  
(+ 7 days) 
Informed 
Consent* 
x 
 
 
 
 
 
 
 
 
History and 
physical 
examination 
x 
x 
x 
x 
x 
x 
x 
x 
x 
GVHD 
prophylaxis 
x 
x 
x 
x 
x 
x 
x 
x 
x 
CYP3A4 
enzyme 
inducers or 
inhibitors * 
x 
x 
x 
x 
x 
x 
x 
x 
 
Acute 
GVHD 
evaluation 
and 
treatment 
 
 
 
 
 
 
 
x 
x 
Full AUC 
analysis ( 
dose 
verification 
part)* 
 
 
X  
 
X 
 
 
 
 
pK trough* 
 
 
X  
x 
 
x 
x 
 
 
pD* 
X 
 
X  
 
 
X 
 
 
 
LFTs/CBCD/
Renal profile 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adverse 
event 
evaluation* 
 
 
Continuous 
Compliance* 
 
x 
x 
x 
x 
x 
x 
x 
 
Chimerism( 
whole blood) 
 
 
 
 
 
 
 
x 
Day + 100 
Survival 
 
 
 
 
 
 
 
 
Day + 100 
 
 

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Study calendar for blood draws for patients undergoing formal AUC analysis-  
Days 
AUC 
Trough drug level 
Pharmacodynamic 
assessment 
Pretransplant 
 
 
x 
Day 0 
X (±3 days) 
 
X (±3 days) 
Day 7 
 
x (±2 days) 
 
Day 10 
X (±3 days) 
 
 
Day 14 
 
x (±3 days) 
X (±3 days) 
Day 21 
 
x (±3 days) 
 
Table 6. Study calendar for blood draws for patients undergoing formal AUC analysis 
 
For patients enrolled after maraviroc dose has been verified, the schedule for lab draws 
is shown on Table 7. 
Days 
Trough drug level 
Pharmacodynamic 
assessment 
Pretransplant 
 
x 
Day 0 
x (±3 days) 
X (±3 days) 
Day 7 
x (±2 days) 
 
Day 14 
x (±3 days) 
X (±3 days) 
Day 21 
x (±3 days) 
 
Table 7- Study calendar for blood draws for patients on second phase of study (after PK study complete 
and dose verified) 
 
Volume of Blood Draws-  
For pharmacokinetic analysis, we will need approximately 3 ml of blood, to be collected 
in an EDTA tube. Real time data results will be available to allow for dosing changes to 

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be made after the first 3 patients. For pharmacodynamics analysis, we will need 2 ml 
blood in a sodium heparin tube. 
 
Discontinuation of therapy- 
Since most patients experience severe toxicities while undergoing an allogeneic SCT, it 
will be the investigator's responsibility to determine whether certain adverse events are 
related to the study drug or not based on previous studies using the agent and the 
current labeling. Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 
will be used to report toxicities. 
The following events will mandate stopping Maraviroc for a specific patient; 
 Grade 3 liver toxicity (ALT> 5xULN or Total Bilirubin > 3xULN) regardless of 
cause 
Maraviroc will not be restarted in these cases. 
 
The following events will mandate holding Maraviroc therapy on a specific patient: 
1. Grade 3 or higher toxicity (exclusive of liver toxicity, see section above), not 
attributable to underlying disease.  
2. Infection, which requires treatment with a strong CYP450 inducer or inhibitor 
(predicted to adversely interact with Maraviroc) such as rifampin.  
3. Drop in renal function to creatinine clearance <40 ml/min as measured by GFR or 
cystatin C. 
The drug can be restarted at the same dose after full recovery from the AEs. Maraviroc 
will be discontinued if the AE recurs after re-challenge. Any grade 3 liver toxicity (ALT> 
5xULN or Total Bilirubin > 3xULN) regardless of cause will lead to permanent 
discontinuation of Maraviroc for that patient. The study will be halted for any grade 4 
liver toxicity occurring within 30 days of study drug administration without clear 
attributable alternative cause (see stopping rules for details). Re-challenge is not 
permissible in the event of Grade 3 or higher liver toxicity (ALT> 5xULN or Total 
Bilirubin > 3xULN) regardless of cause. Any grade 1 or 2 toxicities related to study drug 
will not require study drug to be held. 
 
 

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Early termination of study drug- 
 
Treatment will continue unless one of the following criteria applies: 
1. A dose limiting toxicity (DLT) occurs. A DLT is defined as either- 
a.) Non-engraftment by day 30, if assessed by the investigator to be related to 
the study drug. Engraftment is defined as the first of three consecutive 
measurements of ANC>500/mcL over 3 or more days. 
b.) Grade 4 liver abnormalities, once other causes for liver toxicity have been 
ruled out. 
c.) Other grade 4-5 toxicity determined by the investigator to be related with high 
probability to the study drug. 
2. Any grade 3 or higher liver toxicity (ALT> 5xULN or Total Bilirubin > 3xULN) 
regardless of cause: 
a. Any grade 3 liver toxicity (as defined above) will lead to permanent 
discontinuation of Maraviroc for that patient. 
b. The study will be halted for any grade 4 liver toxicity occurring within 30 
days of study drug administration without clear attributable alternative 
cause. (See stopping rules for specific details.) 
3. Patient decides to withdraw from the study due to inability to take the drug. 
4. Poor compliance to drug (missing either 6 consecutive doses (3 days) or 12 
intermittent doses in the entire administration period (< 80% compliance). 
 
Patients removed from study for unacceptable adverse events will be followed until the 
adverse event resolves or stabilizes. 
 
Toxicity Monitoring- 
Maraviroc is generally well tolerated in children as noted in the phase 1 congenital HIV 
trial. However, a black box warning for hepatotoxicity exists. Therefore, liver function 
tests will be monitored on patients while on maraviroc every 48 hours until day+30 (+ 7 
days).  
 

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General concomitant medication and supportive care guidelines 
 
Maraviroc is not known to significantly affect any metabolic pathway. However, 
inhibitors and inducers of the cytochrome P450 metabolic pathway affect its drug level. 
Generally, patients in this trial will receive prophylactic antifungals as directed by their 
attending physician, which may include either micafungin or ambisome. Other 
concomitant medications are allowed except for strong inducers or inhibitors of the 
cytochrome P450, such as voriconazole, phenytoin, carbamazepine and rifampin. (See 
table 2). 
Should there be emesis within 30 minutes of taking maraviroc, the drug should be re –
administered. However, any emesis after 30 minutes of taking maraviroc will not require 
the drug to be readministered.  
 
Risk to unborn fetus- 
It is recommended that patients on study utilize appropriate methods of contraception to 
prevent getting pregnant or fathering a child as the effects of maraviroc on the unborn 
fetus is unknown. All female patients routinely undergo a pregnancy test as part of pre 
bone marrow transplant evaluation and only proceed with transplant when it is 
confirmed that they are not pregnant. Therefore we will not repeat this test prior to 
starting maraviroc.  
 
Risk associated with blood draws- 
This study will require research blood to be drawn as specified time points as shown in 
the study calendar. This blood will be drawn from a central line whenever possible and 
will be combined with routine clinical blood draws whenever possible and will not 
exceed maximum allowed blood volume for that patient per day per standard of care.  
 
Statistical analysis 
The primary objectives of this phase I/II clinical trial are to establish a therapeutic dose 
of Maraviroc and test the 100 day incidence rate of any GVHD in pediatric patients 
undergoing allogeneic stem cell transplantation against a historical incidence rate. 

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Phase I will consist of the determination of a therapeutic dose. A dose escalation 
procedure outlined in the study design will be conducted until a dose which yields 2 of 3 
patients with AUC > 100ng/ml and no drug related toxicities.   
All patients in phase I treated at the established dose as well as patients treated at a 
lower dose yet achieve a therapeutic pharmacokinetic level will be included in further 
analysis. The historical incidence rate of GVHD in pediatric patients undergoing 
allogeneic stem cell transplantation with GVHD prophylaxis agent of a calcineurin 
inhibitor+ methylprednisolone is 16% (BMT 2012 data at CCHMC). Assuming the 
incidence rate for patients treated at the dose established in phase I is 6% then a 
sample size of evaluable 65 patients provides an 80% power of detecting a difference 
between this rate and the historical incidence rate. This sample size determination was 
computed using a two-sided binomial test. 
The exact two-sided 95% confidence intervals for the day 100 incidence rate of grade 
GVHD will be reported. For time-to-event endpoints, e.g., overall survival and time to 
occurrence of GVHD, we will present Kaplan-Meier curves and corresponding survival 
p-values will be computed using log-rank tests. Demographic information such as age 
and race will be tabulated. Descriptive statistics, including means, standard deviations, 
and ranges for continuous parameters, as well as frequencies for categorical 
parameters, will be presented 
 
Regulatory Issues- 
 
The protocol and informed consent document for this study will be approved in writing 
by the Institutional Review Board (IRB) prior to any patient being registered on the 
study. 
 
Changes to the protocol, as well as a change of study staff, must also be approved by 
the IRB. Records of the Institutional Review Board review and approval of all 
documents pertaining to this study must be kept on file by the investigator and are 
subject to FDA inspection at any time during the study.  
 
Informed consent will be obtained prior to the treatment of participants. 

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This protocol will be performed under an investigator-initiated IND. 
 
Study Monitoring and Auditing: 
Monitoring and auditing procedures will be followed to ensure that the study is 
conducted, documented, and reported in accordance with the IRB approved protocol, all 
applicable federal regulations and guidelines, and applicable regulatory requirements of 
Cincinnati Children’s Hospital Medical Center. 
 
Verification of eligibility will be performed and appropriate documentation of informed 
consent will be documented for all subjects enrolled into the study.  The timeliness of 
Adverse Event and Serious Adverse Event reporting will be monitored to ensure 
regulatory compliance.  All case report forms (CRF) for the first subject enrolled into 
the study will be monitored for completeness and quality by comparing data in the case 
report forms to data in the source documents.  Thereafter, a minimum of 10% of 
enrolled subjects’ CRFs will be monitored for completeness and quality by comparing 
data in the case report forms to data in the source documents.  
 
Data Safety Monitoring Plan  
A qualified physician not associated with this particular protocol will be chosen as 
medical monitor for this study.  The medical monitor will meet with the PI or designee 
and review study data/progress a minimum of every 6 months; more often at the 
discretion of the PI and/or medical monitor. 
 
The medical monitor is required to review all unanticipated problems involving risk to 
subjects or others, unanticipated serious adverse events and all subject deaths 
associated with the protocol and provide an unbiased written report of the review.   
 
At a minimum, the medical monitor should comment on the outcomes of the event or 
problem, and in the case of unexpected serious adverse event or death, comment on 
the relationship to participation in the study.  Based on the review of these events, the 
monitor should make a recommendation regarding study continuation.  All decisions 
regarding study continuation, modification, or termination will be reported immediately or 

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annually, as appropriate, to the IRB, FDA, and other appropriate agencies. Reports for 
events determined by either the investigator or medical monitor to be possible or 
definitely related to study participation and reports of events resulting in death should be 
forwarded in compliance with current IRB policy and applicable federal regulations.      
 
Adverse Event Reporting 
Safety and tolerability for the study drug will be assessed according to the Common 
Terminology Criteria for Adverse Events v4.0 (CTCAE published October 6, 2009).  
The principal investigator or designee will review adverse events closely and assess the 
event’s relationship to study procedures to determine whether the event is unrelated or, 
unlikely, possibly, probably or definitely related to the study procedures, especially in 
relation to the underlying disease and baseline lab values for the patient. All adverse 
events (except as specified below) will be recorded on case report forms and reported 
in compliance with CCHMC IRB and federal guidelines.  All expected and unexpected 
Grade 3 and higher adverse events occurring during this study up through 30 days 
following the last dose of maraviroc will be recorded on the case report forms, unless 
directly attributable to the underlying disease. The principal investigator will review each 
event and assess its relationship to study events to determine whether the event is 
unrelated or, unlikely, possibly, probably or definitely related to the study therapy. 
Additionally for this study, events as previously identified as resulting from 
administration of a stem cell transplant will be considered as expected. The transplant 
regimen is well known to commonly affect systems such as the hematologic, 
immunologic and gastrointestinal systems. The following are known complications of 
transplant- disseminated intravascular coagulation, febrile neutropenia, hemolysis, 
thrombotic thrombocytopenic purpura, adrenal insufficiency, colitis, constipation, 
diarrhea, enterocolitis, gastrointestinal pain, malabsorption, mucositis, nausea, 
pancreatitis, vomiting, dyspepsia, fever, pain, cholecystitis, allergic reaction, serum 
sickness, upper respiratory infection, urinary tract infection, weight gain/loss, acidosis, 
alkalosis, anorexia, dehydration, glucose intolerance, iron overload, generalized muscle 
weakness, reversible posterior leukoencephalopathy syndrome, bladder spasms, 
cystitis, hematuria, urinary frequency, urinary urgency, irregular menstruation, pruritis, 
hypertension, purpura, and petechiae. For the purposes of the study, the listed events 
that are < grade 3 will not be considered adverse events.  
Hematologic toxicities which are attributable to the underlying hematological disease will 
not be considered adverse events; however, grade ≥3 neutropenia will be documented 
and assessed for attribution.  

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In the event that any of these known complications of transplant or hematologic 
toxicities are thought to be at least possibly attributable to the study drug, the 
event will be recorded and subsequently reported to the FDA and IRB according 
to current reporting requirements. 
Adverse reactions must be reported to the principal investigator who is responsible for 
the reporting to the Cincinnati Children's Hospital Medical Center IRB according to 
current guidelines.  All Adverse Event reporting is to comply with the current CCHMC 
IRB policy and applicable federal regulations.  If any serious adverse events occur, 
current guidelines will be followed for expedited reporting to the IRB and FDA.   
 
All serious and medically significant adverse events considered related to maraviroc by 
the investigator will be followed until resolved or considered stable.   
 
Expected events are those that have been previously identified as resulting from 
administration of the protocol therapy, those that can be contributed to the underlying 
condition, and/or those associated with transplant.  An adverse event is considered 
unexpected, for reporting purposes only, when either the type of event or the severity of 
the event is not listed in the drug package insert, consent and/or protocol.  
 
Medical conditions/diseases present before starting study drug are only considered 
adverse events if they worsen after starting study drug.  Abnormal laboratory values or 
test results constitute adverse events only if they induce clinical signs or symptoms, are 
considered clinically significant, or require therapy as determined by the PI.  
 
Other research studies 
Patients enrolled in this study may be enrolled of any one of the several approved 
therapeutic and non-therapeutic BMT research studies. There is no foreseen increase in 
the cumulative risk to the patient enrolled in this study as well as in a therapeutic or non-
therapeutic BMT research study. 
 
 

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Risk assessment recommendation  
This study will be of more than minimal risk but with potential for direct benefit to 
participants  
 
Potential Benefits 
The direct potential benefit to patients will be reduction in the incidence of acute visceral 
graft versus host disease. 
 
Potential Risks, Discomforts, Inconveniences and Precautions 
There are risks to the patients which include allergic reaction to the drug, hepatotoxicity, 
gastrointestinal discomfort, need for placement of a nasogastric tube for reliable 
administration of the drug and possible infectious complications. Safety data for long 
term use of Maraviroc are not available. 
 
Confidentiality 
Any copies of research records will be kept in locked files and any information stored on 
computer will be password protected.  The information from the study may be 
published; however, subjects will not be identified in such publications.  The publication 
will not contain information about the subjects that would enable someone to determine 
their identity as a participant without the subject’s authorization. 
The Institutional Review Board may have access to these records.   
The use of clinical information for research purposes and the protection of privacy will 
be done in compliance with Cincinnati Children’s Hospital Medical Center HIPAA 
requirements. 
 
Period of Time Estimated to Complete Project as Described 
Approximately 65 patients will be enrolled on study, which will occur over a time frame 
of approximately 5 years.  
 

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Funding 
There is no outside funding for this study. Patients will not be charged for the drug, 
pharmacokinetic or pharmacodynamic assays. 
 
Payment for Studies 
 
There will be no compensation to patients. 
 
Methods to be used in procuring consent of subjects 
 
Dr. Khandelwal or one of the other Bone Marrow Transplant Physicians who are co-
investigators will consult with the patient and/or the parent/legal guardian to explain the 
procedures, risks and benefits of the study at the patient/parent’s level of 
understanding.  Opportunity will be given to consider the study and have questions 
answered. Information will be given in a written format in the form of a description of the 
study, which will include a signature space for consent to be given (see attached 
patient/parent document).   
 
Prior to the initiation of the study, acknowledgement of the receipt of this information 
and the subject's freely tendered offer to participate will be obtained in writing from each 
subject in the study.  Participation is voluntary, and all subjects/parents/guardians will 
give informed consent to participate. Assent will be obtained from patients 11-17 years 
of age. Information will also be given verbally, and all patients and/or parents will have 
an opportunity to ask questions.   
 
While we do not plan on targeting non-English speaking patients for enrollment on this 
study, we do periodically have patients who speak Spanish or Arabic. We will not 
exclude these patients from this study. We will use a short form or fully translated 
consent (as applicable) according to the process outlined in the Clinical Management 
and Resource Support Core Standard Operating Procedures (SOP).  
 
 

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Adverse effects of maraviroc reported in HIV populations- 
 
Likely (>10% of patients): 
 Central nervous system: Fever (12%)  
 Respiratory: Upper respiratory tract infection (20%), cough (13%)   
 
Less Likely (2-10% of patients):  
 Cardiovascular: Vascular hypertensive disorder (3%).  
 Central nervous system: Dizziness (8%), insomnia (7%), consciousness 
disturbances (4%), depression (4%), pain (4%).  
 Dermatologic: Rash (10%), pruritus (4%), folliculitis (3%), skin neoplasms 
(benign; 3%), dermatitis (3%).  
 Endocrine & metabolic: Lipodystrophy (3%).  
 Gastrointestinal: Abdominal pain (8%), appetite disorders (7%), constipation 
(5%), dyspepsia (3%), stomatitis (3%).  
 Genitourinary: Urinary tract/bladder symptoms (3% to 5%), genital warts (2%).  
 Hematologic: Neutropenia (grades 3/4: 4%).  
 Hepatic: Transaminases increased (grades 3/4: 2% to 5%), bilirubin increased 
(grades 3/4: 6%).  
 Neuromuscular & skeletal: Parasthesia (5%), sensory abnormality (4%), muscle 
pain (3%), peripheral neuropathy (3%).  
 Respiratory: Bronchitis (6%), sinusitis (6%), breathing abnormality (3%), 
bronchospasm (2%), respiratory tract/sinus disorder (2%).  
 Miscellaneous: Herpes infection (7%), sweat gland disturbances (5%), influenza 
(2%). 
 
Rare but Serious (<2% of patients):  
Abdominal neoplasm, acute cardiac failure, anal cancer, angina, basal cell carcinoma, 
Bowen's disease, C. difficile colitis, cerebrovascular accident, cholangiocarcinoma, 
cholestatic jaundice, coronary artery disease, coronary artery occlusion, creatine kinase 
increased, esophageal candidiasis, esophageal carcinoma, hepatic cirrhosis, hepatic 
failure, hepatotoxicity, liver metastases, lymphoma, MI, myocardial ischemia, myositis, 
osteonecrosis, pneumonia, rhabdomyolysis, rhinitis, septic shock, squamous cell 
carcinoma, syncope, tongue neoplasm, viral meningitis  

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