A Phase II, Single-arm Open-label Multi-center Study of Sirolimus in Previously Treated Idiopathic Multicentric Castleman Disease
Phase: PHASE2
Conditions: Castleman Disease, Castleman's Disease, Multicentric
Sponsor: University of Pennsylvania

 
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A phase II, single-arm open-label multi-center study of 
sirolimus in previously treated idiopathic multicentric 
Castleman disease 
 
  
Site and Lead Principal 
Investigator  
Dr. David Fajgenbaum, MD, MSc, MBA  
University of Pennsylvania 
Site Principal Investigator 
Dr. Frits van Rhee, MD, PhD 
University of Arkansas for Medical Sciences 
Site Principal Investigator 
Dr. David Teachey 
Children’s Hospital of Philadelphia 
Site Principal Investigator 
Dr. Aaron Goodman 
University of California San Diego  
Co-Investigator  
Dr. Sunita Dwivedy Nasta, MD 
University of Pennsylvania 
Co-Investigator 
Dr. Adam D. Cohen, MD 
University of Pennsylvania 
Statistician 
Dr. Hongzhe Li, PhD 
University of Pennsylvania 
NIH Grant Number 
R01-HL141408 
Investigational Product: 
SIROLIMUS (AY-22989, rapamycin, Rapamune®)  
Initial Version Date 
16-Jan-2019 
Version 2 Date 
16-Jul-2019 
Version 3 Date 
17-Feb-2020 
Version 4 Date 
05-Nov-2020 
Version 5 Date 
18-May-2022 
Version 6 Date 
13-Feb-2023 

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Version 7 Date 
20-Mar-2024 
 

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Table of Contents 
 
List of Abbreviations and Definitions .......................................................................................... 7 
Study Summary ......................................................................................................................... 9 
 
Background and Study Rationale .......................................................................................11 
1.1 
Background and Relevant Literature .......................................................................11 
1.2 
Name and Description of the Investigational Product ..............................................12 
1.2.1 
Nonclinical Data ...................................................................................................13 
1.2.2 
Clinical Data to Date ............................................................................................13 
1.3 
Dose Rationale ........................................................................................................14 
 
Study Objectives ................................................................................................................15 
2.1 
Primary Objective ....................................................................................................15 
2.2 
Exploratory Objective ..............................................................................................15 
 
Investigational Plan ............................................................................................................15 
3.1 
General Design .......................................................................................................15 
3.1.1 
Recruitment and Screening Phase .......................................................................16 
3.1.2 
Intervention Phase ...............................................................................................16 
3.1.3 
Follow Up Phase ..................................................................................................17 
3.1.4 
Allocation to Interventional Group ........................................................................17 
3.2 
Study Endpoints ......................................................................................................17 
3.2.1 
Primary Study Endpoints .....................................................................................17 
3.2.2 
Secondary Study Endpoints .................................................................................17 
3.2.3 
Exploratory Study Endpoints ................................................................................17 
3.2.4 
Safety Endpoints ..................................................................................................17 
 
Study Population and Duration of Participation ..................................................................18 
4.1 
Inclusion Criteria ......................................................................................................18 
4.2 
Exclusion Criteria ....................................................................................................18 
4.3 
Subject Recruitment ................................................................................................20 
4.4 
Duration of Study Participation ................................................................................20 
4.5 
Total Number of Subjects and Sites ........................................................................20 
4.6 
Vulnerable Populations: ...........................................................................................20 
 
Study Intervention ..............................................................................................................20 
5.1 
Description ..............................................................................................................20 

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5.2 
Intervention Regimen ..............................................................................................21 
5.3 
Receipt ....................................................................................................................21 
5.4 
Storage ...................................................................................................................22 
5.5 
Preparation and Packaging .....................................................................................22 
5.6 
Administration and Accountability ............................................................................22 
5.7 
Subject Compliance Monitoring ...............................................................................22 
5.8 
Return or Destruction of Investigational Product ......................................................22 
 
Study Procedures ..............................................................................................................23 
6.1 
Screening Phase .....................................................................................................23 
6.1.1 
Screening Visit (Visit 0) ........................................................................................23 
6.2 
Intervention Phase ..................................................................................................24 
6.2.1 
Baseline Visit (Visit 1) ..........................................................................................24 
6.2.2 
Visits 2 and 3 .......................................................................................................24 
6.2.3 
Visit 4 ...................................................................................................................25 
6.2.4 
Visit 5 ...................................................................................................................25 
6.2.5 
Visit 6 ...................................................................................................................25 
6.2.6 
Visit 7 and 8 .........................................................................................................26 
6.2.7 
Visit 9 ...................................................................................................................26 
6.2.8 
Visit 10 and 11 .....................................................................................................27 
6.2.9 
Visit 12 .................................................................................................................27 
6.2.10 
Visits 13 and 14 ...................................................................................................28 
6.2.11 
End of Treatment Visit (Visit 15)...........................................................................28 
6.3 
Follow Up Phase of the Study .................................................................................28 
6.3.1 
Visit 16 .................................................................................................................28 
6.4 
Rescue Therapy ......................................................................................................29 
6.5 
Unscheduled Visits ..................................................................................................29 
6.6 
Subject Withdrawal ..................................................................................................29 
6.6.1 
Data Collection and Follow-up for Withdrawn Subjects ........................................29 
6.7 
Early Termination Visit .............................................................................................29 
 
Study Evaluations and Measurements ...............................................................................30 
7.1 
Medical Record Review ...........................................................................................30 
7.2 
Physical Examination ..............................................................................................30 

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7.3 
Vital Signs ...............................................................................................................30 
7.4 
Laboratory Evaluations ............................................................................................30 
7.4.1 
Clinical Laboratory Tests .....................................................................................31 
7.5 
Pregnancy Testing ..................................................................................................31 
7.6 
Efficacy Evaluations ................................................................................................32 
7.7 
Research Samples ..................................................................................................34 
7.8 
Genetic Testing .......................................................................................................34 
7.9 
Safety Evaluations ...................................................................................................34 
7.10 
Concomitant Therapies ...........................................................................................35 
 
Statistical Plan ...................................................................................................................35 
8.1 
Primary Endpoint .....................................................................................................35 
8.2 
Secondary Endpoints ..............................................................................................36 
8.3 
Exploratory Endpoints .............................................................................................36 
8.4 
Sample Size and Power Determination ...................................................................36 
8.5 
Statistical Methods ..................................................................................................36 
8.5.1 
Efficacy Analysis ..................................................................................................37 
8.5.2 
Interim Analysis ...................................................................................................37 
8.5.3 
Safety Analysis ....................................................................................................37 
8.6 
Subject Population(s) for Analysis ...........................................................................37 
 
Safety and Adverse Events ................................................................................................37 
9.1 
Definitions ...............................................................................................................37 
9.1.1 
Adverse Event .....................................................................................................37 
9.1.2 
Serious Adverse Event ........................................................................................38 
9.2 
Recording of Adverse Events ..................................................................................38 
9.3 
Relationship of AE to Study .....................................................................................38 
9.4 
Reporting of Adverse Events and Unanticipated Problems ......................................38 
9.4.1 
Follow-up report ...................................................................................................39 
9.4.2 
Investigator reporting: notifying the study sponsor ...............................................39 
9.4.3 
Investigator Reporting: Notifying the Penn IRB ....................................................39 
9.4.4 
Sponsor reporting: Notifying participating investigators ........................................41 
9.4.5 
Sponsor reporting: Notifying collaborating companies ..........................................41 
9.5 
Unblinding Procedures ............................................................................................41 

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9.6 
Stopping Rules ........................................................................................................41 
9.7 
Medical Monitoring ..................................................................................................41 
9.7.1 
Data and Safety Monitoring Plan..........................................................................41 
9.7.2 
Data Safety Monitoring Board ..............................................................................41 
 
Study Administration, Data Handling and Record Keeping ..........................................42 
10.1 
Confidentiality ..........................................................................................................42 
10.2 
Data Collection and Management ...........................................................................42 
10.3 
Records Retention ...................................................................................................43 
10.4 
Management of Information for Multi-Center Research ...........................................43 
 
Study Monitoring, Auditing, and Inspecting .................................................................43 
11.1 
Study Monitoring Plan .............................................................................................43 
11.2 
Auditing and Inspecting ...........................................................................................44 
 
Ethical Considerations ................................................................................................44 
12.1 
Risks .......................................................................................................................44 
12.2 
Benefits ...................................................................................................................46 
12.3 
Risk Benefit Assessment .........................................................................................46 
12.4 
Informed Consent Process / HIPAA Authorization ...................................................46 
 
Study Finances ...........................................................................................................47 
13.1 
Funding Source .......................................................................................................47 
13.2 
Conflict of Interest ...................................................................................................47 
13.3 
Subject Stipends or Payments .................................................................................47 
 
Publication Plan ..........................................................................................................47 
 
Appendix .....................................................................................................................47 
15.1 
Diagnostic Criteria for iMCD ....................................................................................48 
15.2 
Cheson Criteria .......................................................................................................48 
15.3 
Study calendar ........................................................................................................50 
15.4 
Laboratory Tests .....................................................................................................51 
15.5 
Example Dose Calculations .....................................................................................53 
 
References .................................................................................................................54 
 
 
 

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List of Abbreviations and Definitions 
 
Abbreviations: 
iMCD 
Idiopathic multicentric Castleman disease 
HHV-8 
Kaposi’s sarcoma virus / human herpes virus-8 
IL 
Interleukin 
PI3K 
Phosphoinositide 3-kinase 
mTOR 
Mechanistic target of rapamycin 
VEGF 
Vascular endothelial growth factor 
sIL2R 
Soluble IL-2 receptor  
CBR 
Clinical benefit response 
CHAP 
high sensitivity C-reactive protein, hemoglobin, albumin and eastern 
cooperative oncology group performance score 
CRP 
C-reactive protein 
ECOG 
Eastern cooperative oncology group  
S6K1 
p70S6 kinase Eukaryotic translation initiation factor 4E-binding protein 1 
4E-BP1 
Eukaryotic translation initiation factor 4E-binding protein 1 
FKBP-12 
FK binding protein-12 
EBV 
Epstein-Barr virus 
MTI 
mTOR inhibitor 
FDA 
Food and Drug Administration 
P-gp 
P-glycoprotein 
CYP3A4 
Cytochrome P450 IIIA4 
GUID 
Global Unique Identifier 
AE 
Adverse event 
SAE 
Serious adverse event 
CTCAE 
Common terminology criteria for adverse events 
eGFR 
Estimated glomerular filtration rate 
ANC 
Absolute neutrophil count 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
HIV 
Human immunodeficiency virus 
CDCN 
Castleman Disease Collaborative Network 
IDS 
Investigational Drug Service 
UAMS 
University of Arkansas for Medical Sciences 
CHOP 
Children’s Hospital of Philadelphia 
IP 
Investigational Pharmacy 
CT 
Computed tomography  
PET 
Positron emission tomography 
EDTA 
Ethylenediaminetetraacetic acid 
IRB 
Institutional Review Board  
ICF 
Informed consent form 
eCRF 
Electronic case report form 
CR 
Complete response 
CRu 
CR/unconfirmed 
PR 
Partial response 
SD 
Stable disease 
PD 
Progressive disease 
SPD 
Sum of the products of the greatest diameters 

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DSMB 
Data Safety Monitoring Board 
HMG-CoA 
3-hydroxy-3-methyl-glutaryl-CoA reductase 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
PHI 
Protected health information 
LAR 
legally authorized representative 
 
Definitions: 
Eligible Subject 
A subject deemed to meet all inclusion criteria and not violate any 
exclusion criteria. 
Enrolled Subject 
A subject who has provided informed consent to participate in this study. 
Anti-IL-6 blockade 
Siltuximab or tocilizumab 
 
 
 

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Study Summary 
Title 
A phase II, single-arm open-label multi-center study of sirolimus in 
previously treated idiopathic multicentric Castleman disease 
Short Title 
Sirolimus in iMCD 
Phase 
Phase II 
Methodology 
Open-label 
Study Duration 
Each subject’s participation will last up to 73 weeks. 
The entire study is expected to last 3 to 3.5 years.  
Study Center(s) 
Multi-center study with four institutions: the University of Pennsylvania, 
the Children’s Hospital of Philadelphia, the University of Arkansas for 
Medical Sciences, and the University of California, San Diego.  
Primary Objective 
To evaluate the efficacy of sirolimus for treatment of symptomatic iMCD 
Exploratory 
Objective 
To investigate the mechanism of action by which sirolimus is efficacious 
in iMCD through cellular and molecular studies in the research laboratory 
Number of Subjects 
To achieve up to 24 evaluable subjects, up to 40 subjects may be 
enrolled across the three sites 
Main Inclusion and 
Exclusion Criteria 
• 
Males or non-pregnant females, ages 2-80  
• 
Documented iMCD history with evidence of active disease at the 
time of enrollment 
• 
Failed, refractory, relapsed, or inability to tolerate anti-IL-6 or anti-
IL-6 receptor therapy 
• 
Certain 
comorbidities 
and 
concurrent 
therapeutics 
are 
exclusionary 
Investigational 
Product, dose, route 
of administration  
Product: SIROLIMUS (AY-22989, rapamycin, Rapamune®)  
 
Dosing (rounded to the nearest mg): Adults: Loading: 5 mg/m2 on day 1 
Daily: 2.5 mg/m2/day  
Children: 2.0 mg/m2/day 
Target trough level:  
Adults: 10-15 ng/mL 
Children: 5-15 ng/mL 
 
Route of Administration: Oral 
Duration of 
Administration 
0 to 12 ± 1 month 
Reference Therapy 
N/A 

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Statistical 
Methodology 
This is a study to understand the impact of sirolimus on iMCD 
symptomology. We will examine the changes in a variety of clinical 
symptoms, laboratory tests, and imaging findings pre- and post-drug 
treatment to determine if sirolimus is efficacious. Parallel research 
laboratory assays will investigate mechanisms of action or failure.  
Safety Evaluations 
• 
Complete blood count with differential  
• 
Lipid panel 
Data and Safety 
Monitoring Plan 
The licensed site investigators will be responsible for monitoring the data 
quality and the ongoing safety of subjects at their respective sites. A data 
safety monitoring board (DSMB) will provide additional guidance and will 
review data quality and subject safety on an ongoing basis.  
 
 
 

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 Background and Study Rationale 
This document is a clinical research protocol and the study described will be conducted in 
compliance with the protocol and in full accordance with all applicable University of Pennsylvania 
Research Policies and Procedures and all applicable Federal and state laws and regulations 
including, as applicable 45 CFR 46, 21 CFR Parts 50, 54, 56, and Good Clinical Practice: 
Consolidated Guidelines approved by the International Conference on Harmonisation. All 
episodes of noncompliance will be documented. 
 
Human herpesvirus (HHV)-8-negative, idiopathic multicentric Castleman disease (iMCD) is a rare 
and deadly hematologic illness. Recent research has suggested a key role for the 
phosphoinositide 3-kinase(PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway in iMCD 
pathogenesis1 and off-label administration of sirolimus,2 an mTOR inhibitor (MTI), resulted in 
Clinical Benefit Response (CBR) (as previously used in the Phase I study of siltuximab3) in two 
iMCD patients experiencing active disease, and a prolonged and ongoing remission in one 
patient. Based on these experiences, we plan to evaluate the efficacy of sirolimus as a therapy 
for iMCD patients who are either unable to tolerate anti-IL-6 blockade therapy (siltuximab or 
tocilizumab), or who fail, relapse, or are refractory to such treatment. 
 
1.1 
Background and Relevant Literature 
iMCD is a rare, deadly hematologic illness. Castleman disease describes a group of related 
diseases defined by characteristic lymph node histopathology - atrophic or hyperplastic germinal 
centers, prominent follicular dendritic cells, hypervascularization, polyclonal lymphoproliferation, 
and/or polytypic plasmacytosis. In addition, iMCD patients can experience episodic disease flares 
characterized by laboratory abnormalities and systemic symptoms, including constitutional 
symptoms, cytopenias, hepatosplenomegaly, fluid accumulation, and cytokine storm-associated 
multiple organ system dysfunction.4 iMCD’s heterogeneous presentation and symptoms, and its 
overlap with hematologic, oncologic, rheumatologic, and infectious disease makes its diagnosis 
and treatment difficult. iMCD is diagnosed in approximately 600-1,000 individuals annually in the 
USA5 and 35% of iMCD patients die within five years of diagnosis.6 The causes, etiological driver 
and pathogenic processes that give rise to iMCD are unknown.  
 
Current therapeutic options are limited and provide benefit for only a subset of patients. Blockade 
of IL-6 signaling with siltuximab, the only FDA-approved iMCD treatment, or tocilizumab,7 
approved for iMCD treatment in Japan, abrogates symptoms and improves lymphadenopathy in 
a portion of patients. However, 66% of patients in the siltuximab Phase II clinical trial did not meet 
response criteria,8 and recent studies found that IL-6 is not significantly elevated in many iMCD 
patients.9 Off-label treatment options are empiric, and include corticosteroids, rituximab, and 
cytotoxic chemotherapy, which have varying efficacies and significant potential toxicities.10 
Identification of molecular and cellular abnormalities for therapeutic targeting is urgently needed 
for anti-IL-6 blockade refractory patients. Unfortunately, no new drugs are in development. 
 
As no animal or cell models exist, our understanding of iMCD is based on analysis of patient 
samples. These data demonstrate a key role for the PI3K/Akt/mTOR pathway in iMCD 
pathogenesis: upregulation of serum vascular endothelial growth factor (VEGF) (16/20 patients),11 
activated T cells (n = 6 patients)12 and elevated serum soluble IL-2 receptor (sIL2R) levels (20/21 
patients), and elevated PI3K/Akt/mTOR signaling in lymph node tissue (n = 10 patients)1 from 
iMCD patients during disease flare. Additionally, gene-set and pathway analyses of plasma 
proteomic data identified PI3K signaling as the most significantly enriched canonical pathway 
during flare compared to remission in six patients, and six of the top 20 most significant 

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compounds predicted to decrease expression of plasma proteins elevated in flare by enrichment 
analysis using the Library of Integrative Network-based Cellular Signatures 1000 database target 
PI3K/Akt/mTOR signaling.13 Most notably, off-label administration of the MTI, sirolimus, to anti-
IL6 blockade refractory patients resulted in CBR in two patients experiencing active disease and 
a prolonged and ongoing remission in one patient2 with a history of five disease flares. Based on 
these experiences, we plan to evaluate the efficacy of sirolimus as a second line therapy to IL-6 
blockade therapy in iMCD, and to conduct research studies aimed at better understanding the 
pathogenesis of iMCD and how blockade of PI3K/Akt/mTOR signaling abrogates the disease. We 
anticipate the results of this work will establish safety and efficacy profiles of sirolimus as a second 
line therapy for iMCD. 
 
The primary endpoint of this study is efficacy, as evaluated by CBR criteria. This evaluation criteria 
was employed as the main efficacy end-point in the open-label Phase I clinical trial of siltuximab,3 
and is a composite of clinical (fatigue, anorexia, fever, night sweats and weight gain), radiologic 
(≥25% bi-dimensional decrease in size of largest lymph node, as measured using Cheson 
criteria14,15 (Appendix 15.2), and laboratory (hemoglobin) measures relevant to the clinical 
management of iMCD. CBR is a well-suited and established criterion for determining efficacy in 
iMCD. 
 
One secondary endpoint of this study is efficacy, as evaluated by modified Cheson response 
criteria. The Cheson response criteria provides standardized response criteria for uniform 
endpoints for clinical trials and was developed by a National Institutes of Cancer supported 
international working group. These standardized response criteria are a result of standardized 
methods for quantifying disease burden.  
 
A secondary endpoint of this study is efficacy as evaluated by the CHAP criteria (C-reactive 
protein (CRP), hemoglobin, albumin and Eastern Cooperative Oncology Group (ECOG) 
performance score).16 Each criterion in the CHAP scoring system provides a graded measure for 
a patient’s disease activity. The sum of the four scores provides an objective scale for measuring 
a patient’s disease activity and monitoring how it changes over time. 
 
A secondary endpoint of this study is efficacy as evaluated by MCD-related Overall Symptom 
Score as measured  by 34 outcome measures (Section 7.6, Efficacy Evaluations), at 3, 6, and 9 
months ± 2 weeks and 12 ± 1 month. Assessments will be compared to those obtained at the 
Baseline Visit. 
 
1.2 
Name and Description of the Investigational Product 
 
SIROLIMUS (AY-22989, rapamycin, Rapamune®)  
 
Source and Pharmacology: Sirolimus is a macrocyclic 
lactone produced by Streptomyces hygroscopicus. The 
chemical name of sirolimus (also known as rapamycin) is 

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(3S,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,34aS)-
9,10,12,13,14,21,22,23,24,25,26,27,32,33,34, 
34a-hexadecahydro-9,27-dihydroxy-3-[(1R)-2-
[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]-1-methylethyl]-10,21-dimethoxy 
6,8,12,14,20,26-
hexamethyl-23,27-epoxy-3H-pyrido[2,1-c][1,4] 
oxaazacyclohentriacontine-1,5,11,28,29 
(4H,6H,31H)-pentone. Its molecular formula is C51H79NO13 and its molecular weight is 914.2 
g/mol. Sirolimus is a white to off-white powder and is insoluble in water, but freely soluble in benzyl 
alcohol, chloroform, acetone, and acetonitrile. The structural formula of sirolimus is illustrated as 
follows. 
 
1.2.1 Nonclinical Data 
Sirolimus inhibits the mTOR protein.17 mTOR is a large protein conserved throughout many 
species.18,19 mTOR is a serine/threonine kinase and is a member of the PI3 kinase-related kinase 
family.19 mTOR acts as a key regulator of cell growth,20,21 protein synthesis, and cell cycle 
progression through interactions with other proteins, including p70S6 kinase (S6K1),21 PI3K22, 
and Eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1)22.  
 
By inhibiting mTOR, sirolimus mimics growth factor withdrawal by inhibition of protein synthesis 
and inhibition of cell cycle progression at the G1 to S transition.18 Sirolimus has been shown to 
have growth inhibitory effects in B cells and T cells.23 In vitro inhibition of mTOR results in down-
regulation of many of the pathway targets, including S6K1, S6, and 4E-BP1. This down-regulation 
results in decreased protein synthesis and inhibition of the cell cycle. Sirolimus inhibits T 
lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (IL-2, IL-
4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. 
Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK 
Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-
12 complex has no effect on calcineurin activity. This complex binds to and inhibits mTOR. This 
inhibition suppresses cytokine-driven T cell proliferation, inhibiting the progression from the G1 to 
the S phase of the cell cycle. 
 
Sirolimus is a potent immunosuppressive agent which prolongs the survival of the host and 
transplanted grafts in animal transplant models of kidney, heart, skin, islet, small bowel, 
pancreatico-duodenal, and bone marrow. In rodent models of autoimmune disease, sirolimus 
suppresses immune-mediated events associated with systemic lupus erythematosus, collagen-
induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic 
encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis. 
 
1.2.2 Clinical Data to Date 
MTIs are a class of signal transduction inhibitors developed as immunosuppressive agents. 
Sirolimus was the first MTI to be used in a clinical setting. Sirolimus has established safety data 
and is approved by the USA FDA for the prevention of allograft rejection in renal transplant 
patients ≥ 13 years of age24,25 and for the treatment of lymphangioleiomyomatosis. Sirolimus is 
well tolerated in humans with minimal toxicities26. It has documented efficacy in patients with 
autoimmune diseases, including rheumatoid arthritis,27 immunodysregulation polyendocrinopathy 
enteropathy X-linked syndrome28 and thrombotic thrombocytopenic purpura.29 It is active in 
Epstein-Barr virus (EBV) lymphoproliferative disease,30 and against lymphoid malignancies.31,32 
Sirolimus also has clear anti-neoplastic activity against a variety of cancers.33,34 Sirolimus causes 
little nephrotoxicity and neurotoxicity, unlike the commonly used immunophilins, cyclosporine and 
tacrolimus, but may cause hyperlipidemia and mild myelosuppression.35  
 

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Off-label administration of sirolimus to two anti-IL6 blockade refractory iMCD patients 
experiencing active disease resulted in CBR in both patients. Additionally, sirolimus therapy 
provided a prolonged and ongoing remission in one patient with a history of five disease flares.2 
 
1.2.2.1 Human Pharmacokinetics 
The pharmacokinetics of sirolimus have been studied in healthy subjects, pediatric dialysis 
patients, hepatically-impaired adult patients, and adult renal transplant patients.36,37 Oral doses 
are rapidly, though variably, absorbed. Mean time-to-peak concentrations range from 1 hour in 
healthy subjects to 2 hours in renal transplant recipients. Half-life is upwards of 2½ days. Patients 
who ingested the drug after a high fat breakfast did have delayed Cmax and it is recommended to 
take sirolimus consistently with or without food. 
 
The plasma protein binding of sirolimus is approximately 92% mainly to albumin, alpha-1-acid 
glycoprotein and lipoproteins, and has a high level of association with erythrocytes. The systemic 
availability of sirolimus was estimated to be approximately 14%. Sirolimus is extensively 
metabolized by O-demethylation and/or hydroxylation to at least seven major metabolites. The 
parent drug contributes to more than 90% of the immunosuppressive activity. The main route of 
elimination is through the feces (91%). The mean half-life increased from 79 ± 12 hours in subjects 
with normal hepatic function to 113 ± 41 hours in patients with impaired hepatic function. Males 
have a 12% lower clearance of sirolimus than females after oral solution administration. In some 
studies, the immunosuppressive effect of sirolimus lasts up to 6 months after discontinuation of 
therapy. No differences were demonstrated between black and non-blacks. Sirolimus is a 
substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein (P-gp). Sirolimus is 
extensively metabolized by the CYP3A4 isozyme in the intestinal wall and liver and undergoes 
counter-transport from enterocytes of the small intestine into the gut lumen by the P-gp drug efflux 
pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued 
metabolism by CYP3A4. Therefore, absorption and subsequent elimination of systemically 
absorbed sirolimus may be influenced by drugs that affect these proteins. Drugs that stimulate or 
inhibit p-450 enzymes will alter clearance of sirolimus and close attention to potential drug 
interactions is crucial. Care should be exercised when drugs or other substances that are 
metabolized by CYP3A4 are administered concomitantly with sirolimus. Grapefruit juice reduces 
CYP3A4-mediated metabolism of sirolimus; subjects will be advised to avoid ingesting grapefruit. 
 
1.2.2.2 Clinical Studies  
The safety and efficacy of sirolimus in the prevention of organ rejection have been demonstrated 
in two randomized, double-blind, multicenter, controlled trials involving over 1000 adult patients. 
In these and most trials, sirolimus has been administered with cyclosporine and corticosteroids 
and limited pharmacokinetic data is available with sirolimus alone in this setting. The major side 
effects 
noted 
in 
these 
studies 
included 
thrombocytopenia, 
hypercholesterolemia, 
hypertriglyceridemia, and diarrhea. Renal function was not worse in these patients. 
 
Sirolimus has also been studied in children, indicating a dose of 2 mg/m2/day is required to 
achieve target sirolimus trough levels.38  
 
1.3 
Dose Rationale  
Sirolimus will be dosed, rounded to the nearest mg, orally as follows: In adults, day 1, a loading 
dose of 5 mg/m2 will be administered; subsequent daily dosing will be at 2.5 mg/m2/day (rounded 
to the nearest mg), adjusted to achieve a target trough level of 10-15 ng/mL. The loading dose 
may be adjusted based on the clinical judgement of the treating physician. In children, no loading 

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dose will be administered, and daily dosing will be at 2 mg/m2/day (rounded to the nearest mg), 
adjusted to achieve a target trough level of 5-15 ng/mL. 
 
This dosing schedule is based on safety and efficacy data of sirolimus in diseases with similarities 
to iMCD. No severe toxicities were observed in any of several single dosing studies with sirolimus 
doses ranging from 3-21 mg/m2. In a Phase I pharmacokinetic study conducted in renal transplant 
patients, doses ranging from 0.5 to 6.5 mg/m2 were administered every 12 hours.37 In two 
randomized, double-blind, multicenter, controlled trials involving over 1000 adult patients typical 
dosing was 2 mg or 5 mg (~1.3 – 3.3 mg/m2) administered daily. Phase III studies to date have 
had concomitant use of cyclosporine, steroid, or both. At a dose of 2 mg/day (~1.3 mg/m2) 
sirolimus trough concentration was 8.6 ± 4.0 ng/ml and at 5 mg/day (~3.3 mg/m2) the trough was 
17.3 ± 7.4 ng/ml. Stable renal transplant patients are dose proportional between 3 and 15 
mg/m2/day. Also, in this population a loading dose of 3 times the maintenance dose provided near 
steady-state concentrations within 1 day in most patients. More recently, a Phase I/II trial of 
sirolimus in patients with active systemic lupus erythematosus, a disease that shares overlapping 
clinical and laboratory abnormalities with iMCD, found efficacy with a dose of 2 mg per day with 
adjustment to maintain a therapeutic range of 6-15 ng/mL.39 
 
 Study Objectives 
 
2.1 
Primary Objective 
To evaluate the efficacy of sirolimus for treating symptomatic iMCD. 
 
2.2 
Exploratory Objective 
To investigate the mechanism of action by which sirolimus is efficacious in iMCD. 
 
 Investigational Plan 
 
3.1 
General Design 
This study is a Phase II open label study of daily administration of sirolimus in up to 24 evaluable 
male or female adults. Up to 40 subjects may be enrolled, defined as providing informed consent 
for the trial, to obtain this target of evaluable subjects. An interim analysis will be conducted after 
14 subjects have completed the Visit 9 intermediate assessment. The mechanism of action of 
sirolimus in clinically active iMCD will also be examined.  
 
Adult subjects will receive a sirolimus loading dose of 5 mg/m2, rounded to the nearest mg, on 
day 1. Loading dose may be lower at the discretion of the prescribing physician. Starting on day 
2, adult subjects will take sirolimus daily at 2.5 mg/m2/day (rounded to the nearest mg), adjusted 
to a target trough level of 10-15 ng/mL. Pediatric subjects will not receive a loading dose, and 
daily dosing will be at 2 mg/m2/day (rounded to the nearest mg), adjusted to achieve a target 
trough level of 5-15 ng/mL. (see Section 5.2, Intervention Regimen). Given that sirolimus is 
extensively metabolized by CYP3A4, sirolimus dosing for subjects receiving strong CYP3A4 
inhibitors or inducer therapy (https://drug-interactions.medicine.iu.edu/main-table.aspx) 
should be monitored carefully and adjusted accordingly. Additionally, sirolimus trough levels 
should be monitored if patients are started on or if their CYP3A4 therapy is altered, and sirolimus 
dosing adjusted to maintain trough levels of 10-15 ng/mL (5-15 ng/mL in children). The dosing of 
adult patients who weigh less than 40 kg should be adjusted, based on body surface area, to 3 

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mg/m2 for the loading dose and 1 mg/m2/day daily. It is recommended that the licensed site 
investigator reduce maintenance dose in patients with hepatic impairment.  
 
Subjects who meet all inclusion criteria and do not violate any exclusion criteria will be determined 
eligible for enrollment into the study by the licensed site investigator. The Lead Principal 
Investigator will confirm the subject’s eligibility. During the Intervention Phase (12 ± 1 month), 
subjects will visit their study site at regular intervals to assess any changes in health status, 
medication, study drug compliance, and treatment response. They will also be monitored remotely 
by their licensed site investigator through lab testing performed as per standard of care at local 
healthcare facilities. During the Follow Up Phase, 12 ± 2 weeks following the End of Treatment 
Visit, site study staff will contact subjects by phone. Peripheral blood will be collected at baseline 
and at regular intervals during the Intervention Phase for research purposes. Subjects will be 
asked to provide their consent to allow any biological samples collected as part of this study or 
collected during their enrollment period in this study, but for purposes outside of the study, to be 
used for laboratory research purposes, including genetic sequencing studies. Subjects will also 
be asked to provide their consent to allow any biological samples from their past medical 
procedures to be used for laboratory research purposes, including genetic sequencing studies.  
 
3.1.1 Recruitment and Screening Phase 
Candidate subjects will be informed of this study as per mechanisms described in Section 4.3, 
Subject Recruitment.  
 
Subjects must meet all inclusion criteria and not violate any exclusion criteria to enroll into this 
study. Signed informed consent will be obtained from all subjects or their legally authorized 
representative (LAR), as appropriate, prior to the performance of any protocol-specific activities. 
The licensed site investigator or his or her designee will obtain consent from subjects at their 
respective sites. After signing the informed consent, subjects will be considered to be enrolled in 
the study. All subjects who have signed an informed consent for participation in the study will be 
assigned a Global Unique Identifier (GUID) using the National Institutes of Health Subjects Global 
Rare Disease Registry GUID tool available at https://grdr-guid.ncats.nih.gov. Once consented, 
subjects will undergo a Screening and Baseline (Visit 1, Section 6.1.1, Baseline Visit) including 
pregnancy testing of female subjects of childbearing potential. The licensed site investigator or 
designated staff member will complete a Patient Evaluation Form confirming all inclusion criteria 
are met and no exclusion criteria are violated. The Lead Principal Investigator will confirm the 
subject’s eligibility. Subjects whose eligibility is confirmed will continue to the Intervention Phase; 
those found to violate any criteria will be considered screening failures. 
 
3.1.2 Intervention Phase 
Adult subjects will receive an oral sirolimus loading dose of 5 mg/m2, rounded to the nearest mg 
(day 1). Loading dose may be lower at the discretion of the prescribing physician. Starting on day 
2, adult subjects will receive oral sirolimus daily at 2.5 mg/m2/day (rounded to the nearest mg), 
adjusted as needed to a target trough level of 10-15 ng/mL. Pediatric subjects will not receive a 
loading dose, and daily dosing will be at 2 mg/m2/day (rounded to the nearest mg), adjusted to 
achieve a target trough level of 5-15 ng/mL. Subjects will remain on treatment for 12 ± 1 month. 
The period between the loading dose/first dose and the last treatment define the “Intervention 
Phase”. Patients will continue to receive standard of care treatment during the Intervention Phase 
consistent with the requirements of Section 6.6, Subject Withdrawal. Subjects will undergo 
regular Intervention Phase visits (Section 6.2, Intervention Phase). The licensed site 
investigator will be ultimately responsible for all treatment decisions, including when to initiate 
rescue therapy (Section 6.4, Rescue Therapy). 

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3.1.3 Follow Up Phase 
Subjects will be contacted via telephone 12 ± 2 weeks following the End of Treatment Visit or 
Early Termination Visit to document changes in health, medications and to monitor for pregnancy. 
 
3.1.4 Allocation to Interventional Group 
All subjects will receive drug; no randomization will occur. 
 
3.2 
Study Endpoints 
 
3.2.1 Primary Study Endpoints 
The primary endpoint of this study will be the proportion of patients achieving a positive CBR 
response (Section 7.6, Efficacy Evaluations) at 12 ± 1 month. Assessments at 12 ± 1 month 
will be compared to those obtained at the Baseline Visit. 
 
3.2.2 Secondary Study Endpoints 
The secondary endpoints of this study will be:  
 
• 
The proportion of patients achieving a positive CBR response (Section 7.6, Efficacy 
Evaluations) at 3, 6, and 9 months ± 2 weeks following administration of sirolimus loading 
dose. Assessments will be compared to those obtained at the Baseline Visit. 
• 
The proportion of patients that remain on study drug for the duration of the study. 
• 
The proportion of patients that indicate that they are currently receiving sirolimus at the 
end of the Follow Up Phase. 
• 
Disease activity, as measured by the CHAP scale, at 3, 6, and 9 months ± 2 weeks and 
12 ± 1 month. Assessments will be compared to those obtained at the Baseline Visit. 
• 
Disease activity, as measured by MCD-related Overall Symptom Score as measured by 
34 outcome measures (Section 7.6, Efficacy Evaluations), at 3, 6, and 9 months ± 2 
weeks and 12 ± 1 month. Assessments will be compared to those obtained at the Baseline 
Visit. 
• 
The proportion of patients achieving a lymph node response, following the modified 
Cheson response criteria (Section 7.6, Efficacy Evaluations). Assessments will be 
compared to those obtained at the Baseline Visit. 
 
3.2.3 Exploratory Study Endpoints 
The exploratory endpoints of this study will be: 
 
• 
Results of correlative studies, in the research laboratory, to investigate the mechanism of 
action of sirolimus in iMCD and clinical and laboratory biomarkers for treatment response. 
Additional correlative findings may also be assessed. 
• 
Spleen size, as measured by PET/CT or CT. 
 
3.2.4 Safety Endpoints  
The safety of sirolimus administration will be evaluated by monitoring for by: 
 
• 
All previously reported adverse events (AEs) associated with sirolimus treatment  
• 
All possible new AEs  
 

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 Study Population and Duration of Participation 
 
4.1 
Inclusion Criteria 
To be eligible, subjects must meet all of the below inclusion criteria: 
 
1. Male or female, age 2-80 
2. Documented disease history consistent with the diagnostic criteria for iMCD (Appendix 
15.1) 
• 
Confirmation of clinico-histopathological features by licensed pathologist, or a CAS 
grade of at least 3 in the companion registry study (ACCELERATE) 
3. Failed/refractory (patient did not achieve sufficient disease control with anti-IL-6 therapy, 
as determined by the site investigator ), relapsed (return of symptoms while on therapy), 
or inability to tolerate anti-IL-6 or anti-IL-6 receptor therapy 
4. Evidence of active disease, defined as at least two abnormalities in the criteria comprising 
the CBR criteria and as defined as abnormal by CTCAE v4.0, including at least one 
objective measurement (hemoglobin, weight loss, or lymph node size) 
• 
Hemoglobin < lower limit of normal  
• 
Fatigue, including fatigue relieved by rest 
 
• 
Anorexia, including loss of appetite without alteration in eating habits 
• 
Fever or night sweats  
• 
Weight  loss ≥ 5% from baseline  
• 
At least one lymph node meeting modified Cheson criteria (Appendix 15.2) 
5. Ability to consume oral medication in the form of a tablet 
6. Ability to provide, or for a LAR to provide on their behalf, informed consent prior to any 
study-specific activities 
 
4.2 
Exclusion Criteria 
To be eligible, subjects must not violate any of the below exclusion criteria. 
 
1. Subjects cannot be pregnant or nursing females  
• 
Women of childbearing potential must have a negative pregnancy test documented 
at the Baseline Visit. Subjects of reproductive potential may not participate unless 
they have agreed, as part of the informed consent, to use an effective 
contraceptive method for the duration of the study and for at least 12 weeks after 
ending treatment 
2. Subjects cannot have received any systemic therapy(ies) intended to treat iMCD other 
than corticosteroids within 14 days of enrollment 
• 
Corticosteroid treatment must have been initiated more than 28 days prior to 
enrollment and be maintained at a stable or tapering dose (prednisone or 
equivalent up to 1 mg/kg/day) prior to enrollment; dose cannot be elevated for the 
duration of the study but can be maintained or tapered 
• 
For subjects who cannot or are unwilling to undergo a 14 day washout period: 
i. Anti-IL-6 therapy may be permitted if the subject has been on therapy for 
at least 3 months, no toxicity has been documented, and sufficient disease 
control is not achieved 
ii. Anti-IL-6 therapy must be discontinued within the first 6 weeks after starting 
sirolimus  
3. Subjects cannot have previously received sirolimus monotherapy to treat iMCD  

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4. Subjects cannot have any of the following: 
• 
ECOG >3 (or Karnofsky/Lansky score ≤ 60 in children) 
• 
Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 or creatinine > 
3.0 mg/dL 
• 
Absolute neutrophil count (ANC) < 1000 x 109/L (< 500 x 109/L in children) 
• 
Hemoglobin ≤ 6.5 g/dL (transfusion independent, defined as not receiving a red 
blood cell transfusion for ≥ 7 days prior)  
• 
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) laboratory 
values greater than three times the upper limit of normal 
• 
Albumin < 2 g/dL (transfusion independent, defined as not receiving intravenous 
albumin for ≥ 7 days prior) 
• 
Platelet count ≤ 40 x 109/L (transfusion independent, defined as not receiving 
platelet transfusion for ≥ 7 days prior) 
• 
Pulmonary involvement or interstitial pneumonitis with dyspnea (adequate 
pulmonary function is defined as pulse oximetry > 94% on room air if there is 
clinical indication for determination [e.g. dyspnea at rest, history of interstitial 
pneumonitis, etc.]) 
• 
Fasting cholesterol > 300 mg/dL or fasting triglyceride > 400 mg/dL 
5. Subjects cannot have uncontrolled infection or infectious disease(s) that is/are 
exclusionary for / mimickers of iMCD (Appendix 15.1) 
• 
Fungal disease must be stable for at least two weeks before enrollment 
• 
Subjects with history of recent bacteremia must have a documented negative 
blood culture before enrollment 
• 
Subjects with past history of non-therapy related opportunistic infection should 
discuss eligibility and possible immunologic evaluation with the licensed site 
investigator prior to enrollment 
6. Subjects cannot have rheumatologic disease(s) that is/are exclusionary for / mimickers of 
iMCD (Appendix 15.1) 
7. Subjects cannot have a prior malignancy except for: (1) adequately treated basal cell or 
squamous cell skin cancer, (2) in situ cervical cancer, or (3) other cancer for which the 
subject has not received treatment within one year prior to enrollment  
• 
Other cancers will only be acceptable if the patient’s life expectancy exceeds five 
years and they are not exclusionary diagnoses for iMCD (Appendix 15.1) 
8. Subjects cannot have a documented history of human immunodeficiency virus (HIV) or 
HHV-8 infection, or severe combined immunodeficiency syndrome 
9. Subjects cannot have a history of liver or lung transplantation 
10. Subjects cannot have ongoing or planned participation in another clinical trial involving 
iMCD directed treatment or that involves immunomodulatory or anti-neoplastic treatment 
11. Subjects cannot have prior sensitivity / allergy to any formulation of sirolimus, its 
components or its analogues 
12. Subjects cannot have serious medical illness, or psychiatric illness or disorders that could 
potentially interfere with the completion of treatment according to this protocol or 
participation in the trial 
13. Subjects cannot have psychiatric disorders that compromise the ability to provide informed 
consent  
14. Subjects cannot have any other condition or finding that in the opinion of the investigator 
would make participation in this trial inappropriate 
 

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4.3 
Subject Recruitment 
Potential subjects will be informed of this study by:  
 
• 
Verbal communication from licensed site investigators during routine patient clinical visits. 
Licensed site investigators may also provide a printed flier about the study to their patients  
• 
Email or phone call, if permitted, to individuals who have consented, in the past as part of 
a separate research study, to being re-contacted for participation in future research 
studies  
• 
Email or phone call, to individuals who have been identified via Epic Best Practice 
Advisories and Slicer Dicer, who have consented to be contacted for participation in 
research studies 
• 
The Castleman Disease Collaborative Network (CDCN), a nonprofit organization 
dedicated to supporting Castleman disease patients and accelerating research.  
• 
The CDCN has a network of physicians located throughout the United States. 
These physicians have expressed interest in providing information to their patients 
about research studies. If a physician in the CDCN chooses to approach their 
patient with information regarding this study, they will provide the individual with a 
flier 
• 
ClinicalTrials.gov, which will list this study along with contact information for the Site 
Principal Investigators and study coordinators 
 
Subject recruitment will not use any University of Pennsylvania media services. Any interested 
subject will be referred to a licensed site investigator for eligibility determination. 
 
4.4 
Duration of Study Participation 
The Screening/Baseline Phase will include an on-site visit and may last 0 - 28 days. The 
Intervention Phase will last up to 12 ± 1 month, and the Follow Up Phase will be approximately 
12 ± 2 weeks. In total, each subject’s participation will last up to 73 weeks. 
 
4.5 
Total Number of Subjects and Sites 
Up to 40 subjects may enroll into this study to achieve the intended goal of up to 24 evaluable 
subjects. To determine if the trial will continue, an interim analysis will be completed after 14 
subjects have completed the Visit 9 intermediate assessment. This trial involves up to four sites, 
which are expected to have approximately equal enrollment rates. 
 
4.6 
Vulnerable Populations: 
Children 2 years of age or older may be considered for this study.  
Pregnant women, fetuses, neonates, and prisoners are not included in this research study. 
 
 Study Intervention  
 
5.1 
Description 
SIROLIMUS (AY-22989, rapamycin, Rapamune®) NSC# 226080 (092405). Sirolimus is available 
as a tan, triangular-shaped tablet containing 0.5 mg sirolimus; a white, triangular-shaped tablet 
containing 1 mg sirolimus; and a yellow to beige triangular-shaped tablet containing 2 mg 
sirolimus. The inactive ingredients in sirolimus tablets include sucrose, lactose, polyethylene 
glycol 8000, calcium sulfate, microcrystalline cellulose, pharmaceutical glaze, talc, titanium 
dioxide, magnesium stearate, povidone, poloxamer 188, polyethylene glycol 20,000, glyceryl 

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monooleate, carnauba wax, and other ingredients. The 2 mg dosage strength also contains iron 
oxide yellow 10 and iron oxide brown 70. Sirolimus is commercially available. The prescribing 
information for Rapamune can be found at:  
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/021083s061,021110s080lbl.p
df. 
 
5.2 
Intervention Regimen 
Adult subjects will receive sirolimus orally, a loading dose of 5 mg/m2, rounded to the nearest mg, 
on day 1. Loading dose may be lower at the discretion of the prescribing physician. Starting on 
day 2, adult subjects will take oral sirolimus daily at 2.5 mg/m2/day (rounded to the nearest mg), 
target trough level 10-15 ng/mL, based on tolerability. Pediatric subjects will not receive a loading 
dose, and daily dosing will be at 2 mg/m2/day (rounded to the nearest mg), adjusted to achieve a 
target trough level of 5-15 ng/mL. Sirolimus trough levels will be determined at approximately Day 
5, Day 14, Months 1, 3, 6, 9, and 12 (see Appendix 15.3 for the study calendar). At the discretion 
of the study doctor, additional sirolimus trough levels may be obtained.  Sirolimus trough levels 
will be determined in a clinical grade laboratory, which may be located at the study center or at a 
clinical facility close to the subject, if more convenient.  
 
Frequent dose adjustments based on non-steady-state sirolimus concentrations can lead to 
overdosing or under dosing because sirolimus has a long half-life. Once maintenance dose is 
adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before 
further dosage adjustment with concentration monitoring. In most patients, dose adjustments can 
be based on simple proportion: new dose = current dose × (target concentration/current 
concentration). Dose adjustments are based on clinical judgment of the licensed site investigator 
after considering clinical toxicity, serum levels, concomitant drug use and the rate of rise or decline 
of the serum level. For levels < 10 ng/mL, it is suggested, but not required, that the dose of 
sirolimus be increased, but not to exceed a maximum daily dose of 40 mg. Conversely, for levels 
> 15 ng/mL, it is suggested, but not required, that the dose be decreased. Alternatively, sirolimus 
can be withheld entirely as long as serum levels are monitored and the drug is restarted when the 
level returns to the therapeutic range and the licensed site investigator feels it is appropriate to 
restart the agent. It is suggested, but not required, that levels of sirolimus be drawn at least weekly 
until steady state, then monitored thereafter unless a change in medication (e.g. use of 
voriconazole) or renal function might result in an acute change in level. At that point, levels should 
be measured as clinically indicated. The anticipated length of treatment will be 12 months. iMCD 
is a chronic condition and, as sirolimus is commercially available for other indications, patients 
who show improvement on sirolimus may remain on treatment indefinitely at the discretion of their 
physician. Examples of dose calculations are provided in Appendix 15.5 Example Dose 
Calculations. 
 
5.3 
Receipt 
All drug will be obtained from a commercial producer (Pfizer) and be received by the 
investigational pharmacy at each participating site. Upon receipt of the study treatment supplies, 
an inventory will be performed and a drug receipt log filled out and signed by the person accepting 
the shipment. The designated study staff will count and verify that the shipment contains all the 
items noted in the shipment inventory. Any damaged or unusable study drug in a given shipment 
will be documented in the study files. The IDS and the IP will notify the Lead Principal Investigator 
of any damaged or unusable study treatments that were supplied. All drug will be supplied in bulk. 
 

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5.4 
Storage 
Sirolimus tablets should be stored at controlled room temperature, which is 20-25 °C with 
excursions permitted between 15 °C - 30 °C. The investigational pharmacist at the IDS and the 
IP will ensure that all study drug is stored in a secured area, under recommended storage 
conditions, including with regards to protection from light and sterile conditions, and in accordance 
with applicable regulatory requirements, and will be dispensed by qualified staff members. The 
pharmacist will maintain accurate records regarding study drug administration and return.  
 
5.5 
Preparation and Packaging 
Sirolimus tablets will be prepared by a commercial producer (Pfizer) and will be packaged by the 
investigational pharmacist at the IDS and the IP in child-resistant bottles for dispensation to 
subjects. Bottles will be labeled to meet state and FDA requirements. 
 
5.6 
Administration and Accountability 
The IDS and IP service will maintain accurate logs of study drug dispensing, and will conduct 
regular drug reconciliation checks to document drug assigned, drug consumed, drug remaining, 
product damage/destroyed and return of damaged/destroyed drug, along with dates of such 
damage and return. This reconciliation will be logged on the drug reconciliation form, and signed 
and dated by the service.  
 
Sirolimus will be provided to patients at on-site visits or shipped to subjects as needed (e.g. if their 
supply is lost, or if results from remote sirolimus trough assays results in a dose adjustment). 
Sirolimus will be administered orally and should be taken at a consistent time of day and at 
consistent intervals with regard to meals. Sirolimus may be given with food as long as it is given 
the same way each time; however, administration with food significantly alters the rate and extent 
of absorption.  
 
5.7 
Subject Compliance Monitoring 
At each on-site visit, compliance with study drug will be reinforced; study drug bottles will be 
returned and compliance will be assessed by pill count. Subjects will be provided a medication 
diary to complete at home, which will be reviewed at each on-site visit. Study medication 
dispensed or returned to IDS or the IP must be recorded for Drug Accountability and 
Reconciliation at each on-site visit in a standard form. Serum trough levels of sirolimus will be 
monitored. Patients will be informed to withhold their daily dose of sirolimus until after a clinical 
blood sample is drawn to assay for trough levels of sirolimus.  
 
Non-compliance is defined as two consecutive study visits with >30% of study drug not consumed. 
Non-compliant patients will receive counseling from the licensed site investigator and be warned 
that they may be removed from the study. If there is a third study visit with >30% of study drug 
not consumed, then the licensed site investigator will determine if the subject should be removed 
from the study. 
 
5.8 
Return or Destruction of Investigational Product 
At the completion of the study – following the last enrolled patient’s final assessment - there will 
be a final reconciliation of drug shipped, drug consumed, and drug remaining by IDS and the IP. 
This reconciliation will be logged on the drug reconciliation form, signed and dated. Any 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction 
of unused study drug. Drug destroyed on site will be documented in the study files. 
 

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 Study Procedures 
 
Radiological Imaging 
Computed tomography (CT) with contrast or positron emission tomography/CT (PET/CT) scan 
images conducted as standard of care treatment for iMCD will be centrally reviewed by a 
radiologist at the University of Pennsylvania. PET/CT will be full body imaging, and CT will include 
neck, chest, abdomen and pelvis. The site physician should maintain consistency, as is medically 
appropriate, in imaging modality utilized for each subject to that used at the Baseline Visit. 
 
Blood Draws 
No more than 100 mL of blood will be drawn at the Baseline Visit, and no more than 55 mL at 
each subsequent Visit specifically for research laboratory (i.e. non-clinical health or sirolimus 
monitoring) purposes. Blood will be drawn into ethylenediaminetetraacetic acid (EDTA) coated 
tubes (Baseline Visit: 80 mL; subsequent Visits: 40 mL) and serum separator tubes (Baseline 
Visit: 14 mL; subsequent Visits: 7 mL).  
 
Research samples obtained during on-site visits will be processed at the site or shipped to the 
University of Pennsylvania for processing. Those obtained during remote visits will be shipped to 
the University of Pennsylvania for processing. Subjects will be provided with appropriate shipping 
materials and instructions regarding how to ship research samples to the University of 
Pennsylvania. 
 
Fecal Sample Collections 
Fecal samples will be collected at the Baseline Visit, prior to starting sirolimus, at Week 2, and at 
Visit 9. Fecal sample collections are optional.   
 
Fluid Sample Collections 
Fluid samples, such as those collected during paracentesis, may be collected and stored for 
research analysis. Samples will be shipped to the University of Pennsylvania or the Children’s 
Hospital of Philadelphia for processing, or may be processed at the site.  
 
Clinical Laboratory Testing 
For standard of care laboratory testing conducted by a third-party provider, the site physician 
should maintain consistency in the provider used for the Baseline Visit testing for each subject, 
as is medically appropriate. 
 
Please see Appendix 15.3 for the study calendar. 
 
6.1 
Screening Phase 
 
6.1.1 Screening Visit (Visit 0) 
Subjects’ eligibility will be confirmed during the screening phase. The below standard of care 
procedures will be conducted unless they occurred within four weeks prior to the screening visit 
as part of standard of care treatment. 
 
• 
Standard Diagnostic Laboratory Tests (Appendix 15.4) 
• 
Vital signs 
• 
Radiological imaging (PET/CT or CT) 
• 
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• 
Review of concomitant medications 
 
The below non-standard of care procedures will be conducted as part of the screening phase for 
all subjects: 
 
• 
Informed consent: a signed and dated Institutional Review Board (IRB) approved informed 
consent form (ICF) that will be documented in the subject’s source documents 
• 
Pregnancy testing for females of childbearing potential 
• 
Recording of demographic information (gender, date of birth, race, etc.) into electronic 
case report form (eCRF) 
• 
Recording of medical history data and Laboratory Tests, as available, (Appendix 15.4) 
from medical records into eCRF 
 
6.2 
Intervention Phase 
 
6.2.1 Baseline Visit (Visit 1) 
The baseline visit should occur within 7 days of the screening visit, following confirmation of 
eligibility. The below standard of care procedures will be conducted unless they occurred within 
four weeks prior to Visit 0 as part of standard of care treatment. 
 
• 
Physical exam including performance score 
• 
Vital signs 
• 
Lipid panel 
• 
Review of concomitant medications 
 
The below non-standard of care procedures will be conducted as part of Visit 1 for all subjects: 
 
• 
Confirmation that subject meets inclusion criteria and does not violate any exclusion 
criteria, including confirmation by the Lead Principal Investigator 
• 
GUID assigned 
• 
Research blood draw 
• 
Collection of fecal sample (optional) 
• 
Recording of medical history data and Laboratory Tests, as available, (Appendix 15.4) 
from medical records into eCRF 
• 
Dispensing of sirolimus loading dose (adults only) 
• 
Dispensing of sirolimus daily dose 
 
6.2.2 Visits 2 and 3 
Subjects will visit the study center, or may visit their local medical provider or facility (e.g. Quest 
Diagnostics), 5 days ± 2 days (Visit 2) and 2 weeks ± 5 days (Visit 3) following administration of 
loading dose/first dose. The below non-standard of care procedures will be conducted as part of 
this study during Visits 2 and 3:  
 
• 
Research blood draw 
• 
Recording of medical history data and Laboratory Test, as available, (Appendix 15.4) 
from medical records into eCRF (at site) 
• 
Phone assessment of AEs, study drug compliance, and review of medication changes 
• 
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• 
Collection of fecal sample (optional – Visit 3 only) 
 
6.2.3 Visit 4 
Subjects will return to the study site 1 month ± 1 week following administration of loading dose. 
At the physician’s discretion, this visit may occur remotely and subject may visit their local medical 
provider or facility (e.g. Quest Diagnostics). The below procedures will be conducted as standard 
of care: 
 
• 
Physical exam including performance score (if visit occurs on site) 
• 
Vital signs (if visit occurs on site) 
• 
Lipid panel 
• 
Standard of Care Laboratory Tests (Appendix 15.4) 
• 
Review of medication changes  
 
The below non-standard of care procedures will be conducted as part of this study during Visit 4:  
 
• 
Research blood draw 
• 
Pregnancy testing for females of childbearing potential (may be self-administered by 
subjects if visit is conducted remotely) 
• 
Sirolimus Trough 
• 
Assess possible AEs 
• 
Return of any non-consumed sirolimus (may be shipped if visit occurs remotely) 
• 
Sirolimus pill count (if visit occurs on site) 
• 
Dispensing of sirolimus daily dose (may be shipped if visit occurs remotely) 
• 
Recording of medical history data, medication changes, AEs and Laboratory Test, as 
available, (Appendix 15.4) from medical records into eCRF 
 
6.2.4 Visit 5 
Subjects will visit the study center, or may visit their local medical provider or facility (e.g. Quest 
Diagnostics), 2 months ± 2 weeks following administration of loading dose. The below non-
standard of care procedures will be conducted as part of this study during Visit 5:  
 
• 
Research blood draw 
• 
Recording of medical history data, AEs, and Laboratory Test, as available, (Appendix 
15.4) from medical records into eCRF (at site) 
• 
Phone assessment of AEs, study drug compliance, and review of medication changes 
 
6.2.5 Visit 6 
Subjects will return to the study site 3 months ± 2 weeks following administration of loading dose. 
It is highly encouraged that this visit occurs at the study site, but at the physician’s discretion, this 
visit may occur remotely and subject may visit their local medical provider or facility (e.g. Quest 
Diagnostics). The below procedures will be conducted as standard of care: 
 
• 
Physical exam including performance score (if visit occurs on site) 
• 
Vital signs (if visit occurs on site) 
• 
Radiological imaging (PET/CT or CT) 
• 
Standard of Care Laboratory Tests (Appendix 15.4) 
• 
Lipid panel 

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• 
Review of medication changes 
 
The below non-standard of care procedures will be conducted as part of this study during Visit 6:  
 
• 
Research blood draw 
• 
Pregnancy testing for females of childbearing potential (may be self-administered by 
subjects if visit is conducted remotely) 
• 
Sirolimus Trough 
• 
Assess possible AEs 
• 
Return of any non-consumed sirolimus (may be shipped if visit occurs remotely) 
• 
Sirolimus pill count (if visit occurs on site) 
• 
Dispensing of sirolimus daily dose (may be shipped if visit occurs remotely) 
• 
Intermediate assessment of primary objective  
• 
Recording of medical history data, medication changes, AEs and Laboratory Test, as 
available, (Appendix 15.4) from medical records into eCRF 
 
6.2.6 Visit 7 and 8 
Subjects will visit the study center, or may visit their local medical provider or facility (e.g. Quest 
Diagnostics), 4 month ± 2 week (Visit 7) and 5 month ± 2 week (Visit 8) following administration 
of loading dose. The below non-standard of care procedures will be conducted as part of this 
study during Visit 7 and 8:  
 
• 
Research blood draw 
• 
Recording of medical history data, AEs and Laboratory Test, as available, (Appendix 
15.4) from medical records into eCRF (at site) 
• 
Phone assessment of AEs, study drug compliance, and review of medication changes 
 
6.2.7 Visit 9 
Subjects will return to the study site 6 month ± 2 week following administration of loading dose. It 
is highly encouraged that this visit occurs at the study site, but at the physician’s discretion, this 
visit may occur remotely and subject may visit their local medical provider or facility (e.g. Quest 
Diagnostics). The below procedures will be conducted as standard of care: 
 
• 
Physical exam including performance score (if visit occurs on site) 
• 
Vital signs (if visit occurs on site) 
• 
Radiological imaging (PET/CT or CT) 
• 
Standard of Care Laboratory Tests (Appendix 15.4) 
• 
Lipid panel 
• 
Review of medication changes  
 
The below non-standard of care procedures will be conducted as part of this study during Visit 9:  
 
• 
Research blood draw 
• 
Collection of fecal sample (optional) 
• 
Pregnancy testing for females of childbearing potential (may be self-administered by 
subjects if visit is conducted remotely) 
• 
Sirolimus Trough 
• 
Assess possible AEs 

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• 
Return of any non-consumed sirolimus (may be shipped if visit occurs remotely) 
• 
Sirolimus pill count (if visit occurs on site) 
• 
Dispensing of sirolimus daily dose (may be shipped if visit occurs remotely) 
• 
Intermediate assessment of primary objective 
• 
Recording of medical history data, medication changes, AEs and Laboratory Test, as 
available, (Appendix 15.4) from medical records into eCRF 
 
6.2.8 Visit 10 and 11 
Subjects will visit the study center, or may visit their local medical provider or facility (e.g. Quest 
Diagnostics), 7 month ± 2 week (Visit 10) and 8 month ± 2 week (Visit 11) following administration 
of loading dose. The below non-standard of care procedures will be conducted as part of this 
study during Visits 10 and 11:  
 
• 
Research blood draw 
• 
Recording of medical history data, AEs and Laboratory Test, as available, (Appendix 
15.4) from medical records into eCRF (at site) 
• 
Phone Assessment of AEs, study drug compliance, and review of medication changes 
 
6.2.9 Visit 12 
Subjects will return to the study site 9 month ± 2 week following administration of loading dose. It 
is highly encouraged that this visit occurs at the study site, but at the physician’s discretion, this 
visit may occur remotely and subject may visit their local medical provider or facility (e.g. Quest 
Diagnostics). The below procedures will be conducted as standard of care: 
 
• 
Physical exam including performance score (if visit occurs on site) 
• 
Vital signs  (if visit occurs on site) 
• 
Radiological imaging (PET/CT or CT) 
• 
Standard of Care Laboratory Tests (Appendix 15.4) 
• 
Lipid panel 
• 
Review of medication changes and updates 
 
The below non-standard of care procedures will be conducted as part of this study during Visit 
12:  
 
• 
Research blood draw 
• 
Pregnancy testing for females of childbearing potential (may be self-administered by 
subjects if visit is conducted remotely) 
• 
Sirolimus Trough 
• 
Assess possible AEs 
• 
Return of any non-consumed sirolimus 
• 
Sirolimus pill count (if visit occurs on site) 
• 
Dispensing of sirolimus daily dose 
• 
Intermediate assessment of primary objective  
• 
Recording of medical history data, medication changes, AEs, and Laboratory Test, as 
available, (Appendix 15.4) from medical records into eCRF 
 

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6.2.10 Visits 13 and 14 
Subjects will visit the study center, or may visit their local medical provider or facility (e.g. Quest 
Diagnostics), 10 month ± 2 week (Visit 13) and 11 month ± 2 week (Visit 14) following 
administration of loading dose. The below non-standard of care procedures will be conducted as 
part of this study during Visits 13 and 14:  
 
• 
Research blood draw 
• 
Recording of medical history data, AEs and Laboratory Test, as available, (Appendix 
15.4) from medical records into eCRF (at site) 
• 
Phone assessment of AEs, study drug compliance, and review of medication changes 
 
6.2.11 End of Treatment Visit (Visit 15) 
Subjects will complete the treatment at 12 ± 1 month following administration of loading dose and 
return to the study site for their final, End of Treatment Visit (Visit 15). Participants who choose to 
discontinue or who are withdrawn from the study will complete an Early Termination Visit (Section 
6.7). It is highly encouraged that this visit occurs at the study site, but at the physician’s discretion, 
this visit may occur remotely and subject may visit their local medical provider or facility (e.g. 
Quest Diagnostics). The below procedures will be conducted as standard of care: 
 
• 
Physical exam including performance score (if visit occurs on site) 
• 
Vital signs  (if visit occurs on site) 
• 
Radiological imaging (PET/CT or CT)  
• 
Standard of Care Laboratory Tests (Appendix 15.4) 
• 
Lipid panel 
• 
Review of medication changes and updates 
 
The below non-standard of care procedures will be conducted as part of this study during Visit 
15:  
 
• 
Research blood draw 
• 
Pregnancy testing for females of childbearing potential (may be self-administered by 
subjects if visit is conducted remotely) 
• 
Sirolimus Trough 
• 
Assess possible AEs 
• 
Return of any non-consumed sirolimus 
• 
Sirolimus pill count (if visit occurs on site) 
• 
Final assessment of primary objective 
• 
Recording of medical history data, medication changes, AEs, and Laboratory Test, as 
available, (Appendix 15.4) from medical records into eCRF 
 
6.3 
Follow Up Phase of the Study 
 
6.3.1 Visit 16 
The subject will be contacted by phone 12 weeks ± 2 weeks after the End of Treatment Visit or 
Early Termination Visit and asked questions regarding their health status, if they have become 
pregnant (if applicable), and if they have continued on drug off-study. 
 

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6.4 
Rescue Therapy 
At the discretion of the licensed site investigator, a subject can be removed from the trial due to 
disease progression or serious AE (SAE). Decision to remove a subject from the trial and which 
rescue therapy(ies) to administer rest solely with the licensed site investigator. 
 
6.5 
Unscheduled Visits 
An unscheduled visit may be required to repeat a laboratory assay or to conduct further safety 
evaluation. Enrollment into this study places no restrictions upon subjects’ ability to visit their 
physician outside of the study’s scheduled visits. Health data generated from such visits will be 
incorporated into the eCRF at the time of the subject’s next scheduled visit. 
 
6.6 
Subject Withdrawal 
The criteria for enrollment must be followed explicitly. If a subject who does not meet enrollment 
criteria is inadvertently enrolled, that subject should be discontinued from the study. A subject 
may voluntarily discontinue participation in this study at any time without impact to their care. The 
licensed site investigator or Lead Principal Investigator may also, at his or her discretion, 
discontinue the subject from participating in this study at any time. If a subject is prematurely 
discontinued from participation in the study for any reason, at any time, at either the licensed site 
investigator’s discretion or the subject’s request, an effort must be made to document the 
reason(s) why a subject failed to return to the study site for necessary visits or is discontinued 
from the study. Subjects withdrawn from the study may be replaced at the Lead Principal 
Investigator’s discretion. The primary reason for discontinuing participation in the study must be 
stated in the CRF and may include, but is not limited to, one of the following: 
 
• 
Progressive disease as determined by the licensed site investigator  
• 
Use of unapproved concomitant medications including any systemic therapy(ies) intended 
to treat iMCD, as described in the eligibility criteria 
• 
Occurrence of intolerable AEs 
• 
Withdrawal of consent by subject 
• 
Noncompliance with protocol, e.g., the subject fails to appear at one or more visits 
• 
Development of an intercurrent illness, injury, or medical condition likely to interfere with 
subject safety, the overall assessment, or the required administration of study medication 
• 
Pregnancy 
• 
Development of any condition for which the licensed site investigator feels treatment 
withdrawal is justified 
• 
Termination of the study  
 
6.6.1 Data Collection and Follow-up for Withdrawn Subjects 
Subjects who withdraw consent to participate in the study will be seen for one final Early 
Termination Visit. 
 
6.7 
Early Termination Visit 
Subjects who discontinue or are withdrawn early from the study will return to the study site for a 
final Early Termination Visit. Unless conducted as standard of care, the below standard of care 
procedures will be performed: 
 
• 
Physical exam including performance score 
• 
Vital signs  

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• 
Standard of Care Laboratory Tests (Appendix 15.4) 
• 
Review of medication changes and updates 
 
The below non-standard of care procedures will be conducted as part of this study during the 
Early Termination Visit:  
 
• 
Research blood draw 
• 
Assess possible AEs 
• 
Return of any non-consumed sirolimus 
• 
Sirolimus pill count 
• 
Recording of medical history data, medication changes, AEs, and Laboratory Test, as 
available, (Appendix 15.4) from medical records into eCRF 
 
 Study Evaluations and Measurements 
 
7.1 
Medical Record Review 
Variables to be abstracted from medical charts (paper or electronic) and entered in the eCRF 
include elements that fall under the below categories, as available through routine clinical practice 
or obtained as part of this study. 
 
• 
Contact information and socio-demographics 
• 
Diagnoses and anthropometric 
• 
Physical exam 
• 
Vital signs 
• 
Pathology 
• 
Laboratory 
• 
Clinical Features 
• 
Radiographic 
• 
Co-morbid conditions 
• 
Medications (previous and current) 
• 
Adverse events 
• 
End of study information (including information on early withdrawal) 
 
7.2 
Physical Examination 
Physical examination will follow standard of care for the treatment of iMCD as well as those 
required for assessing the Study Endpoints. Information may be obtained from the medical record. 
 
7.3 
Vital Signs 
Vital signs will be assessed during each visit in line with standard of care for the treatment of 
iMCD. Body temperature will be assessed with a digital thermometer under the tongue or in the 
axilla. Pulse oximetry will be assessed digitally. Blood pressure and pulse rate will be assessed 
using a digitally-read cuff on individuals sitting up. Respiration rate will be determined by a medical 
professional.  
 
7.4 
Laboratory Evaluations 
Blood sampling will be performed for this study for the following laboratory evaluations. Other 
laboratory tests will be collected as part of standard of care treatment and recorded in the eCRF 
from medical record review. 

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• 
Sirolimus trough levels 
• 
Pregnancy testing (if applicable) 
• 
Lipid panel (if not collected as standard of care) 
 
7.4.1 Clinical Laboratory Tests 
Appendix 15.4 contains a listing of standard of care labs that will be collected from subjects’ 
medical records and recorded into the eCRF as part of this study. 
 
7.5 
Pregnancy Testing 
Women of childbearing potential must have a negative pregnancy test documented during the 
Baseline Visit. Urine pregnancy testing will be conducted at each on-site visit. If a follow-up visit 
is conducted remotely, a subject may perform the pregnancy test at home and provide results to 
the study team via photo.  
 
 

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7.6 
Efficacy Evaluations 
The below measures will be used to assess the efficacy of the study intervention and determine 
if the subject meets criteria for a CBR. All comparisons are against those obtained during the 
Baseline Visit: 
 
Positive response: Relative to baseline, improvement in at least one of the below criterion without 
worsening of any single criterion other than hemoglobin on two consecutive study visits. 
 
Negative response: Relative to baseline, worsening of any single criterion other than hemoglobin 
on two consecutive site visits or failure to achieve improvement for any criterion. 
 
 
Hemoglobin 
Fatigue 
Anorexia 
Fever and 
night sweats 
Weight 
Lymph node size 
Improvement 
≥2 g/dL 
increase 
without 
transfusions 
≥1 grade 
decrease 
by NCI 
CTCAE 
version 
4.0, May, 
2009 
≥1 grade 
decrease 
by NCI 
CTCAE 
version 
4.0, May, 
2009 
≥2˚C 
decrease in 
fever or 
return to 
normal body 
temperature 
(37˚C) or 
improvement 
in night 
sweats, as 
assessed by 
licensed site 
investigator 
≥5% 
increase not 
due to 
increase in 
new or 
existing 
edema 
≥25% decrease 
bi-dimensionally 
in size of largest 
lymph node, as 
measured using 
Cheson criteria 
(Appendix 15.2) 
Worsening 
 
≥2 grade 
increase 
by NCI 
CTCAE 
version 
4.0, May, 
2009 
≥2 grade 
increase 
by NCI 
CTCAE 
version 
4.0, May, 
2009 
≥2˚C 
increase in 
fever or 
worsening in 
night sweats, 
as assessed 
by licensed 
site 
investigator 
≥5% 
decrease 
(weight loss 
not due to 
decreased 
edema)  
≥25% increase bi-
dimensionally in 
size of largest 
lymph node, as 
measured using 
Cheson criteria 
(Appendix 15.2) 
 
The below table provides the CHAP score, which will be used to assess the efficacy of the study 
intervention. All comparisons are against those obtained during the Baseline Visit: 
 
Score: 
0 
1 
2 
3 
4 
CRP (mg/dL) 
<1 
≥1, <5 
≥5, <10 
≥10, <20 
≥20 
Hemoglobin (g/dL) 
≥12 
<12, ≥10 
<10, ≥8 
<8 
Transfusion dependent 
Albumin (g/dL) 
≥3 
<3, ≥2.5 
<2.5, ≥2 
<2, ≥1.5 
<1.5 
Performance Score (ECOG) 
0 
1 
2 
3 
4 
 

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The below table provides the modified Cheson response criteria, which will be used to assess the 
efficacy of the study intervention. Unless otherwise specified, all comparisons are against those 
obtained during the Baseline Visit: 
 
Complete Response (CR) 
All index lesion(s) must have regressed to normal size (≤1.0 cm in 
their 
greatest 
transverse 
diameter. 
No 
new 
sites 
of 
lymphadenopathy >1.5 cm in longest dimension. 
Partial Response (PR) 
≥50% decrease in sum of the products of the greatest diameters 
(SPD) of index lesion(s), and no new sites of lymphadenopathy >1.5 
cm in longest dimension. 
Stable Disease (SD) 
Failure to achieve a CR or PR (see above) without evidence of 
progressive disease (see below). 
Progressive Disease (PD) 
≥50% increase from nadir in the SPD of any index lesion, or 
appearance of any new sites of lymphadenopathy that measure >1.5 
cm in longest dimension during or at the end of therapy. 
 
MCD-related Overall Symptom Score: In addition to the defined CBR, 34 measures of disease 
activity will be prospectively evaluated and graded (as per CTCAE version 4.0, May, 2009), which 
will be used to assess the efficacy of the study intervention. All comparisons are against those 
obtained during the Baseline Visit: 
 
General MCD-related 
• 
Fatigue 
• 
Malaise 
• 
Hyperhidrosis 
• 
Night sweats 
• 
Fever 
• 
Weight loss 
• 
Anorexia 
• 
Tumor pain 
• 
Dyspnea 
• 
Pruritis 
Autoimmune phenomena 
• 
Autoimmune disorder 
• 
Immune system disorder 
Fluid retention 
 
• 
Generalized edema 
• 
Edema face 
• 
Edema limbs 
• 
Edema trunk 
• 
Genital edema 
• 
Localized edema 
• 
Neck edema 
• 
Periorbital edema 
• 
Capillary leak syndrome 

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• 
Ascites 
• 
Pleural effusion 
• 
Pericardial effusion 
Neuropathy 
• 
Peripheral motor neuropathy 
• 
Peripheral sensory neuropathy 
• 
Nervous system disorder, other 
Skin disorders 
 
• 
Rash acneiform 
• 
Rash maculo-papular 
• 
Papulopustular rash 
• 
Purpura 
• 
Skin hyperpigmentation 
• 
Skin induration 
• 
Skin disorder, other 
 
7.7 
Research Samples 
Research samples will be collected and shipped to the University of Pennsylvania for processing 
and storage, or processed at the local site and shipped to the University of Pennsylvania or the 
Children’s Hospital of Philadelphia for storage. Research samples will be coded to maintain 
patient confidentiality and may be stored indefinitely for use in research, including in pursuit of the 
exploratory endpoints described in this protocol. Subjects will be asked to provide their consent 
to allow any biological samples collected as part of this study or collected during their enrollment 
period in this study, but for purposes outside of the study, to be used for laboratory research 
purposes, including genetic sequencing studies. Subjects will also be given the option to consent 
to allow any biological samples from their past medical procedures to be used for laboratory 
research purposes, including genetic sequencing studies. 
 
7.8 
Genetic Testing 
As part of the exploratory objective, genetic testing may be performed on subject’s biological 
samples. Such genetic testing would be strictly exploratory in nature. Samples will be used to 
study the genetic information that may be involved in Castleman disease, and efficacy or failure 
of sirolimus. Clinically significant results of genetic testing may be disclosed to the subjects at the 
discretion of the treating physician. 
 
7.9 
Safety Evaluations 
Enrolled subjects will be carefully monitored throughout the study by study staff, with particular 
attention to known sirolimus AEs (See Section 12.1 Risks for details). Safety will also be 
assessed by changes in laboratory parameters, vital signs, and physical examinations. If any 
safety concerns arise, the licensed site investigators will promptly inform the Lead Principal 
Investigator and the Data Safety Monitoring Board (DSMB). The DSMB members will meet at pre-
established times and as safety concerns arise to review the safety and clinical assessment data. 
 

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7.10 Concomitant Therapies 
Corticosteroids (stable dose) and best supportive care are allowed throughout the course of the 
Intervention Phase. No additional systemic therapies directed at treating iMCD are permitted 
during the Intervention Phase. 
 
 Statistical Plan 
This trial is a Phase II study of the efficacy and mechanism of action of sirolimus in anti-IL-6 
blockade refractory iMCD. The trial is designed to rule out a therapy that has little or no biological 
activity in the examined patient cohort, a treatment-refractory population. The minimal acceptable 
level of activity is ≥ 20%. A common dose and dosing schedule will be employed for all subjects. 
An interim analysis will be conducted after 14 subjects have completed the Visit 9 intermediate 
assessment. If no responses are observed in these first 14 subjects, then the probability(response 
probability≥20%) < 0.05, and the trial should be terminated. If at least one response is observed, 
additional subjects may be enrolled to increase the degree of precision of the standard error, to a 
total of 24 evaluable subjects.  
 
The statistical considerations for this study were developed to answer the two overall research 
questions:  
 
• 
Does sirolimus have activity in the treatment population? The only placebo controlled 
clinical trial in iMCD (NCT01024036) reported a 0% response in placebo. We have access 
to the historic data and plan to apply the study’s endpoints, as applicable, as a benchmark 
for this trial, recognizing that some of the enrollment criteria were more stringent than 
those of this trial, and standard of care for iMCD may have changed since the first patient 
was enrolled into NCT01024036 (March 2010). We propose a maximum of up to 24 total 
evaluable patients with an interim analysis after 14 patients have completed the Visit 9 
intermediate assessment. If no patients demonstrate a positive CBR response at the Visit 
9 assessment, then it will be determined that sirolimus is unlikely to have activity in the 
study population. If one or more patients demonstrate a positive CBR, then additional 
patients may be enrolled in order to better estimate the response rate. Upon study 
completion, primary and secondary endpoints will be analyzed to determine if sirolimus 
has activity in the treatment population. Assessments will be based on the binary (yes/no) 
CBR criteria and continuation on drug, the continuous variable (0-16) CHAP disease 
activity scoring system, and the modified Cheson response criteria. Given the aggressive 
nature of the disease, historic data and preliminary nature of this trial, a placebo arm is 
not included in this study. The null hypothesis is that the intervention will have 0% activity.  
 
• 
What is the mechanism of action by which sirolimus is efficacious in alleviating lymph node 
enlargement and clinical symptoms in iMCD? Cellular and molecular research assays will 
be performed to analyze changes in cell populations and signaling molecules between 
baseline and time points following sirolimus administration. Comparison will be made with 
paired t-tests and post-hoc corrections for multiple comparisons, as appropriate.  
 
8.1 
Primary Endpoint 
The primary endpoint for this study will be the proportion of patients achieving a positive response 
based on the CBR criteria. The CBR criteria consist of six parameters. The CBR and its binary 

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analysis is described in Section 7.6 Efficacy Evaluations. The parameters will be measured as 
part of standard of care using clinically established scales (e.g. CTCAE version 4.0, May, 2009 
grading and Cheson criteria). The primary assessment will occur at 12 ± 1 month. Comparisons 
will be made to values obtained during the patient’s Baseline Visit. 
 
8.2 
Secondary Endpoints 
The secondary endpoints for this study are (1) the proportion of patients achieving a positive 
response based on the CBR criteria during intermediate assessment time points, (2) the 
proportion of patients that remain on study drug for the duration of the study, (3) the proportion of 
patients that indicate that they are currently receiving sirolimus at the end of the Follow Up Phase, 
(4) changes in the patient’s disease activity, as measured by the CHAP score during intermediate 
and final assessment time points, (5) changes in the patient’s disease activity, as measured by 
MCD-related Overall Symptom Score as measured by 34 outcome measures during intermediate 
and final assessment time points and (6) lymph node response, as measured by the Cheson 
criteria during intermediate and final assessment time points. Comparisons will be made against 
values obtained during the Baseline Visit. 
 
8.3 
Exploratory Endpoints 
The exploratory endpoints of this study will be results of correlative studies, in the research 
laboratory, to investigate the mechanism of action of sirolimus in iMCD and clinical and laboratory 
biomarkers for treatment response. Additional correlative findings may also be assessed. Spleen 
size will be measured by radiological imaging (PET/CT or CT).  
 
8.4 
Sample Size and Power Determination 
Up to 24 subjects may be evaluated under this study, with an interim analysis to be conducted 
after 14 subjects have completed the Visit 9 intermediate assessment. Additional subjects may 
be enrolled to increase the degree of precision of the standard error, to a total of 24 evaluable 
subjects. We anticipate enrolling up to 40 subjects to reach our goal of 24 evaluable subjects.  
 
The difference between enrollment and evaluable accounts for potential subjects that may be 
deemed ineligible upon screening, or who drop out of the study but are replaced.  
 
Our expected response rate is ≥20% versus the null hypothesis of 0% response. The placebo 
response rate in the only placebo controlled, double blinded clinical trial in iMCD was 0%. Given 
these parameters, power analysis with type 1 error α = 0.05 and power of 1-β = 0.8 provides a 
samples size of 14 to determine if sirolimus has activity; the drug will be considered not likely to 
have a ≥20% activity if no responses are seen in the interim analysis. 
 
Sample size was chosen based on (1) convenience and the logistical constraints of recruiting a 
rare disease population and (2) our intention to probe for a signal of response and understand 
sirolimus’ mechanism of action. 
 
8.5 
Statistical Methods 
Descriptive analyses will be performed and presented as tables and plots.  
 
Continuous variables: (e.g., age) will be summarized using the following descriptive summary 
statistics: the number of subjects (n), mean, error, median, minimum value (min), and maximum 
value (max). For each continuous variable, the corresponding mean, median, minimum and 
maximum will be presented with error, as determined appropriate. 

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Categorical variables: (e.g., presence of an AE, gender) will be summarized using counts and 
percentages.  
 
8.5.1 Efficacy Analysis 
CBR will be used as the primary endpoint for assessment of treatment response. Response to 
drug will be summarized as CBR and its 95% confidence interval and tested using Chi-square 
(versus historic placebo control data). Difference in CBR in two different study sites will be 
summarized and compared using the Chi-square tests. Significance will be established at α=0.05.  
 
The baseline covariates will be tested for association with CBR using logistic regression or two-
sample t-test and the unadjusted p-values will be reported. When biomarkers are evaluated for 
association with CBR, we will perform logistic regression analysis for each marker adjusting for 
possible baseline covariates. The false discovery rate procedure will be used to adjust for multiple 
comparisons. As an exploratory analysis, if the CBR is not too low, we will also apply the random 
forest method to evaluate whether such biomarkers cab be predictive to CBR. 
 
8.5.2 Interim Analysis 
An interim analysis will be completed after 14 subjects have completed the intermediate 
assessment for CBR at Visit 9. At this time, the safety and preliminary efficacy of the study dose 
will be assessed and if, deemed safe and appropriate, enrollment may continue as needed to 
achieve up to 24 evaluable subjects to increase the degree of precision of the standard error. 
 
8.5.3 Safety Analysis 
All subjects entered into the study will have detailed information collected on AEs for the overall 
study safety analysis. Treatment emergent AEs are defined as AEs with a start date or that 
increase in severity on or after the first study drug dose through Visit 15 of the Follow Up Phase 
of the study. 
 
8.6 
Subject Population(s) for Analysis 
Any subject enrolled into the study that receives at least one dose of investigational product will 
be included for all analyses for each Visit they complete. 
 
 Safety and Adverse Events 
 
9.1 
Definitions 
 
9.1.1 Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in 
severity during the course of the study. Intercurrent illnesses or injuries should be regarded as 
AEs. Abnormal results of diagnostic procedures are considered to be AEs if the abnormality: 
 
• 
results in study withdrawal 
• 
is associated with a serious AE 
• 
is associated with clinical signs or symptoms 
• 
leads to additional treatment or to further diagnostic tests 
• 
is considered by the licensed site investigator to be of clinical significance 
 

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9.1.2 Serious Adverse Event 
AEs are classified as serious or non-serious. A serious adverse event is any AE that is: 
 
• 
fatal 
• 
life-threatening 
• 
requires or prolongs hospital stay 
• 
results in persistent or significant disability or incapacity 
• 
a congenital anomaly or birth defect 
• 
an important medical event 
  
Important medical events are those that may not be immediately life threatening, but are clearly 
of major clinical significance. They may jeopardize the subject, and may require intervention to 
prevent one of the other serious outcomes noted above. For example, drug overdose or abuse, 
a seizure that did not result in in-patient hospitalization, or intensive treatment of bronchospasm 
in an emergency department would typically be considered serious. 
  
All AEs that do not meet any of the criteria for serious should be regarded as non-serious AEs. 
 
9.2 
Recording of Adverse Events 
At each contact with the subject, study staff will seek information on AEs by specific questioning 
and, as appropriate, by examination. Subjects will be monitored for all previously reported AEs 
associated with sirolimus treatment and possible new AEs, as well as Grade 2 or higher allergic 
reaction/hypersensitivity attributed to sirolimus, as judged by the site investigator. AEs will be 
defined by the NCI CTCAE version 5.0, November 2017. All AEs will be recorded in the source 
document, and also in the appropriate AE module of the eCRF. All clearly related signs, 
symptoms, and abnormal diagnostic procedures’ results should be recorded in the source 
document, though should be grouped under one diagnosis. 
 
AEs occurring during the study period (from the time of enrollment through Visit 15) will be 
recorded. The clinical course of each event should be followed by the licensed site investigator 
until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  
 
9.3 
Relationship of AE to Study 
The relationship of each AE to sirolimus should be characterized by the licensed site investigator 
and recorded in the appropriate AE module of the eCRF. The licensed site investigator will classify 
the relationship as either definitely related, probably related, possibly related, unlikely or 
unrelated. 
 
9.4 
Reporting of Adverse Events and Unanticipated Problems 
Licensed site investigators will conform to the AE reporting timelines, formats and requirements 
of the various entities to which they are responsible. 
  
If the report is supplied as a narrative, the minimum necessary information to be provided at the 
time of the initial report includes: 
 

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● Study identifier 
● Study center 
● Subject number 
● A description of the event 
● Date of onset 
● Current status 
● Whether study intervention was discontinued 
● The reason why the event is classified as serious 
● Licensed site investigator’s assessment of the 
association between the event and study 
intervention 
 
Additionally all other events (unanticipated problems, adverse reactions, unanticipated adverse 
effects and subject complaints) will be recorded and reported with respect to institutional and 
federal policies as described in the Penn Manual and below. 
 
9.4.1 Follow-up report 
If an SAE has not resolved at the time of the initial report and new information arises that changes 
the licensed site investigator’s assessment of the event, a follow-up report including all relevant 
new or reassessed information (e.g., concomitant medication, medical history) should be 
completed. The licensed site investigator is responsible for ensuring that all SAE are followed 
until either resolved or stable. 
 
9.4.2 Investigator reporting: notifying the study sponsor 
Licensed site investigators from all participating sites should report all unexpected and related 
AEs, regardless of whether they are serious or not, and all unanticipated problems to the Lead 
Principal Investigator. 
 
Any study-related unanticipated problem posing risk to subjects or others, and any type of SAE, 
will be reported to the Lead Principal Investigator by telephone within 24 hours of the event. To 
report such events, a SAE form will be completed by the licensed site investigator and emailed to 
the Lead Principal Investigator within two business days. The licensed site investigator will keep 
a copy of this SAE form on file at the study site. Report SAEs by phone and email to: 
  
David Fajgenbaum  
215-614-0936 
davidfa@pennmedicine.upenn.edu 
  
Within the following 48 hours, the licensed site investigator will provide further information on the 
SAE or the unanticipated problem in the form of a written narrative. This should include a copy of 
the completed SAE form, and any other diagnostic information that will assist the understanding 
of the event. Significant new information on ongoing SAEs should be provided promptly to the 
Lead Principal Investigator. 
 
9.4.3 Investigator Reporting: Notifying the Penn IRB 
This section describes the requirements for safety reporting by investigators who are Penn faculty, 
affiliated with a Penn research site, or otherwise responsible for safety reporting to the Penn IRB. 
The University of Pennsylvania IRB (Penn IRB) requires expedited reporting of those events 
related to study participation that are unforeseen and indicate that subjects or others are at 
increased risk of harm. The Penn IRB will not acknowledge safety reports or bulk AE submissions 
that do not meet the criteria outlined below. The Penn IRB requires researchers to submit reports 
of the following problems within 10 working days from the time the investigator becomes aware 
of the event: 
 

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• Any AE (regardless of whether the event is serious or non-serious, on-site or off-site) that 
occurs any time during or after the research study, which in the opinion of the Lead 
Principal Investigator is: 
 
Unexpected (An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, 
any applicable investigator brochure, and the current IRB-approved informed consent 
document and other relevant sources of information, such as product labeling and package 
inserts.) 
 
AND 
 
Related to the research procedures (An event is “related to the research procedures” if in 
the opinion of the Lead Principal Investigator, the event was more likely than not to be 
caused by the research procedures.) 
 
Reporting Process 
Unanticipated problems posing risks to subjects or others as noted above will be reported to the 
Penn IRB using the form: “Unanticipated Problems Posing Risks to Subjects or Others Including 
Reportable Adverse Events” or as a written report of the event (including a description of the event 
with information regarding its fulfillment of the above criteria, follow-up/resolution and need for 
revision to consent form and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the 
Principal Investigator’s study file. 
Other Reportable Events 
The following events are also reportable to the Penn IRB: 
 
• Any adverse experience that, even without detailed analysis, represents a serious 
unexpected AE that is rare in the absence of drug exposure (such as agranulocytosis, 
hepatic necrosis, Stevens-Johnson syndrome). 
• Any AE that would cause the sponsor to modify the investigators brochure, protocol or 
informed consent form, or would prompt other action by the IRB to assure protection of 
human subjects. 
• Information that indicates a change to the risks or potential benefits of the research, in 
terms of severity or frequency. For example:  
o An interim analysis indicates that subjects have a lower rate of response to treatment 
than initially expected. 
o Safety monitoring indicates that a particular side effect is more severe, or more frequent 
than initially expected. 
o A paper is published from another study that shows that an arm of your research study 
is of no therapeutic value. 
• Change in FDA safety labeling or withdrawal from marketing of a drug, device, or biologic 
used in a research protocol. 
• Breach of confidentiality 
• Change to the protocol taken without prior IRB review to eliminate apparent immediate 
hazard to a research subject. 
• Incarceration of a subject when the research was not previously approved under Subpart 
C and the investigator believes it is in the best interest of the subject to remain on the study. 

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• Complaint of a subject when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
• Protocol violation (meaning an accidental or unintentional deviation from the IRB approved 
protocol) that in the opinion of the investigator placed one or more subjects at increased 
risk, or affects the rights or welfare of subjects. 
 
9.4.4 Sponsor reporting: Notifying participating investigators 
The Lead Principal Investigator will report AE or findings to all participating licensed site 
investigators in a timely manner. 
 
9.4.5 Sponsor reporting: Notifying collaborating companies 
The Lead Principal Investigator will report AEs to collaborating companies (e.g. Pfizer, Inc.), in 
accordance with contractual agreements.  
 
9.5 
Unblinding Procedures 
N/A 
 
9.6 
Stopping Rules 
N/A 
 
9.7 
Medical Monitoring 
It is the responsibility of the licensed site investigator to oversee the safety of the study at his/her 
site. This safety monitoring will include careful assessment and appropriate reporting of AEs as 
noted above. Medical monitoring will include a regular assessment of the number and type of 
SAEs. Safety will be closely monitored by the licensed site investigators on an ongoing basis for 
all subjects. A DSMB is planned to monitor the safety of this study. 
 
9.7.1 Data and Safety Monitoring Plan 
The investigator at each site will be responsible for monitoring the data quality and the ongoing 
safety of subjects at their respective sites. In addition, eCRF data quality will be periodically 
confirmed via remote audit and review of source documents.  
 
A DSMB will provide additional guidance and will review data quality and subject safety on an 
ongoing basis. The DSMB will be comprised of representatives who are independent of the 
investigators. A DSMB will be formed with a charter containing this information. 
 
9.7.2 Data Safety Monitoring Board 
An independent DSMB will be established to assure the safety of subjects in this trial. The DSMB 
will review the study for safety and overall study conduct. At the end of the study, they may 
adjudicate final outcome based on the clinical information. The membership of the DSMB as well 
as the responsibilities and procedures used to carry out these responsibilities are described 
separately in the DSMB charter. 
 
 

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 Study Administration, Data Handling and Record Keeping 
 
10.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). Those 
regulations require a signed subject authorization informing the subject of the following: 
 
• 
What protected health information (PHI) will be collected from subjects in this study 
• 
Who will have access to that information and why 
• 
Who will use or disclose that information 
• 
The rights of a research subject to revoke their authorization for use of their PHI. 
  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the 
end of their scheduled study period. 
 
To help protect subject confidentiality, at enrollment the licensed site investigator will assign a 
GUID to each study subject. The following information is needed to generate an encrypted GUID: 
 
• 
Complete legal given first, middle and last names of subject at birth 
• 
Date of birth 
• 
Name of city/municipality in which subject was born 
• 
Country of birth 
• 
Physical sex of subject at birth (optional) 
 
At each site, source documents and a master electronic list, which links the coded identifiers for 
subjects enrolled at that site to personal information, will be kept completely separate from the 
eCRF (Section 10.2, Data Collection and Management) on a password protected network 
and/or under lock and key and limited to key research team members. Research team members 
will have access as long as the project is still operating and they remain research qualified.  
 
The GUID enables data from a coded subject to be integrated, tracked over time, and linked 
across research projects, databases and biobanks. This will allow for de-identified data to be 
associated between all studies that use the GUID. 
 
10.2 Data Collection and Management 
Study data, collected as part of the trial, as standard of care treatment during the trial period, and 
historic medical and treatment information will be entered into the eCRF. The eCRF is the primary 
data collection instrument for the study. All data requested on the eCRF must be recorded. All 
missing data must be explained. If a space on the eCRF is left blank because the procedure was 
not done or the question was not asked, write “N/D”. If the item is not applicable to the individual 
case, write “N/A”. 
 
A shared database with common data definitions will be created using REDCap, and housed on 
a secure server at the University of Pennsylvania. REDCap is a secure, web-based application 
with the capacity for direct export to Excel and common statistical packages (SPSS, SAS, Strata, 

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R). REDCap has eCRFs, real-time data entry validation, audit trails, user authentication, data 
logging and encryption. It is HIPAA compliant with mechanisms in place to ensure confidentiality.  
 
To ensure confidentiality of the data, subjects GUIDs will be used for identification in REDCap; 
personal identifiers (e.g. name, social security number, medical record number, etc.) will not be 
entered into the eCRF. Qualified study staff will have access to all study data collected in the 
eCRF. 
 
Specific forms will be used for each component of the subject’s progress. The forms and data 
dictionary will be available online for all individuals who perform data entry. Research personnel, 
trained on data definitions, will enter data via web-based data forms after abstraction from the 
primary medical record and source documents. Logical data checks will be used to assess data 
quality for mis-entry. Suspect data entries will be flagged for re-review and confirmation by the 
investigative team at each site. When data are complete and all suspect entries addressed for a 
time period, the database will be “locked” for analysis. Analysis will use only this final locked 
version. De-identified data will be stored indefinitely. 
 
10.3 Records Retention 
Study essential documents will be retained for at least 2 years after the last subject completes 
the End of Study Visit or Early Termination Visit, as the case may be.  
 
10.4 Management of Information for Multi-Center Research 
University of Pennsylvania IRB will be the single IRB of record for the University of Pennsylvania 
and UAMS. University of Pennsylvania is the lead site and will be responsible for ensuring all sites 
receive the most current version of the protocol, consent and study related documents. The lead 
site will be responsible for management of project timelines, management of data collected from 
each site, submitting progress reports, and reporting to the IRB as needed. UAMS IRB will be 
responsible for ensuring their local consent requirements are met without major changes to the 
IRB approved template. Protocol changes, consent updates and IRB continuing reviews will be 
initiated by the lead site in compliance with Penn's IRB policies. The Children’s Hospital of 
Philadelphia will utilize the CHOP IRB.  
 
Regular meetings will be held for study team members at all sites, and interim communication via 
phone or email will occur as needed to report urgent developments to licensed site investigators.  
 
 Study Monitoring, Auditing, and Inspecting 
 
11.1 Study Monitoring Plan 
The licensed site investigator at each site is responsible for assigning staff for monitoring. The 
Lead Principal Investigator will also ensure that the monitor or other compliance or quality 
assurance reviewer is given access to all the above noted study-related documents and study 
related facilities (e.g. pharmacy, diagnostic laboratory, etc.). Enrollment will be complete when all 
subjects are enrolled into the trial across sites. The following will be reviewed for all subjects after 
the first subject is enrolled at each site, and throughout the trial: 
 
• 
Informed consent documentation  
• 
Eligibility criteria 
• 
Safety Monitoring (adverse event documentation and assessment) 

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• 
Regulatory documentation (IRB – amendments, continuing review and reportable events) 
 
The Regulatory Documents will be maintained in the Regulatory Binder.  
 
11.2 Auditing and Inspecting 
The licensed site investigators will permit study-related monitoring, audits, and inspections by the 
IRB, government regulatory bodies, and University compliance and quality assurance groups of 
all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.). The licensed site investigators will ensure the capability for 
inspections of applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
  
Participation as a licensed site investigator in this study implies acceptance of potential inspection 
by government regulatory authorities and applicable University compliance and quality assurance 
offices. 
 
 Ethical Considerations 
This study is to be conducted accordance with applicable US government regulations and 
international standards of Good Clinical Practice, and applicable institutional research policies 
and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted IRB, in agreement 
with local legal prescriptions, for formal approval of the study conduct. The decision of the IRB 
concerning the conduct of the study will be made in writing to the Lead Principal Investigator and 
a copy of this decision will be provided to the Lead Principal Investigator before commencement 
of this study.  
 
12.1 Risks 
The risk to patients of exposure to the treatment intervention, sirolimus, as related to AEs is 
relatively low. Sirolimus is an FDA-approved therapy with an established safety profile. Although 
uncommon, AEs are possible and will be monitored by study staff and licensed site investigators. 
The most common (≥20%) adverse reactions reported for sirolimus 2 mg/day at a higher incidence 
than reported for placebo include: 
 
• 
peripheral edema 
• 
hyperlipidemia, hypercholesterolemia, hypertriglyceridemia 
• 
increased creatinine 
• 
constipation  
• 
hypertension 
• 
abdominal pain / diarrhea 
• 
headache 
• 
arthralgia 
Other less common serious complications include: 
 
• 
angioedema 
• 
leucopenia 
• 
thrombocytosis / thrombocytopenia 
• 
fluid accumulation 

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• 
impaired wound healing 
• 
proteinuria 
• 
interstitial lung disease/non-infectious pneumonitis 
• 
calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic 
thrombocytopenic purpura/thrombotic microangiopathy 
The below table summarizes the known adverse events (AEs) categorized based on timing and 
frequency: 
 
Known Adverse Events (AEs) 
 
Common 
21-100 out of every 100 
Occasional 
5-20 out of every 100 
Rare 
<5 out of every 100 
Immediate: 
1-2 days of 
receiving drug 
Nausea, vomiting, oral 
ulcers 
Rash 
Allergic reaction (may 
be life threatening) 
Prompt: 
2-3 weeks on 
drug 
Increased cholesterol, 
increased blood 
pressure, decreased 
kidney function, diarrhea 
Infections, swelling, weight 
gain, muscle/joint pain, 
tremor, acne, rash, 
abdominal pain, mucositis, 
headache 
 
Decreased red and 
white blood cells 
generated in bone 
marrow, decreased 
liver function 
Delayed: 
Any time later 
during therapy, 
excluding the 
above 
conditions 
Acne 
 
Malignancy resulting 
from this treatment, 
destruction of red blood 
cells and decreased 
kidney function, 
interstitial lung disease, 
hemolytic uremic 
syndrome/thrombotic 
thrombocytopenic 
purpura* 
Late: 
Any time after 
completion of 
treatment 
 
 
Interstitial lung disease 
Unknown 
Frequency 
and Timing: 
Sirolimus was embryo/feto toxic in rats at dosages of 0.1 mg/kg and above 
(approximately 0.2 to 0.5 is the clinical doses adjusted for body surface area). 
Embryo/feto toxicity was manifested as mortality and reduced fetal weights 
(with associated delays in skeletal ossification). Sirolimus is excreted in trace 
amounts in milk of lactating rats. It is not known whether sirolimus is excreted 
in human milk. 
*Risk increased when sirolimus taken with other medications, including cyclosporine and 
tacrolimus. Increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome / 
thrombotic thrombocytopenic purpura / thrombotic microangiopathy 
 
To monitor for these risks, blood pressure will be monitored from standard of care physical exams. 
Additionally, fasting serum lipids will be monitored from standard of care lipid panels. Treating 
physicians may consider use of a cholesterol-lowering agent, such as an HMG-CoA reductase 
inhibitor, in patients with elevated cholesterol, especially those who have responded to therapy 
and may be on the drug for 6 months or longer. HMG-CoA reductase inhibitors that are also 

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CYP3A4 inhibitors (https://drug-interactions.medicine.iu.edu/main-table.aspx) should be 
avoided. Sirolimus can sometimes impair kidney, liver and bone marrow function. Kidney, liver 
and bone marrow function will be monitored from standard of care metabolic, liver function and 
complete blood counts panels. 
 
In general, immunosuppressive therapy may result in an increased risk of development of 
lymphoma and other malignancies. Such risks will be monitored for by review of subjects’ 
complete blood counts (CBC) and imaging for evidence of malignancy. Additionally, patients 
receiving immunosuppressants, including sirolimus, are at increased risk for opportunistic 
infections, including polyoma virus infections. Polyoma virus infections in immunosuppressed 
patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-
associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus-associated 
progressive multifocal leukoencephalopathy (PML) which have been observed in patients 
receiving sirolimus.  
 
There is a risk of breach of confidentiality in that someone could trace the information in the 
research database back to an individual. The risk that someone will identify an individual is very 
small as data will be stored on a secure database on password protected computers and no 
personal health information will be entered into the database; subjects will be tracked using a 
GUID assigned at enrollment. Only designated study staff at the subject’s site of enrollment will 
have access to the master electronic list linking personal identifiers to the subject’s GUID.  
 
12.2 Benefits 
This study will enroll iMCD patients who have failed the only FDA-approved therapy for treatment 
of the disease. Other therapeutic approaches (e.g. corticosteroids, rituximab, and cytotoxic 
chemotherapy) have been used off-label, but have significant toxicities and their efficacies have 
not been systematically studied. Therefore, if efficacious, sirolimus therapy would provide the 
direct benefit of improved health, with limited toxicity, to these individuals who have few other 
therapeutic options. More broadly, if efficacy is found, this study could have the indirect benefit of 
identifying sirolimus as a standard second line therapy for treatment of iMCD. 
 
12.3 Risk Benefit Assessment 
The risks of participating in this study are outweighed by the potential benefits. Sirolimus related 
AEs are uncommon and generally tolerable. In contrast, iMCD is a life-threatening 
lymphoproliferative disorder with only a single FDA-approved therapy. For patients who do not 
respond, there are few therapeutic options. 
 
12.4 Informed Consent Process / HIPAA Authorization 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study. This consent form is submitted with this protocol for review and approval by the IRB for the 
study. 
 
The consent process will take place during the Screening Visit. The formal consent of a subject 
must be obtained before that subject undergoes any study specific procedure. The licensed site 
investigator or their designated staff will obtain consent for each study subject. Potential subjects 
will be provided the opportunity to discuss any questions they have with the licensed site 
investigator, and will be permitted to provide consent at the time of the consent process. No 
subjects will be unduly influenced, encouraged, or coerced into participating in this study. The 

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consent form must be signed by the subject or legally acceptable surrogate, and the licensed site 
investigator’s designated research professional obtaining the consent. Completed consent forms 
will be kept in a continuously locked file cabinet at the study site. 
 
 Study Finances 
 
13.1 Funding Source 
This work is supported by a grant from the National Heart Lung and Blood Institute of the National 
Institutes of Health (R01HL141408). 
 
13.2 Conflict of Interest 
All University of Pennsylvania Investigators will follow the University of Pennsylvania Policy on 
Conflicts of Interest Related to Research. 
 
13.3 Subject Stipends or Payments 
Due to the rarity of iMCD, subjects may need to travel to their assigned site for on-site visits. If a 
subject is found eligible and enrolls in this study, he or she will be provided $50 to be used for 
meals and travel expenses for each visit that must occur at the study center (Visits 1, 4, 6, 9, 12, 
and 15). Subjects traveling over 100 miles to the study site may be provided with hotel and travel 
arrangements (flight or train tickets), if needed, for each visit that must occur at the study center 
(Visits 1, 4, 6, 9, 12, and 15). Payment or reimbursement for travel expenses will be administered 
using a Greenphire ClinCard, by check, or similar method. Travel arrangements may also be 
made through third-party groups who provide transportation to patients, such as Angel Care East. 
Subjects may be reimbursed for research-related costs such as phlebotomy fees. Subjects will 
not otherwise be paid for their participation in this study. The investigational product will be 
provided at no cost to the subject. 
 
 Publication Plan 
A Publication Committee will include the Principal Investigators, and will be open to site 
investigators and collaborators. The purpose of the Publication Committee is to effectively 
manage and oversee the primary, secondary and ancillary publications generated from the study 
while complying with all applicable guidelines and policies. This includes delivering high-quality 
publications that address the primary evidence needs identified and prioritized by any 
collaborators, site investigators, and the Publication Committee. 
 
 
 Appendix 
 

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15.1 Diagnostic Criteria for iMCD 
 
 
15.2 Modified Cheson Criteria 
 
Lymph node selection: Up to six dominant lymph nodes (“index lesions”) should be selected 
according to the following features:  
 

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• 
they should be clearly measurable in at least two perpendicular dimensions, ≥1.0 cm in 
the long axis, and ≥1.0 cm in the longest perpendicular transverse dimension to the long 
axis 
• 
they should be from as disparate regions of the body as possible and chosen such that 
they are representative of the subject’s disease 
• 
they should include mediastinal and retroperitoneal areas of disease whenever these sites 
are involved 
Lymph node measurement: The long axis and the longest perpendicular transverse dimension to 
the long axis of each lymph node should be measured (together, the greatest diameters).  
 
Calculating lymph node response: 
 
CBR response criteria: The largest of the index lesions selected at baseline should be analyzed 
to determine CBR response. 
 
Positive Response: ≥25% decrease in the product of the greatest diameters, as compared 
to the same lymph node at baseline. 
 
Negative Response: ≥25% increase in the product of the greatest diameters, as compared 
to the same lymph node at baseline. 
 
Example: If at baseline, the long axis = 3.0 cm and the longest perpendicular 
transverse dimension = 2.0 cm, then the baseline value calculated for this node 
would be 6.0. To achieve a positive response, the node would have the shrink so 
that that product of the two measurements is ≤ 4.5. (e.g. 2 cm x 2.25 cm).  
 
Cheson response criteria: all index lesions should be considered. When determining response, 
nodal measurements should be calculated independently and as the sum of the product of the 
greatest diameters, as described in (Section 7.6 Efficacy Evaluations). 
 
If a single lymph node mass breaks apart into multiple discrete lymph nodes during the course of 
therapy, that group of nodes should continue to be considered as a single lesion on the eCRF. 
The measurement of the group of nodes should be recorded as the sum of the products of the 
greatest diameters of all of the nodes in the group. Under the “Site of Lesion” section of the Tumor 
Assessment CRFs please use the word “multiple” to clearly note that the measurement reported 
is a sum of several lesions that have broken apart. If several masses are separate at screening 
and in subsequent measurements appear to coalesce, this is usually an indication of PD or a 
technical issue with the CT scans. Please assess these lesions accordingly.

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15.3 
Study calendar 
 
 
 

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15.4 
Laboratory Tests 
 
Standard Diagnostic Laboratory Tests 
1. Complete blood count with differential (hemoglobin, red blood cell count, hematocrit, 
white blood cell count, platelet count, ANC, absolute lymphocyte count, absolute 
monocyte count, absolute basophil count, absolute eosinophil count) 
2. Albumin 
3. CRP 
4. Basic metabolic panel (sodium, potassium, chloride, bicarbonate, glucose, blood urea 
nitrogen, creatinine/eGFR) 
5. Erythrocyte sedimentation rate  
6. sIL2R 
7. VEGF 
8. Quantitative antibodies (IgG, IgA, IgM) 
9. Liver function tests (AST, ALT, gamma-glutamyl transpeptidase, alkaline phosphatase) 
10. Urine protein test 
11. Bilirubin, total 
12. Fibrinogen 
13. Ferritin  
14. IgE 
15. Immunofixation (serum) 
16. Free light chains (Kappa) 
17. Free light chains (Lambda) 
18. Serum IgG4 (as clinically indicated) 
19. Echo-cardiogram (as clinically indicated) 
20. Genetic testing (as clinically indicated) 
 
If required to confirm diagnosis as per diagnostic guidelines, the below (26-33) serological and 
autoantibody studies should be conducted as part of the Standard Diagnostic Laboratory Tests: 
21. EBV PCR (quantitative) 
22. HHV-8 PCR (quantitative) 
23. HIV screen 
24. Hepatitis B (HBsAg, HBsAb, HBcAb) 
25. Hepatitis C (HCV Ab) 
26. Cytomegalovirus PCR (quantitative) 
27. Anti-nuclear antibody (anti-ANA) reflex panel (anti-ANA: if positive, anti-Sjogren’s 
syndrome-related antigen (SS)A, anti-SSB, anti-double stranded DNA, anti-smith) 
28. Rheumatoid factor 
 
Standard of Care Laboratory Tests 
• 
Standard Diagnostic Laboratory Tests 1-11 (above) 
 
iMCD Additional Laboratory test (non-standard of care [i.e. optional]) 
• 
Absolute T cell count (CD3, CD4, CD8) 
• 
Absolute CD19 cell count 
• 
Absolute CD56 cell count 

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• 
Cytokines (IL-1β, IL-4, IL-5, IL-8, IL-10, IL-12, IL-13, tumor necrosis factor-α, 
granulocyte-macrophage colony-stimulating factor, interferon-γ) 
• 
Prothrombin time  
• 
Partial Thromboplastin Time 
• 
D-Dimer 
 
 
 
 

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15.5 Example Dose Calculations 
The table below provides examples of suggested dose corrections based on current dose and 
sirolimus trough levels. In all dose calculations, adjustments should ultimately be based on 
clinical judgment of the licensed site investigator after considering clinical toxicity, serum levels, 
concomitant drug use and the rate of rise or decline of the serum level. 
 
Current 
dose 
(mg) 
Trough 
level 
(ng/ml) 
Target 
trough 
level 
(ng/ml) 
Calculated 
new dose 
(mg) 
New dose (rounded) (mg) 
2 
20 
10 
1.00 
1 
1 
2 
10 
3.33 
3 
5 
30 
10 
1.67 
2 
1 
30 
10 
0.33 
Withhold drug 
2 
15 
10 - 15 
N/A 
No change (within target range) 
 
In the table above, an example patient currently on a dose of 2mg per day may present with a 
sirolimus trough level of 20 ng/ml, above the target of 10 - 15 ng/ml. Using 10 ng/ml as a target, 
a new dose may be calculated using the equation New Dose = current dose × (target 
concentration/current concentration) In this example, new dose = 2 * (10/20) = 1. and the dose 
should be adjusted to 1mg per day. 
 
 
 

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