A Phase II Study of Lenalidomide for Adult Histiocyte Disorders
Phase: PHASE2
Conditions: Langerhans Cell Histiocytosis (LCH), Histiocytoses Erdheim-chester Disease, Histiocytic Sarcoma (HS)
Sponsor: Dana-Farber Cancer Institute

1 
 NCI Protocol #: 
N/a 
 
DF/HCC Protocol #: .15-197 
 
DF/HCC Biomedical Protocol Template: June 20, 2014 
 
TITLE:  A Phase II study of lenalidomide for adult histiocyte disorders 
 
 
Coordinating Center: 
 
 
n/a 
 
*Principal Investigator (PI): 
Eric Jacobsen, MD 
 
Dana-Farber Cancer Institute 
 
edjacobsen@partners.org 
 
Other Investigators: 
 
David C. Fisher, MD 
Ann Lacasce, MD 
Caron Jacobson, MD 
Arnold Freedman, MD 
Philippe Armand, MD 
Matthew Davids, MD 
Jennifer Brown, MD,PhD 
 
 
Statistician: 
 
  
 
 
 
Robert Redd 
 
DFCI 
 
Robert_Redd@dfci.harvard.edu 
 
 
 
 
 
 
Responsible Research Nurse: 
Responsible Data Manager:  
      Karen Polinski, RN 
      DFCI 
      Karen_Polinski@dfci.harvard.edu 
 
 
NCI-Supplied Agent(s):  n/a 
Other Agent(s):  Lenalidomide 
 
 
 
 
Study Exempt from IND Requirements per 21 CFR 312.2(b).   

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Protocol Type / Version # / Version Date: 
Version 1.0, May 15, 2015 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lenalidomide 
days 1-21 of 
28 day cycle 
 
Day 22-28 
toxicity  
assessment 
Week 8 
disease 
assessment 
Escalate dose  
No 
Adjust dose per 
protocol 
Week 8 
disease 
assessment * 
PD = off 
protocol 
NAD or 
AD = 
continue 
per 
protocol 
PD = off 
protocol 
NAD or 
AD = 
continue 
per 
protocol 
Yes 

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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................3 
1. 
OBJECTIVES ......................................................................................................................6 
1.1 
Study Design ............................................................................................................6 
1.2 
Primary Objectives...................................................................................................6 
1.3 
Secondary Objectives...............................................................................................6 
2. 
BACKGROUND .................................................................................................................7 
2.1 
Study Disease(s).......................................................................................................7 
2.2 
Study Agent .............................................................................................................9 
2.3 
Rationale ................................................................................................................11 
2.4 
Correlative Studies Background ............................................................................12 
3. 
PARTICIPANT SELECTION ...........................................................................................13 
3.1 
Eligibility Criteria ..................................................................................................14 
3.2 
Exclusion Criteria ..................................................................................................15 
3.3 
Inclusion of Women and Minorities ......................................................................16 
4. 
REGISTRATION PROCEDURES ...................................................................................16 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...................................16 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................16 
4.3 
General Guidelines for Other Investigative Sites ..................................................17 
4.4 
Registration Process for Other Investigative Sites.................................................17 
5. 
TREATMENT PLAN ........................................................................................................17 
5.1 
Treatment Regimen ................................................................................................17 
5.2 
Pre-Treatment Criteria ...........................................................................................18 
5.3 
Agent Administration.............................................................................................19 
5.4 
General Concomitant Medication and Supportive Care Guidelines ......................21 
5.5 
Criteria for Taking a Participant Off Protocol Therapy .........................................21 
5.6 
Duration of Follow Up ...........................................................................................22 
5.7 
Criteria for Taking a Participant Off Study ...........................................................22 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................23 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................27 
7.1 
Expected Toxicities ................................................................................................26 
7.2 
Adverse Event Characteristics ...............................................................................29 
7.3 
Expedited Adverse Event Reporting ......................................................................29 
7.4 
Expedited Reporting to Hospital Risk Management .............................................30 
7.5 
Routine Adverse Event Reporting .........................................................................30 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................31 
8.1 
Lenalidomide .........................................................................................................29 

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9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................33 
9.1 
Biomarker Studies ..................................................................................................33 
9.2 
Laboratory Correlative Studies ..............................................................................35 
10. 
STUDY CALENDAR .......................................................................................................35 
11. 
MEASUREMENT OF EFFECT........................................................................................38 
11.1 
Definitions.............................................................. Error! Bookmark not defined. 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................42 
12.1 
Data Reporting .......................................................................................................42 
12.2 
Data Safety Monitoring..........................................................................................42 
12.3 
Multicenter Guidelines...........................................................................................43 
12.4 
Collaborative Agreements Language .....................................................................43 
13. 
STATISTICAL CONSIDERATIONS...............................................................................43 
13.1 
Study Design/Endpoints.........................................................................................43 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................44 
13.3 
Stratification Factors ..............................................................................................44 
13.4 
Interim Monitoring Plan ........................................................................................44 
13.5 
Analysis of Primary Endpoints ..............................................................................44 
13.6 
Analysis of Secondary Endpoints ..........................................................................44 
13.7 
Reporting and Exclusions ......................................................................................45 
14. 
PUBLICATION PLAN .....................................................................................................45 
REFERENCES ..............................................................................................................................46 
APPENDIX A 
PERFORMANCE STATUS CRITERIA ..................................................48 
APPENDIX B 
NCI CTC Version 4.03 ..............................................................................46 
 

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1. OBJECTIVES 
 
 
This is an open-label phase II study to evaluate the efficacy and safety of lenalidomide in 
participants with relapsed/refractory ECD or LCH and in any patient with HS requiring systemic 
therapy. Patients will receive up to 12 cycles of lenalidomide with treatment occurring on days 1-
21 of each 28 day cycle. In cycle one patients will receive lenalidomide 10 mg daily due to the 
unknown incidence of tumor flare in this population (tumor flare has been observed in other 
diseases such as chronic lymphocytic leukemia).  Patients who tolerate the 10 mg dose well will 
be escalated to 25 mg for future cycles.  There will also be the possibility of dose reduction for 
patients who do not tolerate the 10 mg starting dose. Dosage thereafter will be adjusted based 
upon toxicity.  Lenalidomide is known to increase the risk of venous and arterial 
thromboembolic events.  Patients not already receiving systemic anticoagulation for other 
clinical indications will be required to take aspirin 325 mg daily for the duration of the protocol 
or for one month following treatment discontinuation, whichever is longer. 
 
Disease assessments will occur at baseline and then again at cycle 3 day 1, cycle 6 day 1, cycle 9 
day 1 and cycle 12 day 1 as well as every 3 months thereafter until month 24 from study 
initiation when disease assessment will occur every 6 months until month 36 from the initiation 
of treatment.  Disease assessments will consist initially of an MRI of the brain/pituitary and 
PET/CT (although a CT of the chest, abdomen and pelvis along with a bone scan is allowed if 
PET/CT is rejected by insurance).  Clinical documentation of skin lesions with photography is 
highly encouraged.  Measurement and documentation of all skin lesions is required even if 
photography is not performed.  A repeat MRI is not required beyond baseline if the MRI at 
baseline is normal and there is no clinical suspicion of CNS or pituitary involvement.  A bone 
marrow biopsy is only required if the patient has at least one cytopenia of grade 2 or greater at 
baseline or has evidence of bone marrow involvement on PET/CT.  The bone marrow biopsy 
only needs to be repeated if abnormal at baseline. 
 
Patients will be followed for 3 years (thirty-six months) from the initiation of therapy or until 
they initiate a new therapy for their underlying disease, whichever occurs first. 
 
 
1.1 
Study Design 
 
This is a single agent, phase II open-label study of single agent lenalidomide in patients with 
relapsed/refractory ECD, LCH, or HS. 
 
1.2 
Primary Objectives 
 
To estimate the response rate of patients with relapsed/refractory ECD, LCH, and HS with single 
agent lenalidomide. 
 
1.3 
Secondary Objectives 
 

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• To define the progression free survival (PFS) after treatment with lenalidomide 
• To define the overall survival (OS) after treatment with lenalidomide 
• To describe the safety profile of lenalidomide in LCH, ECD, and HS 
• To assess quantitative changes in urinary and plasma cell free DNA harboring the 
BRAF V600E mutation and correlate the presence or absence of the BRAF V600E 
mutation with response 
• To assess serial changes in TNF-alpha levels in patients treated with lenalidomide 
• To assess the mutational landscape of these diseases using Oncopanel 
 
 
 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
Langerhans Cell Histiocytosis (LCH) is a rare disease (1-10 cases per million) of 
unknown etiology distinguished by the clonal proliferation of pathologic histiocytes derived 
from bone marrow dendritic cells (1).  BRAF mutations have been identified in approximately 
50% of cases but the inciting event remains unclear (2). Clinical manifestations are related to the 
pattern of infiltration or organ involvement which is heterogeneous, can involve single or 
multiple organs, and can be associated with varying, often unpredictable outcomes ranging from 
spontaneous regression to multiple episodes of reactivation, long term debilitating sequelae, 
rapid progression, and death. 
 
The natural history of LCH is ill defined in adults. Studies of disease outcomes have 
been primarily undertaken in the pediatric population [3]. Assessments of adult 
patients with LCH have reported death events in 28-32% of patients with 4-6.5 year 
follow up [4,5]. There is no agreed standard of care in adults for either first-line or reactivation 
disease. As such, there is an unmet need for a well-tolerated, efficacious agent to treat adult 
LCH.  
 
 
A recently completed international adult study (LCH-A1) attempted to define and 
implement a uniform treatment approach in adults with respect to smoking cessation and 
the use of prednisone, vinblastine, and 6-mercaptopurine. Although final analysis of the 
data have not been completed at the present time, preliminary analysis indicates that 
many adult patients were unable to tolerate the standard pediatric multi-agent regimen of 
prednisone and vinblastine, due to neuropathy attributable to the latter agent. This was 
corroborated at Baylor College of Medicine where a study of vinblastine in LCH was terminated 
early when 5 or the first 7 adults treated developed Grade 3-4 toxicity at some point during 
therapy, and only 2/7 patients were able to complete the treatment course as prescribed 
by the protocol. Within a median of 6 months after starting therapy, 3/6 patients were in 
remission and 3/6 had active disease [6]. 
 
Reported disease reactivation rates after frontline therapy in adults vary widely. Multisystem 
LCH reactivation has been reported in 26-43% of patients [4, 7, 8] treated with a variety of 

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steroid and cytotoxic regimens.  Nucleoside analogues such as cladribine and cytarabine have 
proven to be effective in this setting but are not without issue. Cytarabine can have significant 
hematologic toxicity (9). Cladribine cannot be administered for longer than six months due to 
concerns about secondary myelodysplasia (MDS) while studies have suggested that outcomes 
are better when LCH is treated with a given agent for at least 12 months (10,11). Clofarabine has 
proven to be effective in patients with cladribine and cytarabine-resistant disease, but causes 
significant hematologic and hepatic toxicity as well as cause hand-foot syndrome (12).  The 
BRAF inhibitor vemurafenib can be effective in cases of LCH that harbor the BRAF mutation 
but there are significant concerns about the potential for secondary skin cancers (13).  
Monitoring of BRAF mutational burden in cell free DNA may be a useful marker for disease 
progession in this patient population, however (14). 
 
Histiocytic sarcoma is an aggressive neoplasm deriving from non-Langerhans dendritic cells.  
When localized, surgery and/or radiation can be effective.  However, disseminated HS responds 
poorly to chemotherapy and is typically fatal within six months (15).  Therefore, new therapies 
are required for all patients with multifocal HS and for patients of relapsed/refractory LCH.  
Erdheim-Chester disease (ECD) is a rare histiocyte disorder characterized most commonly by 
distal symmetric osteosclerosis of the long bones and retroperitoneal soft tissue infiltration.  
However, the disease also frequently affects periorbital soft tissue and can cause cardiac, 
neurologic, and pulmonary dysfunction.  The optimal therapy for ECD remains to be defined, 
though interferon is used frequently in the front-line setting (16). BRAF V600E mutations occur 
in approximately 50% of patients and can BRAF inhibitors such as vemurafenib are efficacious 
in the treatment of ECD but skin toxicity can be limiting (17). Recent evidence has implicated 
TNF-alpha in the pathogenesis of ECD (18). 
TNF-alpha is thought to promote the proliferation and survival of dendritic cells and histiocytes 
and thalidomide inhibits TNF-alpha production by affecting the gene promoter as well as other 
anti-cytokine effects (19).  Thalidomide has reported activity in histiocyte disorders, including 
HS and LCH. Thalidomide has several drawbacks, including the common side effects of 
neuropathy and somnolence.  Lenalidomide is potentially a more potent TNF-alpha inhibitor and 
does not cause neuropathy, making it potentially a more useful agent for prolonged 
administration.  There are case reports describing the activity of lenalidomide in a variety of 
histiocyte disorders (20, 21).  There is also emerging evidence on the important role of activation 
of RAS-PI3K-AKT signaling in histiocyte disorders and the AKT inhibitor afuresertib has been 
studied in LCH patients (22, 23). Lenalidomide potentially has inhibitory effects on AKT as well 
(24). We therefore planned a broader study to more systematically evaluate the efficacy of 
lenalidomide and describe the toxicity of lenalidomide in a population of patients with LCH and 
HS.  Given the putative mechanism of action we seek to correlate serum TNF-alpha levels with 
response.  In patients with a known BRAF V600E mutation we also wish to explore the 
possibility of using BRAF mutation burden assessed in urine and plasma cell free DNA as a 
biomarker of disease activity. 
  
 
 

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2.2 
Study Agent 
 
Lenalidomide is an immunomodulatory compound (IMiD) compound, a class of agents that have 
both immunomodulatory and anti-angiogenic properties.  Lenalidomide has been demonstrated 
to possess anti-angiogenic activity through inhibition of bFGF, VEGF and TNF-alpha induced 
endothelial cell migration, due at least in part to inhibition of Akt phosphorylation response to 
bFGF (20).  In addition, lenalidomide has a variety of immunomodulatory effects.  Lenalidomide 
stimulates T cell proliferation, and the production of IL-2, IL-10 and IFN-gamma, inhibits IL-1 
beta and IL-6 and modulates IL-12 production (25).0  Upregulation of T cell derived IL-2 
production is achieved at least in part through increased AP-1 activity (26). 0 
Although the exact antitumor mechanism of action of lenalidomide is unknown, a number of 
mechanisms are postulated to be responsible for lenalidomide’s activity.  The majority of this 
information has been derived from studied in multiple myeloma.  Lenalidomide increases T cell 
proliferation, which leads to an increase in IL-2 and IFN-gamma secretion.  The increased level 
of these circulating cytokines augment natural killer cell number and function, and enhance 
natural killer cell activity to yield an increase in multiple myeloma cell lysis.  In addition, 
lenalidomide has direct activity against multiple myeloma and induces apoptosis or G1growth 
arrest in multiple myeloma cell lines and in multiple myeloma cells of patients resistant to 
melphalan, doxorubicin and dexamethasone5.  
 
Indications and Usage: 
Lenalidomide is indicated for the treatment of patients with transfusion-dependent anemia due to 
Low- or Intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q 
cytogenetic abnormality with or without additional cytogenetic abnormalities.  Lenalidomide is 
approved in combination with dexamethasone for the treatment of patients with multiple 
myeloma. Lenalidomide is also approved in patients with mantle cell lymphoma whose disease 
has relapsed or progressed after two therapies, one of which included bortezomib 
Adverse Events 
The most frequently reported adverse events reported during clinical studies with lenalidomide in 
oncologic and non-oncologic indications, regardless of presumed relationship to study 
medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, 
nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, 
Upper respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, 
chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, 
generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural 
effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord 
compression, syncope, disease progression, death not specified and fractures. 

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Second New Cancers 
 
In clinical studies of newly diagnosed multiple myeloma, a higher number of second cancers 
were reported in patients treated with lenalidomide as induction therapy and/or bone marrow 
transplant  followed by lenalidomide.  This risk seems to be greatest when the duration of 
lenalidomide therapy exceeded 2 years.  
 
Complete and updated adverse events are available in the Investigational Drug Brochure and the 
IND Safety Letters. 
 
Lenalidomide Description 
Lenalidomide, a thalidomide analogue, is an immunomodulatory agent with anti-angiogenic 
properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -2H-isoindol-2-yl) piperidine-
2,6-dione and it has the following chemical structure:  
  
 
Chemical Structure of Lenalidomide 
 
N
N
H
O
O
O
NH2
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 259.3.  
Lenalidomide is an off-white to pale-yellow solid powder. It is soluble in organic solvent/water 
mixtures, and buffered aqueous solvents. Lenalidomide is more soluble in organic solvents and 
low pH solutions. Solubility was significantly lower in less acidic buffers, ranging from about 
0.4 to 0.5 mg/ml. Lenalidomide has an asymmetric carbon atom and can exist as the optically 
active forms S(-) and R(+), and is produced as a racemic mixture with a net optical rotation of 
zero. 
 
Clinical Pharmacology 
 
Mechanism of Action:  
The mechanism of action of lenalidomide remains to be fully characterized. Lenalidomide 
possesses immunomodulatory and antiangiogenic properties.  Lenalidomide inhibited the 
secretion of pro-inflammatory cytokines and increased the secretion of anti-inflammatory 
cytokines from peripheral blood mononuclear cells.  Lenalidomide inhibited cell proliferation 
with varying effectiveness (IC50s) in some but not all cell lines.  Of cell lines tested, 
lenalidomide was effective in inhibiting growth of Namalwa cells (a human B cell lymphoma 
cell line with a deletion of one chromosome 5) but was much less effective in inhibiting growth 

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of KG-1 cells (human myeloblastic cell line, also with a deletion of one chromosome 5) and 
other cell lines without chromosome 5 deletions.  Lenalidomide inhibited the expression of 
cyclooxygenase-2 (COX-2) but not COX-1 in vitro.   
Pharmacokinetics and Drug Metabolism 
Absorption: 
Lenalidomide, in healthy volunteers, is rapidly absorbed following oral administration with 
maximum plasma concentrations occurring between 0.625 and 1.5 hours post-dose. 
Co-administration with food does not alter the extent of absorption (AUC) but does reduce the 
maximal plasma concentration (Cmax) by 36%. The pharmacokinetic disposition of 
lenalidomide is linear. Cmax and AUC increase proportionately with increases in dose. Multiple 
dosing at the recommended dose-regimen does not result in drug accumulation. 
Pharmacokinetic analyses were performed on 15 multiple myeloma patients treated in the phase I 
studies.  Absorption was found to be rapid on both Day 1 and Day 28 with time to maximum 
blood levels ranging from 0.7 to 2.0 hours at all dose levels (5mg, 10mg, 25mg, and 50mg).  No 
plasma accumulation was observed with multiple daily dosing.  Plasma lenalidomide declined in 
a monophasic manner with elimination half-life ranging from 2.8 to 6.1 hours on both Day 1 and 
28 at all 4 doses.  Peak and overall plasma concentrations were dose proportional over the dosing 
range of 5mg to 50mg.  Exposure (AUC) in multiple myeloma patients is 57% higher than in 
healthy male volunteers.  
 
Pharmacokinetic Parameters 
Distribution 
In vitro (14C)-lenalidomide binding to plasma proteins is approximately 30%. 
 
Metabolism and Excretion 
The metabolic profile of lenalidomide in humans has not been studied. In healthy volunteers, 
approximately two-thirds of lenalidomide is eliminated unchanged through urinary excretion. 
The process exceeds the glomerular filtration rate and therefore is partially or entirely active.  
Half-life of elimination is approximately 3 hours.  
 
Supplier 
Celgene Corporation will supply lenalidomide (Revlimid®) to study participants at no charge 
through Celgene’s Revlimid Risk Evaluation and Mitigation Strategy™ (REMS) (formerly 
known as RevAssist® Program).   
 
 
2.3 
Rationale 
There have been a number of case reports indicating responses with thalidomide and to a lesser 
extent lenalidomide in LCH.  However, these agents have not been systematically studied and 
the mechanism of action remains unclear 

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2.4 
Correlative Studies Background 
 
Preclinical data suggest that polymorphisms of the TNF-α promoter occur in LCH patients and 
that TNF-α levels are elevated in patients with LCH.  We will therefore measure baseline TNF-α 
levels and obtain serial measurements every 2 months for one year or until the patient is removed 
from protocol (whichever is sooner).  This assay will be performed by a reference laboratory 
(Mayo Clinic). 
 
V600E mutations have been described in up to 50% of patients with ECD and LCH.  A 
commercially available cell free DNA urine assay now exists.  In a study of ECD patients with 
available archival tissue, the result of BRAF mutation analysis was concordant with plasma and 
urine cfDNA results in all 3 patients (100% agreement, kappa 1.00). In all 6 patients studied on 
this protocol, BRAF mutation analysis of plasma and urine cfDNA was concordant in 5 of 6 
patients (83% agreement, kappa 0.67). We therefore will check baseline urine cell free DNA for 
BRAF V600E mutations and perform tissue testing for the V600E mutation whenever feasible 
(either by immunohistochemistry or molecular analysis depending on tissue availability).  In 
addition, we will perform droplet digital PCR assays for BRAF mutations through the blood 
biomarker lab of the Belfer Institute. The Belfer group has developed a novel assay utilizing droplet 
digital PCR (ddPCR) technology to perform noninvasive and quantitative genotyping on cfDNA collected 
from plasma samples. This assay utilizes ddPCR to emulsify collected cfDNA from patient plasma into 
approximately 20 000 droplets that undergo individualized PCR reactions and analysis allowing for the 
quantification of mutant versus wildtype copy number [Figure 1]. Previously published work by this 
group (Oxnard et al, CCR, 2014) has demonstrated the technical feasibility and accuracy of this plasma 
genotyping assay for detecting BRAF mutations in NSCLC patients. This assay is both highly sensitive 
and quantitative which creates unique advantages over previous plasma genotyping methods. In addition, 
the quantitative nature of this assay combined with quality control methods can minimize the false 
positive results that have plagued earlier assays. The quantitative nature of this assay may also be 
exploited to allow prediction of early treatment failure as well as the development of treatment resistance. 
 
 

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Patients who have a detectable BRAF V600E mutation in the urine and/or plasma at baseline 
will have serial measurements every 2 months for 12 months or until protocol discontinuation 
(whichever occurs sooner). Note, if patients have a positive urine or serum BRAF assay both 
tests will repeated at all of the aforementioned timepoints. The results of urine and ddPCR-based 
plasma genotyping will be compared to tissue genotyping for BRAF V600E. 
 
In a descriptive fashion we will investigate whether serum TNF-α levels, ddPCR for BRAF 
and/or urine cell free DNA harboring the BRAF V600E serves as a biomarker for response.   
 
 
3. PARTICIPANT SELECTION 
 
Patients aged 18 or older with histologically confirmed Langerhans cell histiocytosis, Erdheim-
Chester disease, or histiocytic sarcoma will be eligible.  Confirmation of pathology at Brigham 
and Women’s Hospital is preferred but patients may be enrolled based upon outside review of 
pathology if in the opinion of the principle investigator the pathology is consistent with LCH, 
ECD, or HS and if a delay in treatment due to review of pathology at BWH would be detrimental 
to the patient.  Tissue will be requested for Oncopanel testing on all patients but this is not an 
eligibility criteria.  Patients will be consented to DFCI protocol 11-104 for Oncopanel testing.  
Patients who decline participation in this companion protocol will not have material sent for 
Oncopanel. 
 
Patients with LCH must require systemic treatment according to the Histiocyte Society LCH 
Evaluation and Treatment Guidelines (2009).  There is no limit on the number of prior therapies 
received so long as the patient otherwise meets eligibility criteria. Patients with HS that cannot 
be surgically excised and/or encompassed in a radiation field will be eligible even if they have 
not received prior systemic therapy.   
 
Laboratory tests required for eligibility must be completed within 14 days of registration and 
radiographic tests must be completed within 30 days of registration. 
 
Figure 1: Plasma genotyping using droplet digital PCR (ddPCR). Cell free DNA (cfDNA) is extracted 
from a plasma specimen and emulsified with oil into ~20,000 droplets, each containing approximately 
0-1 molecules of target DNA. PCR is performed to endpoint in each droplet. These droplets are run 
through a flow cytometer, where droplets containing mutant and wildtype DNA emit different colored 
signals. The count of these signals allows quantification of allelic prevalence.  

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Since the response criteria differ for histiocyte disorders than for other malignancies, 
radiographically detectable disease is required but does not need to be bidimensionally 
measurable as in Cheson criteria.   
 
 
3.1 
Eligibility Criteria  
 
3.1.1 Patients must have histologically or cytologically confirmed LCH, ECD or HS.  
Confirmation of outside pathology at BWH will be performed but is not mandatory prior 
to study enrollment (see section 3).  
 
 
3.1.2 Detectable disease by at least one of the following modalities: CT, PET, bone scan, or 
MRI.  
 
3.1.3 Patients with LCH must require systemic therapy according to the Histiocyte Society 
LCH Evaluation and Treatment Guidelines (HS 2009) 
Or 
Patients with HS requiring systemic treatment as defined by disease that cannot be 
surgically resected and/or encompassed in a single radiation field.   
 
 
 
 
 
 
 
3.1.4 Age  18 years or older.   
 
3.1.5 ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A) 
 
3.1.6 Participants must have normal organ and marrow function as defined below: 
 
− 
absolute neutrophil count 
≥1,000/mcL 
− 
platelets 
≥100,000/mcL 
− 
total bilirubin 
within 1.5 times normal institutional limits 
− 
AST(SGOT)/ALT(SGPT) 
≤3 × institutional upper limit of normal 
− 
creatinine 
within 2 times normal institutional limits 
OR 
− 
creatinine clearance 
≥30 mL/min/1.73 m2. Note, dose adjustments are 
required for CrCl > 30 mL/min but < 60 ml/min. 
 
3.1.7 Able to take aspirin 81 mg daily as prophylactic anticoagulation if not on warfarin, low 
molecular weight heparin or oral factor Xa inhibitor. Patients intolerant to ASA may use 
warfarin or low molecular weight heparin at doses designed to treat deep venous 
thrombosis. 
 
3.1.8 All study participants must be registered into the mandatory Revlimid REMS® program, 
and be willing and able to comply with the requirements of the REMS® program.  
 

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3.1.9    Women of child-bearing potential and men must agree to use adequate contraception 
 
 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
 
 
duration of study participation. 
 
3.2.0     Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 Prior chemotherapy or radiation within 2 weeks (6 weeks for nitrosoureas or mitomycin 
C) prior to entering the study or those who have not recovered from adverse events due to 
agents administered more than 2 weeks earlier.  
 
3.2.2 Participants who are receiving any other investigational agents. 
 
3.2.3 Prior treatment with lenalidomide.  Patients previously treated with thalidomide who 
discontinued treatment for reasons aside from an adverse reaction to thalidomide are 
permitted. 
3.2.4 History of another invasive malignancy unless treated with curative intent 5 years or 
more prior to study entry.  Patients with localized carcinoma of the cervix, non-
melanoma skin cancer, or early stage prostate cancer requiring observation only are 
eligible regardless of timing of diagnosis.   
 
3.2.5 Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements. 
 
3.2.6 Pregnant women are excluded from this study because lenalidomide has known 
teratogenic effects.  Because there is an unknown but potential risk for adverse events in 
nursing infants secondary to treatment of the mother with lenalidomide, breastfeeding 
should be discontinued if the mother is treated with lenalidomide. 
3.2.7 Known active hepatitis B (HBV) or hepatitis C (HCV) infection.  Patients who are 
positive only for HBV surface antibody as a result of prior vaccination are eligible.  
Patients with a positive HBV core antibody but undetectable HBV viral load are eligible. 
 
3.2.8 HIV-positive participants on combination antiretroviral therapy are ineligible because of 
the potential for pharmacokinetic interactions with lenalidomide. In addition, these 
participants are at increased risk of lethal infections when treated with marrow-
suppressive therapy.  Appropriate studies will be undertaken in participants receiving 
combination antiretroviral therapy when indicated. 
 
3.2.9 Concomitant corticosteroids unless patient has been on a stable dose of prednisone (or 
equivalent) of <  10 mg daily for at least 2 weeks prior to first dose of study drug. 
 
3.2.10 Inability to swallow pills. 
 

DF/HCC Protocol #: 15-197 
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16 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants with the DF/HCC Quality Assurance Office for 
Clinical Trials (QACT) central registration system. Registrations must occur prior to the 
initiation of protocol therapy. Any participant not registered to the protocol before protocol 
therapy begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
QACT protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Notify the QACT Registrar of registration cancellations as soon as 
possible.  
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
The QACT registration staff is accessible on Monday through Friday, from 8:00 AM to 5:00 PM 
Eastern Standard Time. In emergency situations when a participant must begin protocol therapy 
during off-hours or holidays, call the QACT registration line at 617-632-3761 and follow the 
instructions for registering participants after hours. 
 
The registration procedures are as follows: 
 
• Obtain written informed consent from the participant prior to the performance of any 
protocol specific procedures or assessments.  
 
• Complete the QACT protocol-specific eligibility checklist using the eligibility 
assessment documented in the participant’s medical record and/or research chart. To be 
eligible for registration to the protocol, the participant must meet all inclusion and 
exclusion criterion as described in the protocol and reflected on the eligibility 
checklist. 
 
Reminder: Confirm eligibility for ancillary studies at the same time as eligibility for a 
treatment protocol. Registration to both treatment and ancillary protocols will not be 
completed if eligibility requirements are not met for all studies.  

DF/HCC Protocol #: 15-197 
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17 
 
• Fax the eligibility checklist(s) and all pages of the consent form(s) to the QACT at 617-
632-2295. For Phase I protocols, attach participant dose level assignment confirmation 
from the sponsor. 
 
• The QACT Registrar will (a) review the eligibility checklist, (b) register the participant 
on the protocol, and (c) randomize the participant when applicable. 
 
• An email confirmation of the registration and/or randomization will be sent to the Overall 
PI, study coordinator(s) from the Lead Site, treating investigator and registering person 
immediately following the registration and/or randomization. 
 
4.3 
General Guidelines for Other Investigative Sites 
 
N/A 
 
4.4 
Registration Process for Other Investigative Sites 
 
N/A 
 
 
5. TREATMENT PLAN 
 
Treatment will be administered on an outpatient basis. Expected toxicities and potential risks as 
well as dose modifications for lenalidomide are described in Section 6 (Expected Toxicities and 
Dosing Delays/Dose Modification). No investigational or commercial agents or therapies other 
than those described below may be administered with the intent to treat the participant’s 
malignancy. 
 
5.1 
Treatment Regimen 
 
For cycle 1, lenalidomide will be administered at a dose of 10 mg daily on days 1-21 of a 28 day 
cycle.  Patients will be assessed for toxicity between days 22 and 28.  If no grade 3 or greater 
toxicity has occurred the dose will be escalated to 25 mg daily on days 1-21 of a day 28 cycle 
(patients with a baseline CrCl of 30 to <  60 will stay at the 10 mg dose). Patients with a baseline 
CrCl of 30 to < 60 can be dose escalated to 25 mg if there is no grade 3 or greater toxicity at 
week 8 visit if CrCl has improved to >60.  No dose escalation is permitted past week 8. Once a 
dose reduction has occurred the dose will not be re-escalated unless it is a toxicity due to 
neutropenia in which case the dose can be escalated if there is no recurrent neutropenia with 
growth factor support for two continuous cycles. Treatment will be administered on an outpatient 
basis.  The maximum number of cycles is 12 (inclusive of cycle 1 and/or 2 dosing at 10 mg).  
Reported adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the participant's 
malignancy. 
 

DF/HCC Protocol #: 15-197 
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18 
 
 
 
Lenalidomide dosing 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Lenalidomide 
None 
 
10 mg 
tablet (cycle 
1)* 
 
PO at 
approximately 
the same time 
each day(+/- 2 
hours) 
Days 1-21  
28 days  
 
 
 
 
Lenalidomide 
None 
25 mg 
tablet  
(cycle 2 and 
subsequent)* 
PO at 
approximately 
the same time 
each day 
Days 1-21  
*Reference treatment plan and schema for dose instructions for patients with baseline 
CrCl of 30 to < 60 
 
 
 
The participant will be requested to maintain a medication diary of each dose of medication.  The 
medication diary will be returned to clinic staff at the end of each cycle. 
 
 
5.2 
Pre-Treatment Criteria 
 
 
5.2.1 Cycle 1, Day 1 
 
Participants must meet all of the inclusion criteria, have none of the exclusion criteria, and 
must be registered to the protocol prior to initiating therapy. 
 
The following studies and evaluations should be carefully reviewed to determine the patient’s 
suitability to initiate study treatment. 
1. Diagnosis of LCH, ECD, or HS is established by disease evaluations and laboratory 
studies and confirmed histologically 
2. Complete physical examination. 
3. Medical history: Detailed documentation of disease and treatment history with 
outcomes. 
4. Performance status ≥60%  
5. Concurrent medical conditions.   
6. Hematology: CBC with automated differential. 

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19 
7. Serum chemistries: Albumin, alkaline phosphates, total bilirubin, bicarbonate, 
BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium.  
8. Baseline adverse event assessment from time of signing informed consent. 
 
5.2.2 Subsequent Cycles  
A new course of treatment may begin on the scheduled Day 1 of a new cycle if: 
• The ANC is ≥ 1000/mm³;  
• The platelet count is ≥75,000 /mm³   
• Any drug-related rash that may have occurred has resolved to ≤ grade 1 severity 
• Any other drug-related adverse events that may have occurred have resolved to ≤ 
grade 2 severity.  
If these conditions are not met on Day 1 of a new cycle, the subject will be evaluated 
weekly and a new cycle of treatment will not be initiated until the toxicity has resolved as 
described above.  If a given toxicity has not resolved to an acceptable level within 28 
days of the planned initiation of a cycle, the participant will be permanently removed 
from treatment. 
 
5.3 
Agent Administration 
 
In general, there is a +/- 3 day window for lenalidomide administration to allow for scheduling 
related issues. 
 
Lenalidomide 
Celgene Corporation will supply lenalidomide to study participants at no charge through 
Celgene’s Revlimid Risk Evaluation and Mitigation Strategy™ (REMS) (formerly known as 
RevAssist® Program).  Lenalidomide will be supplied as capsules for oral administration and 
will be taken on days 1-21 of a 28 day cycle.  The first cycle will be dosed at 10 mg with a dose 
escalation to 25 mg at cycle 2 in the absence of toxicity.  If the creatinine clearance is 30 to < 60 
then the starting dose will be still be 10 mg at cycle 2. In the absence of grade 3 or greater 
toxicity during cycle 1 the dose will stay at 10 mg during cycle 2 in this patient population.  In 
the absence of grade 3 or greater toxicity at the week 8 assessment the dose can be escalated to 
25 mg daily on days 1-21 of a 28 day cycle in patients whose baseline CrCl was 30 to < 60 and 
in whom CrCl subsequently improves to >60.  No dose escalation if permitted after week 8. The 
maximum number of cycles is 12 inclusive of the dose escalation cycle(s). Lenalidomide will be 
taken at approximately the same time every day (+/- 2 hours) and there are no dietary 
considerations. Vomited doses will not be made-up.  Missed or forgotten doses can be made up if 
taken within twelve hours of the scheduled administration on the same calendar day.  For 
example, if the patient is scheduled to take lenalidomide at 8 AM a missed dose can be made up 
prior to 8 PM on the day of treatment.  However, if the patient was scheduled to take a dose at 4 
PM and that dose is missed, the dose must be taken before midnight of the same calendar day.  If 

DF/HCC Protocol #: 15-197 
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20 
these conditions cannot be fulfilled the dose should be skipped. 
 
Packaging 
Lenalidomide will be shipped directly to patients from a specialty pharmacy.   Bottles will 
contain a sufficient number of capsules for one cycle of dosing.   Lenalidomide supplies are 
dispensed in individual bottles of capsules.  Each bottle will identify the contents as study 
medication.  In addition, the label will bear Celgene’s name, quantity contained and the standard 
caution statement as follows:  “Caution: New drug - Limited by Federal law to investigational 
use.” The study drug label must be clearly visible.  Additional labels must not cover the Celgene 
label.  
 
Return 
Patients should return all unused study medication to the study site at each applicable study visit. 
 
AccountabilityThe disposition of all Lenalidomide study drug should be documented from the 
time of receipt at the site through patient dispensing and return. 
 
The Investigator and/or the responsible site personnel must maintain accurate records of the 
receipt of all study drug shipped by Celgene Corporation or its designee. Study drug 
accountability records must also be maintained that include the patient number to whom the 
study drug was dispensed, the date and quantity of the study drug dispensed. 
 
The study drug supply should be retrieved from patients at the end of each dosing cycle. The 
quantity of study drug and the date returned by the patient should be recorded in the study drug 
accountability records. 
 
Remaining unused study drug supply will be destroyed at the clinical site, standard institutional 
policy should be followed. Records documenting the date of study drug destruction, relevant lot 
numbers, and destroyed should be maintained,  
 
Storage 
Lenalidomide should be stored at room temperature away from direct sunlight and protected 
from excessive heat and cold.     
 
Unused study drug supplies 
Patients will be instructed to return empty bottles or unused capsules to the clinic site. Celgene 
will instruct the Investigator (or designee) on the return or destruction of unused study drug.  If 
any study drug is lost or damaged, its disposition should be documented in the source 
documents.  Study drug supplies will be retained at the clinical site pending instructions for 
disposition by Celgene.   
 
Lenalidomide should not be handled by females of child-bearing potential unless wearing gloves.  
 
 

DF/HCC Protocol #: 15-197 
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21 
5.3.1 CTEP and/or CIP IND Agent(s), or other IND agent 
N/A 
 
5.3.2 Other Agent(s): N/A 
 
5.3.3 Other Modality(ies) or Procedures 
 
 N/A 
 
 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
Anti-emetics will be prescribed per physician and patient preference with the exception that 
steroids should not be utilized as an anti-emetic.  If patients require glucocorticoids for any 
reason during treatment they should be removed from the protocol unless the expected duration 
of treatment is less than 7 days and the glucocorticoids will not be given on a recurring basis.  
Erythroid growth factors are not permitted on protocol due to concerns about augmenting 
clotting risk.  Filgrastim and pegfilgrastim are not permitted during cycle 1 but are permitted 
during the second and subsequent cycles as outlined in section 6 on dose modification (note, 
filgrastim and pegfilgrastim are not allowed during the first 8 weeks in patients with a CrCl of 30 
to < 60). 
 
Because there is a potential for interaction of lenalidomide with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must capture the 
concurrent use of all other drugs, over-the-counter medications, or alternative therapies.   
 
Lenalidomide is known to increase the risk of arterial and venous thrombosis.  Patients not 
already on systemic anticoagulation (warfarin, low molecular weight heparin, or equivalent) for 
other medical reasons are required to take aspirin 81 mg daily for the duration of the study. 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue for 
12 cycles or until one of the following criteria applies: 
 
• 
Disease progression 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Unacceptable adverse event(s) 
 
• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
 

DF/HCC Protocol #: 15-197 
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22 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
• 
Recurrent toxicity (see section 6) 
 
• 
Patient becomes pregnant or cannot comply with birth control requirements. 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant is removed from 
protocol therapy. This form can be found on the QACT website or obtained from the QACT 
registration staff. 
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, Eric Jacobsen, MD at 617-632-6633 or 617-632-3000 (pager ID 41475).  
 
 
5.6 
Duration of Follow Up 
 
Participants will be followed for 3 years from the initiation of treatment, until subsequent therapy 
or until removal from study or death, whichever occurs first. Participants removed from protocol 
therapy for unacceptable adverse event(s) will be followed until resolution or stabilization of the 
adverse event. 
 
5.7 
Criteria for Taking a Participant Off Study 
 
 
Participants will be removed from study when any of the following criteria apply: 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Initiation of subsequent therapy  
• Death 
• Completion of all study procedures 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
A QACT Treatment Ended/Off Study Form will be filled out when a participant comes off study. 
This form can be found on the QACT website or obtained from the QACT registration staff.  
 
 

DF/HCC Protocol #: 15-197 
Protocol Version Date: 15-MAY-2015 
 
23 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated in the following table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 will be utilized for dose delays and dose modifications 
and version 3.0 should be used for tumor flare. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
Note that tumor flare reaction is managed differently from other AEs as outlined in Table 4. 
Lenalidomide should be held for any grade 3 or higher toxicity except in the incidence of a 
blistering skin rash, in which case lenalidomide should be permanently discontinued though 
patients will be followed for resolution of toxicity and for survival. In the event of a blistering 
skin rash the patient should have an urgent dermatology referral if grade 1 or 2 and should be 
hospitalized if grade 3 or 4. If a patient develops venous thromboembolism and/or pulmonary 
embolism while on therapeutic anticoagulation lenalidomide treatment should be permanently 
discontinued regardless of grade unless anticoagulation dosing was low (e.g., INR or anti-factor 
Xa was not in the generally accepted therapeutic range). Patients experiencing a venous 
thromboembolic event while on aspirin alone may stay on protocol at the discretion of the 
treating physician as long as the patient is subsequently on systemic anticoagulation with 
warfarin, low molecular weight heparin or equivalent for the duration of the study and as 
clinically indicated thereafter by the nature and extent of the thrombotic event.  Patients 
experiencing an arterial thromboembolic event will be removed from study regardless of the 
anticoagulation status at the time of the event.  
 
Per table 2, participants may be dose reduced if toxicities occur during cycle 1 at the starting 
dose of 10 mg daily.  No more than 2 dose reductions will be permitted.  If the participant cannot 
tolerate therapy after 2 dose reductions they should be permanently removed from the protocol.  
 
Dose reductions for cycle 2 and subsequent cycles that involve a dose of 25 mg daily are 
outlined in table 1.  If a participant is receiving the 25 mg dose, a total of 3 dose reductions will 
be allowed.  If the participant cannot tolerate treatment despite 3 dose reductions then the 
participant should be permanently removed from the protocol. Once a dose reduction occurs 
patients will not be dose escalated unless the dose reduction is a result of neutropenia and no 
recurrent neutropenia occurs with filgrastim or pegfilgrastim support for 2 continuous cycles. 
 
Regardless of dosing level, held doses will not be made-up.  Missed doses or forgotten doses will 
not be made up unless lenalidomide is taken within 12 hours of the scheduled time of 
administration on the same calendar day of the missed or forgotten dose.  Vomited doses will not 
be made up. 
 
 
 
Dose Reduction Steps for toxicity aside from TFR. 
 

DF/HCC Protocol #: 15-197 
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24 
Table 1: LENALIDOMIDE Dose Reduction Steps when dose is 25 
mg 
 
Dose at Prior Cycle 
25 mg daily on Days 1-21 every 28 
days 
 
Dose Level – 1 
20 mg daily on Days 1-21 every 28 
days 
Dose Level – 2 
15 mg daily on Days 1-21 every 28 
days 
Dose Level – 3 
10 mg daily on Days 1-21 every 28 
days 
 
 
Table 2: LENALIDOMIDE Dose Reduction Steps when dose is 10 
mg  
 
Dose at Prior Cycle 
10  mg daily on Days 1-21 every 28 
days  
Dose Level – 1 
5 mg daily on Days 1-21 every 28 days  
Dose Level – 2 
2.5 mg daily on Days 1-21 every 28 
days  
 
There are no dose reductions below dose level -2 if dose reductions are necessary at the 10 mg 
starting dose or dose level -3 once the patient has been dose escalated to 25 mg. Patients who 
cannot tolerate lenalidomide at these dose reductions will discontinue treatment. 

DF/HCC Protocol #: 15-197 
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25 
Instructions for dose modifications or interruption during a cycle 
Table 3: Dose Modifications 
NCI CTC Toxicity 
Grade 
Dose Modification Instructions  
 
Grade 3 neutropenia 
associated with fever 
(temperature ≥ 38.5º 
C) or Grade 4 
neutropenia 
• Hold (interrupt) lenalidomide dose. 
• Follow CBC weekly. 
• If neutropenia has resolved to ≤ grade 2 prior to Day 21 
of the current cycle, restart lenalidomide at next lower 
dose level and continue through the scheduled Day 21 of 
the current cycle.  Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at 
the start of the next cycle.  Omitted doses are not made 
up.  If neutropenia is the only toxicity for which a dose 
reduction is required, G-CSF may be used and the 
lenalidomide dose maintained. 
Thrombocytopenia 
≥Grade 3 (platelet 
count < 50,000/mm³) 
• Hold (interrupt) lenalidomide dose. 
• Follow CBC weekly. 
• If thrombocytopenia resolves to ≤ grade 2 prior to Day 21 
of the current cycle, restart lenalidomide at next lower 
dose level and continue through the scheduled Day 21 of 
the current cycle.  Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at 
the start of the next cycle.  Omitted doses are not made 
up. 
Platelet count < 
50,000/mm³ 
• Hold prophylactic anti-coagulation, if applicable. 
• Restart prophylactic anti-coagulation when platelet count 
is ≥ 50,000/mm³. 
Non-blistering rash 
 
Grade 3 
 
 
 
 
             Grade 4 
 
• If Grade 3, hold (interrupt) lenalidomide dose.  Follow 
weekly. 
• If the toxicity resolves to ≤ grade 1 prior to Day 21 of the 
current cycle, restart lenalidomide at next lower dose 
level and continue through the scheduled Day 21 of the 
current cycle.  Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at 
the start of the next cycle.  Omitted doses are not made 
up. 
 
 
• If Grade 4, discontinue lenalidomide.  Remove patient 
from study. 

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26 
Table 3: Dose Modifications 
NCI CTC Toxicity 
Grade 
Dose Modification Instructions  
 
Desquamating 
(blistering) rash- any 
Grade  
• Discontinue lenalidomide.  Remove patient from study. 
Immediate referral to dermatology and/or hospitalization 
if deemed clinically appropriate. 
Neuropathy 
 
Grade 3 
 
 
 
 
Grade 4 
 
• If Grade 3, hold (interrupt) lenalidomide dose.  Follow at 
least weekly. 
• If the toxicity resolves to ≤ grade 1 prior to Day 21 of the 
current cycle, restart lenalidomide at next lower dose 
level and continue through the scheduled Day 21 of the 
current cycle.  Otherwise, omit for remainder of cycle 
and reduce the dose of lenalidomide by 1 dose level at 
the start of the next cycle.  Omitted doses are not made 
up. 
 
• If Grade 4, discontinue lenalidomide.  Remove patient 
from study. 
Venous 
thrombosis/embolism 
≥ Grade 3 
• Hold (interrupt) lenalidomide and start therapeutic 
anticoagulation, if appropriate. If VTE occurs while 
patient is on therapeutic anti-coagulation (not counting 
aspirin) permanently discontinue treatment. 
• Restart lenalidomide at investigator’s discretion 
(maintain dose level). 
• See Anticoagulation Consideration (Section 5.6.1.2) 
Hyperthyroidism or 
hypothyroidism 
• Omit lenalidomide for remainder of cycle, evaluate 
etiology, and initiate appropriate therapy.  
• See Instructions for Initiation of a New Cycle and reduce 
the dose of lenalidomide by 1 dose level. 
Other non-
hematologic toxicity 
≥ Grade 3 
• Hold (interrupt) lenalidomide dose.  Follow at least 
weekly. 
• If the toxicity resolves to ≤ grade 2 prior to Day 21 of the 
current cycle, restart lenalidomide and continue through 
the scheduled Day 21 of the current cycle.  Otherwise, 
omit for remainder of cycle.  Omitted doses are not made 
up.  For toxicity attributed to lenalidomide, reduce the 
lenalidomide dose by 1 dose level when restarting 
lenalidomide. 
 

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27 
Table 4. Tumor Flare Reaction Treatment (TFR) 
Treatment of TFR is up to the discretion of the investigator, depending upon the severity 
and clinical situation. It is suggested that Grades 1 and 2 TFR be treated with NSAIDs 
(i.e., ibuprofen 400 to 600 mg orally every 4 to 6 hours as needed), corticosteroids, 
and/or narcotic analgesics for pain management.  
In mild to moderate (Grades 1 and 2) cases, it is suggested that study drug be 
continued along with symptomatic treatment as above. In more severe cases, study 
drug should be interrupted. 
 
Tumor Flare Reaction 
(TFR)a 
Grades 1-2 
 
• 
Continue lenalidomide, maintain dose level 
• 
At the investigator’s discretion may initiate therapy with 
NSAIDs, limited duration corticosteroids, and/or narcotics 
Grades 3-4 
• 
Hold (interrupt dose) and initiate therapy with NSAIDs, 
corticosteroids, and/or narcotics 
• 
When symptoms resolve to ≤ Grade 1, restart at same 
dose level for the rest of the Cycle 
 
 
Treatment of Overdose 
In the case of overdose, clinic staff should be notified immediately and supportive care is to be 
given as indicated. Patients should be informed to contact their doctor immediately if they have 
taken an overdose and should stop taking lenalidomide.  There is no known antidote for 
lenalidomide. 
 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. 
 
 
 
7.1 
Adverse Event List(s) for lenalidomide 
 
The most frequently reported adverse events reported during clinical studies with lenalidomide in 
oncologic and non-oncologic indications, regardless of presumed relationship to study 
medication include: anemia, neutropenia, thrombocytopenia and pancytopenia, abdominal pain, 
nausea, vomiting and diarrhea, dehydration, rash, itching, infections, sepsis, pneumonia, UTI, 
Upper respiratory infection, atrial fibrillation, congestive heart failure, myocardial infarction, 

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chest pain, weakness, hypotension, hypercalcemia, hyperglycemia, back pain, bone pain, 
generalized pain, dizziness, mental status changes, syncope, renal failure, dyspnea, pleural 
effusion, pulmonary embolism, deep vein thrombosis, CVA, convulsions, dizziness, spinal cord 
compression, syncope, disease progression, death not specified and fractures. 
 
Second New Cancers 
In clinical studies of newly diagnosed multiple myeloma, a higher number of second cancers 
were reported in patients treated with lenalidomide as induction therapy (treatment for several 
cycles to reduce number of cancer cells) and/or bone marrow transplant  followed by 
lenalidomide  for a long period of time compared to patients treated with induction therapy 
and/or bone marrow transplant then placebo (a capsule containing no lenalidomide). Patients 
should make their doctors aware of their medical history and any concerns they may have 
regarding their own increased risk of other cancers.  
Tumor Flare 
Tumor flare assessments are conducted in Cycle 1 on Days 1, 8, and 15 (±1 day), and 
when clinically indicated thereafter. Tumor flare reaction (TFR) is defined in the 
NCI-CTCAE version 3 as a constellation of signs and symptoms of tumor pain, 
inflammation of visible tumor, hypercalcemia, diffuse bone pain, and other electrolyte 
disturbances in direct relation to initiation of therapy (Cancer therapy evaluation 
program, 2003).  
Tumor flare reaction is an adverse effect of lenalidomide previously reported in subjects 
with CLL (27). In clinical studies of lenalidomide in subjects with non-Hodgkin lymphoma 
(NHL) (28), TFR has also been reported at a lower rate in NHL patients than in CLL 
patients (29,30).  The onset of TFR has been as early as within a few hours after the 
first dose of lenalidomide and occurs within the first 2 to 3 weeks of the first Cycle in the 
vast majority of TFR cases. TFR subsides over time and usually resolves in 1 to 2 
weeks with or without intervention (28). 
 
Pregnancy 
Lenalidomide is known to be teratogenic thus women of child-bearing potential and men must 
agree to use adequate contraception as outlined in the REMS® program.  Pregnancies and 
suspected pregnancies (including a positive pregnancy test regardless of age or disease state) of a 
female subject occurring while the subject is on lenalidomide, or within  28 days of the subject’s 
last dose of lenalidomide, are considered immediately reportable events. Lenalidomide  is to be 
discontinued immediately. The pregnancy, suspected pregnancy, or positive pregnancy test must 
be reported to Celgene Drug Safety immediately by facsimile or email using the Pregnancy 
Initial Report Form. The female subject should be referred to an obstetrician-gynecologist, 
preferably one experienced in reproductive toxicity for further evaluation and counseling. The 
Investigator will follow the female subject until completion of the pregnancy, and must notify 
Celgene Drug Safety immediately about the outcome of the pregnancy (either normal or 
abnormal outcome) using the Pregnancy Follow-up Report Form.  If the outcome of the 

DF/HCC Protocol #: 15-197 
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29 
pregnancy was abnormal (e.g., spontaneous or therapeutic abortion), the Investigator should 
report the abnormal outcome as an AE. If the abnormal outcome meets any of the serious 
criteria, it must be reported as an SAE to Celgene Drug Safety immediately by facsimile, or other 
appropriate method, within 24 hours of the Investigator’s knowledge of the event using the SAE 
Report Form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard to 
causality, as SAEs. In addition, any infant death after 28 days that the Investigator suspects is 
related to the in utero exposure to the IP should also be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, within 24 hours of the Investigator’s 
knowledge of the event using the SAE Report Form.  
 
Complete and updated adverse events are available in the Investigational Drug Brochure and the 
IND Safety Letters 
 
 
7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Expedited Adverse Event Reporting  
 

DF/HCC Protocol #: 15-197 
Protocol Version Date: 15-MAY-2015 
 
30 
7.3.1 Investigators must report to the Overall PI any serious adverse event (SAE) that occurs 
after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form.  
 
Expedited Reporting by Investigator to Celgene 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene 
in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 
24 hours of being aware of the event.  The written report must be completed and supplied 
to Celgene by facsimile within 24 hours/1 business day.  The initial report must be as 
complete as possible, including an assessment of the causal relationship between the 
event and the investigational product(s).  Information not available at the time of the 
initial report (e.g., an end date for the adverse event or laboratory values received after 
the report) must be documented on a follow-up report.  A final report to document 
resolution of the SAE is required.  The Celgene tracking number (RV-CL-OTHER-PI-
004617) and the institutional protocol number should be included on SAE reports (or on 
the fax cover letter) sent to Celgene.  A copy of the fax transmission confirmation of the 
SAE report to Celgene should be attached to the SAE and retained with the patient 
records. 
 
Celgene Drug Safety Contact Information: 
Celgene Corporation      
Global Drug Safety and Risk Management    
Connell Corporate Park      
300 Connell Dr.  Suite 6000     
Berkeley Heights, NJ  07922        
Fax:                 (908) 673-9115 
E-mail:             drugsafety@celgene.com 
 
 
7.3.2 DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC and DF/PCC will report SAEs directly to the DFCI 
Office for Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
 
 
 
7.4 
Expedited Reporting to Hospital Risk Management.  
 
Participating investigators will report to the Risk Management office any participant safety 
reports or sentinel events that require reporting according to institutional policy.  
 
7.5 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 

DF/HCC Protocol #: 15-197 
Protocol Version Date: 15-MAY-2015 
 
31 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent 
administered in this study can be found in Section 7.1. 
 
 
8.1 
Lenalidomide 
 
8.1.1 Description 
REVLIMID®  (lenalidomide), a thalidomide analogue, is an immunomodulatory agent 
with anti-angiogenic properties.  The chemical name is 3-(4-amino-1-oxo 1,3-dihydro -
2H-isoindol-2-yl) piperidine-2,6-dione and it has the following chemical structure:  
1.1.1.1.1.1.1 Chemical Structure of Lenalidomide 
 
N
N
H
O
O
O
NH2
 
3-(4-amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl) piperidine-2,6-dione 
The empirical formula for lenalidomide is C13H13N3O3, and the gram molecular weight is 
259.3.  
 
 
 
8.1.2 Form 
 
Lenalidomide will be supplied as off-white capsules for oral administration.  Capsule 
strengths are 2.5 mg, 5 mg, 10 mg, 15 mg, 20 mg and 25 mg. Lenalidomide will be 
shipped directly to patients or to the clinic site.   Bottles will contain a sufficient number 
of capsules for one cycle of dosing.    
 
 
8.1.3 Storage and Stability 
 
Lenalidomide should be stored at room temperature away from direct sunlight and 
protected from excessive heat and cold.     
 

DF/HCC Protocol #: 15-197 
Protocol Version Date: 15-MAY-2015 
 
32 
8.1.4 Compatibility 
 
Not applicable 
 
8.1.5 Handling 
 
- 
Females of childbearing potential should not handle or administer lenalidomide unless 
they are wearing gloves.  Females of reproductive potential must adhere to the scheduled 
pregnancy testing as required in the Revlimid REMS® program. 
 
 
8.1.6 Availability 
 
Celgene Corporation will supply Revlimid® (lenalidomide) to study participants at no 
charge through Celgene’s Revlimid Risk Evaluation and Mitigation Strategy™ (REMS) 
(formerly known as RevAssist® Program).  Lenalidomide will be provided in accordance 
with the  Celgene Corporation’s Revlimid REMS® program.  Per standard Revlimid 
REMS® program requirements,  all physicians who prescribe lenalidomide for research 
subjects enrolled into this trial, and all research subjects enrolled into this trial, must be 
registered in, and must comply with, all requirements of the Revlimid REMS® program.   
 
 
8.1.7 Preparation 
 
Lenalidomide will come pre-prepared by the manufacturer. 
 
8.1.8 Administration 
 
The subject will self-administer lenalidomide at home.

DF/HCC Protocol #: 15-197 
Protocol Version Date: 15-MAY-2015 
 
33 
 
 
8.1.9 Ordering 
Lenalidomide will be shipped on a per patient basis by the contract pharmacy to the 
patient.  Only enough lenalidomide for one cycle of therapy will be supplied to the 
patient. Lenalidomide supplies are dispensed in individual bottles of capsules.  Each 
bottle will identify the contents as study medication.  In addition, the label will bear 
Celgene’s name, quantity contained and the standard caution statement as follows:  
“Caution: New drug - Limited by Federal law to investigational use.” Lenalidomide 
should not be handled by FCBP unless wearing gloves.  
 
The study drug label must be clearly visible.  Additional labels must not cover the 
Celgene label. 
 
 
 
8.1.10 Accountability 
 
The Investigator or designee is responsible for taking an inventory of each shipment of 
study drug received by the patient, and comparing it with the patient’s drug diary.  The 
Investigator or designee will verify the accuracy of the information on the drug diary, 
sign and date it, and retain a copy in the study file, and return a copy to Celgene or its 
representative upon request.   
 
8.1.11 Destruction and Return 
 
Patients will be instructed to return empty bottles or unused capsules to the clinic site.  
Celgene will instruct the Investigator on the return or destruction of unused study drug.  
If any study drug is lost or damaged, its disposition should be documented in the source 
documents.  Study drug supplies will be retained at the clinical site pending instructions 
for disposition by Celgene.  
 
 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
 
9.1 
Biomarker Studies 
 
BRAF is a human gene encoding a cellular growth signalling protein, which has been shown to 
be mutated in certain cancers including up to 50% of cases of LCH.  The frequency of BRAF 
mutation in HS is unknown but appears to be minimal. The Trovagene cell free DNA (cfDNA) 
urine assay uses a proprietary method for extracting cell-free transrenal DNA from large volume 
urine samples and a PCR assay to amplify small DNA fragments while enriching for mutant 
alleles.  These are then detected by droplet digital PCR (ddPCR). 

DF/HCC Protocol #: 15-197 
Protocol Version Date: 15-MAY-2015 
 
34 
 
 
This test was developed using urine samples from patients with stage IV / metastatic cancer. This 
test confirms the presence of a BRAF V600E mutation in urine DNA at levels of ≥0.03% in 
comparison to the wild-type BRAF genes. 
 
This is a laboratory developed test (LDT). This test was developed and its performance 
characteristics determined by Trovagene.  It has not been cleared or approved by the FDA as 
clearance or approval of LDTs is not currently required.    
 
Trovagene's laboratory is certified by the State of California LICENSE CLF 00338242 in 
compliance with CLIA (Clinical Laboratory Improvement 
Amendments) LICENSE 05D1094618, and is accredited by the College of American 
Pathologists LICENSE LAP 7190902. 
• 
Optimal testing requires a 90-110ml urine sample 
• 
No refrigeration necessary - collect and ship at room temperature 
• 
Collection kits will be provided by the manufacturer.  
Plasma genotyping of cfDNA will be performed by the Belfer Institute blood biomarker lab 
using a validated ddPCR-based assay for the detection of BRAF V600E. Samples from venous 
blood draws will undergo centrifugation within 1 hour of sample collection and standard plasma 
collection (Appendix C - SOP). The plasma will then be transported directly to the Belfer 
Institute. Immediate extraction of cfDNA will then be performed on 2 mL of plasma using the 
QIAmp Circulating Nucleic Acid Kit (Qiagen) according to the manufacturer’s protocol. DNA 
will then be eluted in 100 uL of AVE buffer and frozen at -80C until genotyping is performed. 
DNA quantification will be be performed using a fluorescence absorbence PicoGreen assay 
(Invitrogen). 
Genotyping will subsequently be performed by ddPCR using standard reagents ordered from 
Bio-Rad. Allele specific probes for BRAF V600E will be used in participants. The design and 
optimization of these primers and the associated methodology has previously been described by 
our group (Oxnard et al., CCR, 2014). 
Patients will undergo urine and plasma cfDNA testing at study entry.  The results of this test will 
be compared with standard BRAF testing via immunohistochemistry and/or PCR on available 
tissue samples.  If patients have a detectable BRAF mutation burden in cfDNA in the urine at 
study entry the test will be repeated at various timepoints as outlined in the study calendar 
(section 10).  If the test is negative at baseline it will not be repeated.  Results will be recorded in 
a quantitative fashion. This test may be performed in clinic (preferred) or taken home and 
shipped in a prepaid, addressed overnight mailer provided with the test kit. 
 
 

DF/HCC Protocol #: 15-197 
Protocol Version Date: 15-MAY-2015 
 
35 
9.2 
Laboratory Correlative Studies 
 
 
9.2.1 Serum TNF-alpha 
 
9.2.1.1.1. 
Specimens will be collected in a DFCI clinical space (lab or 
infusion floor).  One red top tube will be collected at specified timepoints.  
The test can be ordered via Lab Order Entry (LOE) in which a standard 
collection and processing workflow already exists. 
9.2.1.1.2. 
The specimen will be frozen per standard DFCI lab procedure 
9.2.1.1.3. 
Specimens are delivered via courier from DFCI lab control to 
the Mayo Clinic Laboratory three times daily 
9.2.1.1.4. 
Collection of the specimen will occur at DFCI.  The assay will 
be run at the Mayo Clinic Laboratory per current standard procedure.   
 
 
 
 
10. STUDY CALENDAR 
 
 
Baseline evaluations are to be conducted within 1 week prior to start of protocol therapy.  Scans 
and x-rays must be done <4 weeks prior to the start of therapy.  In the event that the participant’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. 
 
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted. 

DF/HCC Protocol #: 15-197 
Protocol Version Date: 15-MAY-2015 
 
36 
 
 
 
Pre- 
Study 
C1 
D1 
C1 
D15 
C2 
D1 
C2 
D15 
C3 
D1 
C3 
D15 
C4 
D1 
C5 
D1 
C6 
D1 
C7 
D1 
C8 
D1 
C9 
D1 
C10 &
11 
D1 
C12 
D1 
Off 
Treatmentl Follow 
Upm 
Lenalidomide 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Anticoagulation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xh 
  
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
 
X-----------------------------------------------------------------------------------------------------------------X 
Physical exam 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
Vital signsa 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
Height 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
Weight 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
Performance status 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
X 
X 
CBC w/diff, plts 
X 
Xj 
X 
Xj 
Xk 
X 
Xk 
X 
 
X 
 
X 
X 
 
X 
X 
X 
Serum chemistryb 
X 
X 
X 
X 
Xk 
X 
Xk 
X 
 
X 
 
X 
X 
 
X 
X 
X 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone marrow 
biopsy 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xi 
Adverse event 
evaluation 
 
X-----------------------------------------------------------------------------------------------------------------X 
Tumor 
measurementsc 
X 
 
 
 
 
X 
 
 
 X 
 
 
X 
 
X 
 
X 
X 
Radiologic 
evaluationd 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
B-HCGe 
Xb 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
Urine/ Plasma 
Assay for BRAF 
mutationf 
Xe 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
Serum TNF-alphag 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
a: 
Temperature, BP, HR and O2 saturation by pulse oximetry at rest. 
b: 
 Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium.  
c:      Tumor measurements are repeated at C3D1, C6D1, C9D1 and C12D1 and then every 3 months thereafter until month 24.  After month 24 
tumor assessments will occur every 6 months (+/- 2 weeks) until month 36 from treatment initiation.  Documentation (preferably radiologic) 
must be provided for participants removed from study for progressive disease. A window of +/- 1 week is allowed prior to month 24 but 
tumor assessments must occur prior to dosing on the relevant cycle when active treatment is being administered  
d:  
MRI of the brain is required for all patients but only needs to be repeated at follow-up if abnormal at baseline; PET/CT from scalp to toes is 
preferred for all patients but if PET/CT is not covered by insurance CT of chest, abdomen and pelvis as well as bone scan is an acceptable 
alternative; the same imaging modality should be used at each response time point. Radiologic measurements should be performed on 
C3D1, C6D1, C9D1, and C12D1 and then every 3 months thereafter until month 24.  After month 24 tumor assessments will occur every 6 
months (+/- 2 weeks) until month 36 from treatment initiation.  A window of +/- 1 week is allowed prior to month 24 but tumor assessments 
must occur prior to dosing on the relevant cycle when active treatment is being administered.  
e: 
Serum pregnancy test [women of childbearing potential defined as a sexually mature female who 1) has not undergone a hysterectomy or 
bilateral oopherectomy; or 2) has not been naturally menopausal for at least 24 consecutive months]. WCBP must have a pregnancy test 
prior to each cycle.  This will be performed in clinic when there is an evaluation on day 1 of any cycle scheduled.  Pregnancy testing will 
occur per the REMS program when a patient is not scheduled for clinic evaluation on day 1 of any cycle. 
f: 
Urine/serum assay will only be repeated at the time points indicated if abnormal at baseline. Urine assay for BRAF mutation has a +/- 7 day 
window. Serum assay has a +/- 3 day window.  
g: 
Samples can  be drawn pre or post dose at the time points indicated, they are not dependent on dosing. 
h:       If patient did not experience a venous thromboembolic event and there is no other clinical indication for anticoagulation then per protocol 
anticoagulation can be discontinued at this juncture.  If there is separate clinical indication for anticoagulation, including a thromboembolic 
event while on protocol, the nature and duration of anticoagulation should be determined as clinically indicated by standard of care and the 
discretion of the treating physician. 
i:      Only required if at least one unexplained cytopenia of grade 2 or greater is present at baseline or if PET/CT suggests bone marrow 
involvement; only needs to be repeated if abnormal at baseline. 

DF/HCC Protocol #: 15-197 
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37 
j:       CBC with automated differential will be checked every 7 days (+/- 1 day)  during cycles 1 and 2; local labs are acceptable. 
k:       Labs only necessary if dose escalation occurs.  Note, these labs can be obtained at a local laboratory.  Window for labs is +/- 3 days. 
l: 
Window for end of treatment visit is +/- 7 days from the date of last dose. 
m:     The first follow up visit will occur 3 months from the date of last dose and then every 3 months thereafter. Window for follow up visits is 
+/- 2 weeks. 
 
 

DF/HCC Protocol #: 15-197 
Protocol Version Date: 15-MAY-2015 
 
38 
 
11. MEASUREMENT OF EFFECT 
 
 
11.1 
Definitions 
 
Evaluable for toxicity: All participants who receive at least one dose of study treatment 
will be evaluable for toxicity from the time of their first treatment. 
 
Evaluable for objective response: Any patient who receives at least one dose of 
lenalidomide will be considered evaluable for response. These participants will have their 
response classified according to the definitions stated below. Patients not evaluable for 
response will not be replaced by another protocol participant. 
 
11.1.1 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
 
Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules) and ≥5 mm in diameter as assessed using calipers.  In the 
case of skin lesions, documentation by color photography, including a ruler to estimate 
the size of the lesion, is recommended. Skin lesions are considered non-target lesions for 
response assessment and will be described qualitatively as resolved, improved, stable, or 
progressive. 
 
PET/CT: this is the preferred method of evaluation for all patients.  Because of the 
propensity of histiocyte disorders to involve the skin and the bones of the skull, the 
PET/CT should encompass the area from the scalp to the toes.  If PET/CT is not covered 
by insurance, a CT of the chest, abdomen and pelvis in combination with a bone scan is 
an acceptable alternative. 
 
MRI:  MRI is required for all patients at baseline and must be repeated at specified 
timepoints only if abnormal at baseline or if normal at baseline but there is subsequent 
clinical suspicion of a CNS recurrence. 
 
 
 
 
 

DF/HCC Protocol #: 15-197 
Protocol Version Date: 15-MAY-2015 
 
39 
 
 
 
 
11.1.2 Response Criteria 
 
In contrast to lymphoma or other malignancies the terms “remission” or “relapse” should be 
avoided. In accordance with the nature of LCH the following definitions should be applied to 
judge the effect of treatment. The response criteria stated below has been designed by the 
Histiocyte Society to be applied in therapeutic studies of LCH and should be used for therapeutic 
decisions: 
 
Table 3 Definition of disease state by organ system 
 
NON ACTIVE DISEASE 
(NAD) 
no evidence of disease 
resolution of all signs or symptoms 
 
regressive disease  
regression of signs or symptoms, no 
new lesions 
ACTIVE DISEASE (AD) 
stable disease 
persistence of signs of symptoms, no 
new lesions 
 
progressive disease 
progression of signs or symptoms 
and/or appearance of new lesions 
 
Definition of response criteria 
Table 4 Three categories of overall response 
 
                                                            complete resolution                      NAD 
BETTER  
                                                              regression                                 AD better 
                                                                                                 mixed  new lesions in one site,           
INTERMEDIATE                                                                 regression in another site 
 
                                                                 Stable                                       Unchanged 
WORSE                                                 progression* 
 
* In isolated bone disease progression is defined as appearance of new bone lesions or 
lesions in other organs. 
 
11.1.2.1 
Evaluation of Target Lesions 
 
Unfortunately the Histiocyte Society does not specify what constitutes radiographic 
regression or progression of disease.  Since histiocyte disorders are hematologic 
malignancies we will use modified Cheson criteria to assign response as outlined 
below. 
 

DF/HCC Protocol #: 15-197 
Protocol Version Date: 15-MAY-2015 
 
40 
Response 
Definition 
Nodal Masses 
Spleen and Liver 
Bone Marrow 
CR 
Disappearance of all 
evidence of disease 
(a) FDG-avid or PET 
positive prior to therapy; 
mass of any size 
permitted if PET negative 
(b) Variably FDG-avid or 
PET negative; regression 
to normal size on CT 
Not palpable, 
nodules 
disappeared 
Infiltrate cleared on repeat 
biopsy; if indeterminate 
by morphology, 
immunohistochemistry 
should be negative 
PR 
Regression of 
measurable disease 
and no new sites 
≥50% decrease in SPD of 
up to 6 largest dominant 
masses; no increase in 
size of other nodes 
(a) FDG-avid or PET 
positive prior to therapy; 
one or more PET positive 
at previously involved 
site 
(b) Variably FDG-avid or 
PET negative; regression 
on 
CT 
≥50% decrease in 
SPD of nodules 
(for 
single nodule in 
greatest transverse 
diameter); no 
increase in size of 
liver or spleen 
Irrelevant if positive prior 
to therapy 
 
SD 
Failure to attain 
CR/PR or PD 
(a) FDG-avid or PET 
positive prior to therapy; 
PET 
positive at prior sites of 
disease and no new sites 
on CT or PET 
(b) Variably FDG-avid or 
PET negative; no change 
in 
size of previous lesions 
on CT 
Any but PD below 
Any but PD below 
PD 
Any new lesion or 
increase 
by _ 50% of 
previously 
involved sites from 
nadir 
Appearance of a new 
lesion(s) > 1.5 cm in any 
axis, 
≥ 50% increase in SPD of 
more than one node, 
or ≥50% increase in 
longest diameter of a 
previously identified node 
> 1 cm in short axis 
Lesions PET positive if 
FDG-avid lymphoma or 
PET 
positive prior to therapy 
>50% increase 
from nadir in the 
SPD of any 
previous lesions 
New or recurrent 
involvement 
 
 
Deauville Criteria for PET scan interpretation in lymphoma will be used in this 
study as outlined below:  
 
Five-point scale: 
1. No Uptake 
2. Uptake ≤ mediastinum 
3. Uptake >mediastinum but ≤ liver 
4. Uptake moderately increased compared to liver at any site 
5. Uptake markedly increased compared to the liver at any site or/and new sites of 
disease 
 
A score of 1-3 is PET NEGATIVE. 
A score of 4-5 is PET POSITIVE.  
 

DF/HCC Protocol #: 15-197 
Protocol Version Date: 15-MAY-2015 
 
41 
11.1.2.2 
Evaluation of skin lesions 
 
Skin lesions are not always detectable by PET/CT or other radiographic techniques.  
Skin lesions will be assessed by direct measurement.  Photographs are encouraged but 
not required.  Responses in skin are outlined below: 
 
Complete resolution:  no detectable skin abnormality 
Regression:  50% or greater reduction in the sum of the cumulative area of skin lesions 
Stable: not fulfilling criteria for resolution, regression, or progression 
Progression: new skin lesions (biopsy confirmation preferred but not mandatory) or 50% increase 
in area of at least one skin lesion 
 
 
 
11.1.2.3 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria. Responses should be maintained for at least 8 weeks.  If a patient has multiple 
sites of disease and any of these sites are active the patient is considered to have a best 
overall response of active disease. 
 
 
11.1.3 Duration of Response 
 
Duration of overall response:  The duration of overall response will be measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started, or death due to any cause. Participants without events reported are censored at the 
last disease evaluation). 
 
Duration of overall complete response: The duration of overall CR will measured from 
the time measurement criteria are first met for CR until the first date that progressive 
disease is objectively documented, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation. 
 
 
Duration of stable disease:  Stable disease will be measured from the start of the 
treatment until the criteria for progression are met, taking as reference the smallest 
measurements recorded since the treatment started, including the baseline measurements.  
 
11.1.4 Progression-Free and Overall Survival 
 
 

DF/HCC Protocol #: 15-197 
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42 
Overall Survival: Overall Survival (OS) is defined as the time from randomization (or 
registration) to death due to any cause, or censored at date last known alive. 
 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
randomization (or registration) to the earlier of progression or death due to any cause. 
Participants alive without disease progression are censored at date of last disease 
evaluation. 
 
 
11.1.5 Response Review 
 
Radiology will be centrally reviewed by the DF/HCC Tumor Imaging Metrics Core 
(TIMC) and the treating clinician will add clinical data (e.g., status of skin lesions not 
assessable by radiology) as appropriate.   
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
 
The QACT will collect, manage, and perform quality checks on the data for this study. 
 
 
12.1.2 Responsibility for Data Submission 
 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the QACT according to the schedule set by the QACT. 
 
 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 

DF/HCC Protocol #: 15-197 
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43 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
 
12.3 
Multicenter Guidelines 
 
N/a 
 
12.4 
Collaborative Agreements Language 
 
 N/A 
 
 
 
13. STATISTICAL CONSIDERATIONS 
 
 
13.1 
Study Design/Endpoints 
 
The primary endpoint of this study is to evaluate the overall response rate of lenalidomide 
in patients with LCH. This is a pilot study with a planned accrual of 12 patients. A small 
sample size was selected due to the rarity of the disease and the difficulty in accruing a 
larger number of patients at a single center. 
 
Study treatment will be considered worthy of further evaluation if at least three (25%) of 
12 patients experience a response. The 90% exact binomial confidence limits for three 
responses in 12 patients is 7-53%. We will consider a response rate of 5% unworthy of 
further study for this patient population, and note that two responses in 12 patients is the 
maximum number of responses which still includes the unworthy response rate of 5% in 
its confidence limits.  
 
The limited sample size may cause us to miss a small but potentially clinically 
meaningful response rate or to overestimate the response rate. We are willing to accept 
this in order to complete the trial in a reasonable time period while recognizing that the 
results of this trial will be used to determine whether a larger phase II trial of 
lenalidomide is warranted in which case such a trial would be proposed to the 
Histiocytosis Society. 
 
Secondary endpoints will include: 
 
- 
Duration of response 
- 
Progression free survival 

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44 
- 
Overall survival 
- 
Description of toxicity 
- 
Quantitative serial measurements of urine and plasma cell free 
DNA for BRAF mutation as a biomarker of response 
- 
 Quantitative serial measurements of serum TNF-alpha levels as a 
biomarker of response 
 
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
The planned accrual is 12 patients.  The estimated accrual is 5 patients per year so we anticipate the accrual 
will occur over a 2 to 2.5 year period.  Up to an additional 6 months of follow-up will be required on the 
last participant accrued to assess response.  Thus the total study duration is anticipated to be 2.5 to 3 years.  
 
 
 
 
13.3 
Stratification Factors 
 
n/a  
 
13.4 
Interim Monitoring Plan 
 
The study will be referred to the DSMC for review of dosing and toxicity at the first occurrence of a toxic 
death. 
 
13.5 
Analysis of Primary Endpoints 
 
The primary endpoint will be the proportion of responders.  A responder is defined as an eligible, evaluable 
participant who achieves either complete resolution or regression of disease, per section 7, as the best 
overall response at any point during study therapy. 
 
13.6 
Analysis of Secondary Endpoints 
 
Secondary endpoints are  
 
a) Duration of response defined as the time elapsing between the documentation of the onset of remission 
until clinical and/or radiographic evidence of progression. 
b) Progression-free survival (PFS), where time to event for PFS is the time from study enrollment until 
the time of first occurrence of new lesions, progressive disease, or death from any cause, or until last 
contact if no event occurs; 
 
c) Overall survival (OS), calculated as the time from enrollment until death or last contact; and, 
 
d) The proportion of participants reporting grades 3-4 toxicity, for each CTC v4 toxicity code 
 
e) Serial quantification of BRAF mutation in urine and plasma cell free DNA in patients with an 
identifiable BRAF mutation at baseline. 
 
f) 
Serial quantification of serum TNF-alpha levels in all patients, even if not elevated at baseline. 

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45 
 
 
13.7 
Reporting and Exclusions 
 
 
13.7.1 Evaluation of Toxicity 
 
All patients receiving at least one dose of lenalidomide will be evaluable for toxicity 
 
13.7.2 Evaluation of the Primary Efficacy Endpoint 
 
All participants included in the study who receive at least one dose of lenalidomide will be assessed for 
response to treatment, even if there are major protocol treatment deviations.  
 
14. PUBLICATION PLAN 
 
 
The results will be made public within 24 months of reaching the end of the study. The end of the study is the time 
point at which the last data items are to be reported, or after the outcome data are sufficiently mature for analysis, as 
defined in the section on Sample Size, Accrual Rate and Study Duration. If a report is planned to be published in a 
peer-reviewed journal, then that initial release may be an abstract that meets the requirements of the International 
Committee of Medical Journal Editors. A full report of the outcomes should be made public no later than three (3) 
years after the end of the study.  

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19.McClain KL, Kozinetz CA, A phase II trial using thalidomide for Langerhans cell 
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29. Corazzelli G, De Filippi R, Capobianco G, Frigeri F, DeRosa V, Laccarino G, et al. Tumor 
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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 
APPENDIX B 
 
NCI CTC Version 4.03 
Toxicity will be scored using NCI CTC Version 4.03 for toxicity and adverse event reporting. A 
copy of the NCI CTC Version 4.03 can be downloaded from the CTEP homepage: 
(http://ctep.info.nih.gov). All appropriate treatment areas have access to a copy of the CTC 
Version. 
 
APPENDIX C 
 
SOP plasma preparation for EDTA & Streck tubes 
 

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NOTE: Time period from draw to freezing of plasma must be less than 3 hours. 
 
1. Draw venous blood into one (1) 10 mL tubes (either EDTA or Streck) labeled CFDNA and 
immediately gently invert the tubes 8-10 times. Write the patient and draw date number on the 
tube.  
 
2. Immediately centrifuge for 10 minutes at 1500 (+\- 150) x g. NOTE: Brake switch must be off 
so the cell/plasma interface is not disturbed. 
 
3. Pipette the plasma layer into a 15 mL tube labeled “CFDNA/with patient #”. Do not ship. 
NOTE: Do not dip the tip of the pipette into the plasma/cell interface.  Leave a thin plasma layer 
intact over the interface. 
 
4. Centrifuge the 15 mL tube containing the plasma only for 10 minutes at 3000 (+/- 150) x g. 
 
5. Transfer using a fresh pipette, the supernatant into a second 15 mL tube labeled “CFDNA 
super.do not ship”. NOTE: Leave about 0.3 mL of supernatant in the centrifuged 15 mL tube. 
This leftover 0.3 mL contains cellular debris. 
 
6. Using a fresh pipette, transfer 1 mL of plasma from the “super.do not ship” tube into max four 
(4) 2 mL cryovials labeled CFDNA.ship.patient#/ 
 
7. Freeze immediately upright at -70ºC or colder until shipping.