Phase II Study of Clofarabine in Patients With Recurrent or Refractory Langerhans Cell Histiocytosis and LCH-related Disorders
Phase: PHASE2
Conditions: Langerhans Cell Histiocytosis
Sponsor: Dana-Farber Cancer Institute

Clofarabine for Langerhans Cell Histiocytosis 
                               Page 1 of 70 
June 12, 2019  
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Protocol Version 06-12-2019 
 
DFCI/HCC Protocol Number: 15-005 
 
TITLE: Phase II Study of Clofarabine in Patients with Recurrent or Refractory 
Langerhans Cell Histiocytosis and LCH-related Disorders  
 
Coordinating Center: 
Department of Pediatric Oncology 
Dana-Farber Cancer Institute/Boston Children’s Hospital 
450 Brookline Ave. 
Boston, MA 02215 
 
*Principal Investigator (PI): 
Barbara Degar, MD 
Pediatric Oncology 
Dana-Farber Cancer Institute/Boston Children’s Hospital 
450 Brookline Ave., D3-137 
Boston, MA 02215 
Phone: 617-632-5186 
Email: Barbara_Degar@dfci.harvard.edu  
Fax: 617-632-4811 
Other Investigators:         
 
 
Eric Jacobsen, MD 
Medical Oncology 
Dana-Farber Cancer Institute 
450 Brookline Ave., D1B30 
Boston, MA 02215 
Phone: 617-632-6633 
Email: EdJacobsen@partners.org  
Fax: 617-582-8413 
 
 
David Ebb, MD 
Pediatric Hematology-Oncology 
Massachusetts General Hospital 
55 Fruit Street 
Boston, MA 02114 
Phone: 617-726-2737 
Email: DEBB@mgh.harvard.edu 
Fax: 617-724-0702 
 
 
Patrick Campbell, MD, PhD 
Department of Oncology 
St. Jude Children’s Research Hospital 
262 Danny Thomas Place, MS 260 
Memphis, TN 38105-3678 
Phone: 901-595-2153 
Email: Patrick.Campbell@stjude.org  
Fax: 901-521-9001 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 2 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Michael Henry, MD 
Hematology/Oncology 
Phoenix Children’s Hospital 
1919 East Thomas Road 
Phoenix, AZ 85016 
Phone: 602-933-0920 
Email: MHenry@phoenixchildrens.com  
Fax: 602-933-2492 
 
 
Carl Allen, MD, PhD 
Pediatric Hematology/Oncology 
Texas Children’s Hospital, Baylor College of Medicine 
1102 Bates Street 
Houston, TX 77030 
Phone: 832-824-4312 
Email: ceallen@txch.org  
Fax: 832-825-1206 
 
 
Michael D. Hogarty, MD 
Division of Oncology 
The Children’s Hospital of Philadelphia 
3501 Civic Center Boulevard, CTRB Room 3012  
Philadelphia, PA 19104  
Phone: 215-590-2821  
Email: hogartym@email.chop.edu  
Fax: 215-590-3770 
 
 
Michelle Hermiston, MD, PhD 
Department of Pediatrics 
University of California San Francisco Medical Center-Parnassus  
505 Parnassus Ave., M649 
San Francisco, CA 94143  
Phone: 415-476-3831 
Email: HermistonM@peds.ucsf.edu 
Fax: 415-502-4372 
 
 
Rima Jubran, MD 
Division of Hematology-Oncology 
Children’s Hospital of Los Angeles 
4650 Sunset Blvd. 
Los Angeles, CA 90027 
Phone: 323-361-5639 
Email: rjubran@chla.usc.edu 
Fax: 323-660-7128 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 3 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Kimo Stine, MD 
Pediatric Oncology 
Arkansas Children’s Hospital 
1 Children’s Way 
Little Rock, AR 72202 
Phone: 501-364-1494 
Email: StineKimoC@uams.edu 
 
 
Ashish Kumar, MD, PhD 
Langerhans Cell Histiocytosis Center 
Cincinnati Children’s Hospital Medical Center 
3333 Burnet Avenue MLC 7015 
Cincinnati, OH 45229 
Phone: 513-636-7287 
Email: michael.jordan@cchmc.org 
Fax: 513-803-1969 
 
 
Razia Akhtar, MD 
Pediatric Hematology and Oncology 
Mount Sinai Hospital Center 
One Gustave L. Levy Place Box 1129  
New York, NY 10029 
Phone: 212-241-7022 
Email: razia.akhtar@mssm.edu 
Fax: 212-360-6921 
 
 
Stephan Ladisch, MD 
Hematology/Neuro-Oncology 
Children’s National Health System 
111 Michigan Ave., NW  
Washington, DC 20010 
Email: sladisch@childrensnational.org  
 
 
 
Jean-Marie Leclerc, MD 
Department of Pediatrics Hematology-Oncology 
CHU Sainte-Justine 
3175 Cote Sainte-Catherine 
Montreal, QC H3T 1C5, Canada 
Phone: 514-345-4931 
Email: anne-sophie.carret@umontreal.ca 
Fax: 514-345-4881 
 
 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 4 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
Oussama Abla, MD 
Hematology/Oncology 
Toronto SickKids 
555 University Ave. 
Toronto, ON M5G 1X8, Canada 
Phone: 416-813-7879 
Email: oussama.abla@sickkids.ca 
Fax: 416-813-5327 
 
Statistician: 
Wendy B. London, PhD 
Pediatric Oncology 
Dana-Farber Cancer Institute/Children's Hospital Boston 
450 Brookline Ave., SW300B 
Boston, MA 02215 
Phone: 617-632-4895 
Email: Wendy.London@childrens.harvard.edu 
 
Clinical Research 
Coordinator:          
Victoria Koch 
 
Pediatric Oncology 
Dana Farber Cancer Institute/Boston Children’s Hospital 
450 Brookline Avenue 
Boston MA, 02215 
Phone: 617-632-4878 
Email: Victoria_Koch@dfci.harvard.edu  
 
Research Nurse: 
Christine Braun, RN, BSN, CPHON 
Pediatric Oncology 
Dana-Farber Cancer Institute/Boston Children’s Hospital 
450 Brookline Avenue 
Phone: 617-632-2420 
Email: Christine_braun@dfci.harvard.edu  
 
Agent: 
Clofarabine (IND#114482) – Sanofi-Aventis 
 
 

Clofarabine for Langerhans Cell Histiocytosis                                                                                   Page 5 of 70  
June 12, 2019 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
SCHEMA 
 
 
* See Section 3 for stratification factors. 
# Participants removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse events. 
 
 
Consent 
Pre-treatment evaluations  
Labs: within 14 days;  
Other Studies: within 30 days 
Documentation of eligibility 
Induction Treatment 
(Weeks 1-8) 
Clofarabine, Two 
cycles 
Disease Evaluation (End of Cycle 2)  
Disease Progression? 
Maintenance Treatment  
Clofarabine, Four additional cycles 
Follow Up Studies#: annual visits at 12, 24, and 36 months, for a total of three years of 
follow-up 
Yes 
No 
End of Therapy Evaluations 
Diagnosis of LCH or LCH-related disorder 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 6 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
TABLE OF CONTENTS 
SCHEMA …………………………………………………………………………………………………5 
1. 
OBJECTIVES ..............................................................................................................................10 
1.1 
Overview ........................................................................................................................................10 
1.2 
Study Design ..................................................................................................................................10 
1.3 
Primary Objective ..........................................................................................................................10 
1.4 
Secondary Objectives ....................................................................................................................10 
2. 
BACKGROUND ..........................................................................................................................11 
2.1 
Study Disease .................................................................................................................................11 
2.2 
IND Agent ......................................................................................................................................14 
2.3 
Rationale for the use of clofarabine in recurrent or refractory LCH ...........................................16 
3 
PARTICIPANT SELECTION ...................................................................................................18 
3.1 
Inclusion Criteria ..........................................................................................................................18 
3.2 
Exclusion Criteria..........................................................................................................................20 
3.3 
Inclusion of Women, Minorities and Other Underrepresented Populations .................................20 
4 
REGISTRATION PROCEDURES............................................................................................21 
4.1 
General Guidelines for DF/HCC Institutions ...............................................................................21 
4.2 
Registration Process for DF/HCC Institutions .............................................................................21 
4.3 
General Guidelines for Other Investigative Sites ..........................................................................21 
4.4 
Registration Process for Other Investigative Sites ......................................................................21 
5 
TREATMENT PLAN..................................................................................................................22 
5.1 
Criteria to Proceed with Cycle 1 ...................................................................................................23 
5.2 
Criteria to Proceed with Subsequent Cycles .................................................................................23 
5.3 
Drug Administration ......................................................................................................................24 
5.4 
General Concomitant Medication and Supportive Care Guidelines .............................................24 
5.5 
Duration of Therapy ......................................................................................................................26 
5.6 
Duration of Follow Up ..................................................................................................................26 
5.7 
Criteria for Removal from Protocol Therapy ................................................................................26 
5.8 
Criteria for Removal from Study ...................................................................................................27 
6 
DOSE DELAYS/DOSE MODIFICATIONS.............................................................................27 
6.1 
Anticipated Toxicities ....................................................................................................................27 
6.2 
Toxicity Management ....................................................................................................................29 
6.3 
Dose Modifications/Delays ............................................................................................................29 
7 
DRUG FORMULATION AND ADMINISTRATION ............................................................30 
7.1 
Nomenclature.................................................................................................................................30 
7.2 
Molecular Structure .......................................................................................................................30 
7.3 
Description ....................................................................................................................................30 
7.4 
Form ..............................................................................................................................................30 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 7 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
7.5 
Storage and Handling ....................................................................................................................31 
7.6 
Preparation ....................................................................................................................................31 
7.7 
Handling ........................................................................................................................................31 
7.8 
Availability.....................................................................................................................................31 
7.9 
Administration ...............................................................................................................................31 
7.10 
Ordering ........................................................................................................................................31 
7.11 
Accountability ................................................................................................................................32 
7.12 
Destruction and Return .................................................................................................................32 
8 
STUDY CALENDAR ..................................................................................................................32 
9 
CRITERIA FOR RESPONSE – STRATUM 1 .........................................................................34 
9.1 
Definition of Response Criteria .....................................................................................................34 
9.2 
CRITERIA FOR RESPONSE – STRATUM 2 ................................................................................34 
9.3 
Other Response Parameters ..........................................................................................................38 
10 
ADVERSE EVENT REPORTING REQUIREMENTS ..........................................................39 
10.1 
Adverse Event (AE) Characteristics, Collection and Routine Reporting ......................................39 
10.2 
Serious Adverse Events (SAE) and Expedited Reporting ..............................................................40 
10.3 
AESI: An adverse event of special interest: ...................................................................................41 
10.4 
New safety finding: ........................................................................................................................41 
10.5 
Reporting to the Institutional Review Board (IRB) .......................................................................42 
10.6 
Reporting to Regulatory Agencies .................................................................................................42 
10.7 
Reporting to Hospital Risk Management .......................................................................................42 
10.8 
Pharmacovigilance Specifications and reporting to Sanofi ..........................................................42 
11 
DATA AND SAFETY MONITORING .....................................................................................43 
11.1 
Data Reporting ..............................................................................................................................43 
11.2 
Safety Meetings ..............................................................................................................................43 
11.3 
Monitoring .....................................................................................................................................43 
12 
REGULATORY CONSIDERATIONS .....................................................................................44 
12.1 
Protocol Review and Amendments ................................................................................................44 
12.2 
Informed Consent ..........................................................................................................................44 
12.3 
Ethics .............................................................................................................................................44 
12.4 
Study Documentation .....................................................................................................................45 
12.5 
Records Retention ..........................................................................................................................45 
12.6 
Multi-Center Guidelines ................................................................................................................45 
13 
STATISTICAL CONSIDERATIONS .......................................................................................46 
13.1 
Overview ........................................................................................................................................46 
13.2 
Sample Size/Accrual Rate ..............................................................................................................46 
13.3 
Study Design/Endpoints .................................................................................................................46 
13.4 
Evaluability ....................................................................................................................................47 
13.5 
Monitoring Rules ...........................................................................................................................47 
13.6 
Statistical Methods to Address Objectives .....................................................................................48 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 8 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
14 
PUBLICATION PLAN ...............................................................................................................49 
15 
REFERENCES ............................................................................................................................50 
16 
APPENDIX I: PERFORMANCE STATUS CRITERIA.........................................................55 
17 
APPENDIX II: DANA-FARBER/HARVARD CANCER CENTER MULTI-CENTER 
DATA AND SAFETY MONITORING PLAN ......................................................................................56 
17.1 
Introduction ...................................................................................................................................56 
17.2 
General Roles and Responsibilities ...............................................................................................57 
17.3 
DF/HCC Requirements for Multi-Center Protocols .....................................................................59 
17.4 
Requisitioning Investigational Drug .............................................................................................65 
17.5 
Monitoring: Quality Control .........................................................................................................65 
17.6 
Auditing: Quality Assurance .........................................................................................................69 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 9 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
 
List of Tables 
Table 1: Treatment Plan for all Patients ..................................................................................................... 22 
Table 2: Required Data / Study Calendar .................................................................................................. 33 
Table 3: Definition of Disease State .......................................................................................................... 34 
Table 4: Three Categories of Response ..................................................................................................... 34 
Table 5: CMR / CR .................................................................................................................................... 35 
Table 6: PMR / PR ..................................................................................................................................... 36 
Table 7: NMR/ SD ..................................................................................................................................... 37 
Table 8: PMD / PD ..................................................................................................................................... 38 
Table 9: Performance Status Criteria ......................................................................................................... 55 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 10 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
1. OBJECTIVES 
 
1.1 Overview 
 
The Histiocytoses are a group of rare neoplastic diseases involving histiocytes.  Langerhans Cell 
Histiocytosis (LCH), the most common of the group, is a disease caused by clonal proliferation of 
Langerhans cells that is characterized by a spectrum of varying degrees of organ involvement and 
dysfunction. Treatment of LCH is risk-adapted; patients with single lesions may respond well to local 
treatment, whereas patients with multi-system disease and risk-organ involvement (hematopoietic, liver, 
spleen) require more intensive therapy. While survival for patients without organ dysfunction is excellent, 
mortality rates for patients with organ dysfunction may reach 30 to 40%. For patients with low-risk disease, 
while cure is almost universal, disease reactivation rates are in excess of 30%.  Related disorders, including 
Juvenile Xanthogranuloma (JXG), Rosai Dorfman Disease (RDD), Erdheim Chester Disease (ECD), 
Histiocytic Sarcoma (HS), and Interdigitating Dendritic cell Sarcoma/Histiocytosis (IDCMH) share some 
histopathologic and clinical features with LCH.   There is currently no established therapy for any of these 
entities.  Thus, new treatments are needed. Nucleoside analogues such as cladribine and cytarabine have 
proven to be effective in the management of Histiocytoses. More recently, clofarabine has proven to be 
effective in patients with refractory LCH and LCH-related disorders, thus suggesting that this newer 
nucleoside analogue should be investigated. In this Phase II study we are proposing to evaluate the efficacy 
of clofarabine in participants with recurrent or refractory LCH. In a separate stratum, we aim to register 
participants with histiocytic diseases other than LCH who require systemic therapy to accumulate 
experience with clofarabine in this rare patient population. 
 
1.2 Study Design 
 
 
This is a phase II efficacy study of clofarabine in patients with recurrent or refractory Langerhans Cell 
Histiocytosis (LCH) and LCH-related disorders that require chemotherapy. 
 
1.3 Primary Objective 
 
To estimate the response rate of participants with recurrent or refractory LCH to clofarabine. 
 
1.4 Secondary Objectives 
 
a) To estimate the progression-free survival and overall survival of participants with recurrent or 
refractory LCH to clofarabine. 
b) To determine if clofarabine therapy can be delivered as planned (‘chemotherapy feasibility’), and 
to describe toxicities of clofarabine in participants with LCH. 
c) To describe the toxicities and responses to clofarabine treatment in participants with LCH-related 
disorders. 
 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 11 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
2. BACKGROUND 
 
2.1 Study Disease 
 
Langerhans Cell Histiocytosis (LCH) is a proliferative disorder of activated Langerhans cells (LC) with 
highly variable biological behavior and clinical severity.1 The histopathology of the lesion is uniform 
regardless of the clinical severity of the disease, and consists of collections of LC, interdigitating cells and 
macrophages, accompanied by T lymphocytes with variable numbers of multinucleated giant histiocytes 
and eosinophils.2 The pathogenesis of LCH is poorly understood. Because LCH has been demonstrated to 
be a monoclonal disease it may be considered a neoplastic disorder.3 However, different patterns of clinical 
involvement indicate other pathogenetic mechanisms. The occurrence of spontaneous remission 4 and the 
benign histopathological appearance of the lesions in LCH suggest a reactive clonal disorder rather than a 
malignant process, at least in some cases. Langerhans cells, like other dendritic cells, have a critical role 
in the immune system, and it has been suggested that LCH could be the result of immune dysregulation. 
Although no consistent immunologic abnormalities have been described, there is increasing evidence that 
LCH may be the result of an uncontrolled and abnormal proliferation of Langerhans cells secondary to 
either immune dysregulation or following exposure to a yet undetermined stimulus.5 In order to reconcile 
the clonal origin of the pathologic Langerhans cells with the evidences for immune dysregulation, a 
hypothesis has emerged that proposes that the monoclonal expansion seen in LCH could represent a host 
response to chronic antigenic stimulation. Under conditions of chronic stimulation, dominant clones of 
dendritic cells might emerge. These clones might still retain some ability to respond to normal immune 
regulatory loops, as exemplified by the therapeutic effect of cyclosporine. 
 
Treatment of LCH 
 
The treatment of LCH over the years has reflected the changing concepts of the disease process. Indeed, 
the difficulties in developing more effective therapies are linked to the deficiencies in the understanding 
of the pathogenesis of LCH. Retrospective studies of Lahey 6 and Komp et al 7 showed that, although many 
organs can harbor proliferating Langerhans cells, only if organ function were disrupted was such 
involvement of prognostic significance. Patients could then be stratified into different risk categories based 
on the extent of their disease and the degree of organ dysfunction. Two large cooperative trials 8,9 later 
confirmed those findings, and also identified a subgroup of patients (defined by age > 2 years and absence 
of organ dysfunction) with an excellent prognosis despite multi-system involvement. Treatment for 
patients with LCH is currently risk-adapted.  Patients with single-system disease confined to a single site 
usually require only local therapy or observation. Patients with more extensive disease (multiple bone 
lesions or multiple lymph nodes) usually require systemic therapy. The best therapeutic option in these 
cases has not been defined, and responses have been observed with short courses of steroids with or without 
the addition of chemotherapeutic agents.10 The treatment recommended by the Histiocyte Society for this 
group of patients includes a 6-week induction with prednisone and vinblastine, followed by continuation 
treatment with pulses of the same agents every 3 weeks. The prognosis for this group of patients is usually 
excellent, although approximately 30% of the patients will experience disease reactivations that continue 
to respond to treatment.  
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 12 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Five major cooperative trials have addressed treatment for patients with multi-system disease: the Italian 
AIEOP-CNR-HX 83 protocol,8 the Austrian/German DAL-HX 83/90 protocol,9 and the three trials of the 
Histiocyte Society (LCH-I,11 LCH-II,12 and LCH-III protocols). All these protocols were risk-adapted, and 
were based in different combinations of prednisone, vinblastine, etoposide, methotrexate and 6-
mercaptopurine.  In all those studies, survival rates are in excess of 90% for patients with multi-system 
disease without involvement of risk organs.  For this group of patients, the treatment currently 
recommended by the Histiocyte Society is a 12-month regimen with prednisone and vinblastine.  
Involvement of the risk organs carries the worse prognosis. This high-risk group of patients is characterized 
by early age at presentation (usually < 2 years), and different degrees of liver, spleen, hematopoietic, and 
lung involvement. Patients respond poorly to treatment, and mortality rate is approximately 40%.  
 
Treatment of Recurrent LCH 
 
Disease reactivation is common in patients with LCH, and two groups of patients are identified:  
 
a) Patients with “low-risk” disease. Includes patients with reactivation of multifocal bone disease or low-
risk multisystem disease (without risk organ involvement); disease reactivations occur in 
approximately one-third of patients, and they usually respond well to second-line therapy. Many 
regimens have been described, including oral 6-mercaptopurine and methotrexate,13 indomethacin,14 
bisphosphonates,15 and cladribine.16  
b) Patients with “high-risk” disease. This high-risk group is characterized by the presence of risk organ 
involvement, and poor response to standard treatment. Mortality is high, and recent data suggest that 
an intense regimen with cladribine and high-dose cytarabine may be effective.17,18 Allogeneic 
hematopoietic stem cell transplantation has also been proposed for those cases. 19 
 
Treatment of Recurrent or Refractory LCH with Nucleoside Analogues  
 
Treatment of LCH with 2-CdA 
The enzyme adenosine deaminase (ADA) has an essential role in the intracellular degradation of purine 
nucleosides derived from DNA breakdown. In ADA deficient cells, deoxyadenosine is metabolized by 
deoxycytidine kinase (dCk), resulting in increased cellular concentrations of deoxyadenosine mono-, di-, 
and tri-phosphates (dAMP, dADP, and dATP), that are toxic to the cells.20 2-chlorodeoxyadenosine (2-
CdA, cladribine) is a purine analog resistant to ADA but not to dCk. This results in accumulation of 
chlorinated deoxyadenosine nucleotides that may be eventually incorporated into the DNA of dividing 
cells, which results in induction of arrest in the S phase of the cell cycle,21 and activation of the apoptotic 
pathway. However, in contrast with conventional antimetabolites, 2-CdA is extremely toxic to mature, 
non-dividing lymphocytes. High concentrations of deoxynucleotides might interfere with the repair of 
DNA breaks, thus initiating the process of programmed cell death. 22In children, 2-CdA has mainly been 
used in the treatment of AML, where responses of up to 59% are obtained as a single agent. 23Normal 
mature lymphocytes and monocytes express high levels of dCk.24 In vitro studies have shown that 2-CdA 
is a highly selective anti-monocyte agent, which causes decreased monocyte function and viability and 
decreased IL-6 secretion.25 Because tissue histiocytes are derived from the same stem cells as circulating 
monocytes, 2-CdA has been investigated for the treatment of patients with histiocytic disorders. Excellent  
clinical responses, with an overall response rate of 82% have been reported in adults with recurrent LCH.26 
In children, the role of 2-CdA has been explored in two scenarios.  

Clofarabine for Langerhans Cell Histiocytosis 
     Page 13 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
a) For patients with low-risk disease reactivation, cladribine has shown to induce responses in > 90% 
of the patients, although further reactivations still occur.16,27-29 One additional benefit of cladribine 
is its effect on CNS disease (a common complication of LCH).30,31A major limitation with the use 
of cladribine is its limitation to a short treatment course; more than 4 or 6 courses of treatment are 
associated with prolonged myelosuppression, causing a clinical picture similar to myelodysplasia.  
b) For patients with high-risk disease, cladribine as a single agent has little effect, 28 and a more 
intensive regimen is needed. The combination of high-doses of cladribine (9 mg/m2/day x 5 days) 
with cytarabine (1 gr/m2/day x 5 days) has induced complete responses in patients with refractory 
disease.17,32 While this treatment seems to be effective, it is associated with high morbidity, with 
treatment-related mortality in excess of 20%.  
 
Treatment of LCH-related Disorders 
 
Several rare entities that occur in children and adults are defined by the proliferation and/or accumulation 
of cells of the histiocyte lineage but differ from LCH in histology, immunohistochemistry and clinical 
behavior.   
 
Rosai-Dorfman Disease (RDD), also known as Sinus Histiocytosis with Massive Lymphadeopathy, is a 
disease of children and young adults that is characterized by proliferation of S100 positive, CD1a negative 
histiocytes. RDD most often presents as massive bilateral cervical lymphadenopathy, sometimes associated 
with symptoms of systemic inflammation.  Many RDD patients experience a relapsing/remitting course 
but one that is ultimately benign and self-resolving.  For the subset of RDD patients who have extranodal 
involvement or nodal disease with risk for life threatening complications, systemic treatment is indicated.  
A variety of chemotherapy and immunomodulatory agents have been tried with variable success.  There is 
currently no standard treatment approach.  Cladribine33 and clofarabine34 have shown encouraging activity 
in limited published experience in RDD.    
 
Juvenile Xanthogranuloma (JXG) is a rare, benign histiocytic disorder that most often presents in infancy 
as single or multiple skin nodules. Biopsy shows Touton giant cells that are negative for CD1a and langerin 
(and usually S100 as well), but positive for Factor XIIIa, fascin, CD14, CD68, and CD163. Ocular, CNS, 
liver/spleen and lung involvement occurs in a small minority of JXG cases. Treatment of extra-cutaneous 
JXG with LCH- based regimens,35cladribine36 and clofarabine34 has met with some success.   
    
Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytic disorder most commonly 
characterized by multifocal osteosclerotic lesions of the long bones demonstrating sheets of foamy 
histiocytes on biopsy with or without histiocytic infiltration of extraskeletal tissues. The pathogenesis of 
Erdheim-Chester disease (ECD) is poorly understood. Attempts to establish clonality have produced varied 
results, and although occasional clonal cytogenetic aberrations have been identified, none are characteristic 
or diagnostic.37  An activating point mutation of the BRAF isoform of RAF (BRAF V600E) is identified 
in approximately 50 percent of cases of ECD and several case series have reported clinical responses to 
the BRAF inhibitor vemurafenib.38-40 There is no standard treatment regimen for patients with symptomatic 
ECD, and patients should be encouraged to enroll in a clinical trial. Most patients are treated with 
conventional or pegylated interferon-alpha rather than systemic chemotherapy.41. The BRAF inhibitors 
vemurafenib or dabrafenib are reasonable options for patients with a BRAF V600E  mutation who fail to 
respond to or cannot tolerate interferon-alpha. Systemic chemotherapy agents such as cladribine, 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 14 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
methothrexate and cyclophosphamide may be effective but are poorly studied.42,43 The optimal treatment 
of patients who fail interferon and who are not candidates for or do not respond to BRAF inhibitors remains 
unclear. Given the activity of clofarabine in other histiocyte disorders additional study in ECD is warranted. 
 
Histiocytic sarcoma (HS) is an extremely rare and generally aggressive malignancy typically comprised of 
non-cohesive, large cells that are polygonal or ovoid with spindling and abundant eosinophilic cytoplasm. 
Occasionally, the neoplastic cells can have a foamy appearance, but this is not nearly as pronounced as in 
Erdheim-Chester disease. There is typically a prominent inflammatory infiltrate, but necrosis is minimal. 
Hemophagocytosis may occasionally be present. The malignant cells usually expressed CD68, lysozyme, 
CD4, and CD 163. CD1a, S100, T and B-cell markers aside from CD4, and epithelial markers are usually 
absent. Birbeck granules are lacking.44 HS can occur as a de novo disease or concomitant with or 
subsequent to other hematologic neoplasms including follicular lymphoma, myeloid leukemias, and germ 
cell tumors. Patients with localized disease have a favorable prognosis after surgical resection, radiation, 
or both.45 Unfortunately, patients with disseminated disease have a very poor prognosis.  Patients are often 
treated with regimens used in aggressive lyphomas such as CHOP and ICE but response rates are poor.46 
There are anecdotal reports of responses to agents such as cladribine47 and alemtuzumab48 but new 
therapeutic options are desperately needed. There are reports of responses with clofarabine in HS34 and 
given the general lack of other effective options further study is warranted. 
 
Interdigitating dendritic cell sarcoma (Interdigitating cell malignant histiocytosis or IDCMH) is an 
extremely rare neoplasm of unknown cause. The neoplastic cells are usually found in the paracortical 
region of lymph nodes and are consistently positive for S 100 and vimentin. Fascin is also often positive. 
Expression of CD68, lysozyme and CD45 is variable. CD1a and CD207 are negative and the Ki67 
proliferative index is low. The majority of patients have localised disease at diagnosis. Isolated nodal 
disease makes up 47% of reported cases, isolated extranodal disease 25% and combined nodal and 
extranodal 28%.49 Extranodal sites include the liver, spleen, tonsils, bone marrow, lungs, skin, soft tissue, 
bowel, and bladder. Patients with metastatic disease have a poor outcome (38% survival at 1 year) though 
patients with localized disease can do well (85% survival at 1 year). The median survival for patients with 
metastatic disease is 9 months (0.25 – 72 months).49  Patients with metastatic disease are usually treated 
with chemotherapy.  A range of chemotherapy treatments have been reported but responses are often 
absent/short-lived, and outcomes remain poor. Chemotherapy regimens reported include ABVD 
(doxorubicin, bleomycin, vinblastine, dacarbazine); CHOP (cyclophosphamide, doxorubicin, vincristine 
and prednisolone); docetaxel + gemcitabine; IE (ifosfamide and eoposide).49 Given the poor outcome of 
patients with metastic diseases inclusion in a clinical trial with a new therapeutic agent known to have 
activity in histiocyte disorders is appropriate. 
 
2.2 IND Agent 
 
Clofarabine (2-chloro-9-[2’-deoxy-2’-fluoro--D-arabinofuranosyl] adenine; Cl-F-ara A; CAFdA) is a 
rationally designed, second generation purine nucleoside analogue.  Clofarabine was designed as a hybrid 
molecule to overcome the limitations and incorporate the best qualities of both fludarabine (F-ara-A) and 
cladribine (2-CdA, CdA) both of which are currently approved by various regulatory authorities for 
treatment of hematologic malignancies.  Because clofarabine has a chloro- group at the 2-position of 
adenine, its chemical structure is more closely related to 2-CdA than to F-ara-A.  Halogenation at the 
2-position of adenine renders this class of compounds resistant to intracellular degradation by the enzyme 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 15 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
adenosine deaminase.  Substitution of a fluorine at the C-2’-position of the arabinofuranosyl moiety of 
clofarabine increases its stability in gastric acid50,51 and decreases its susceptibility to phosphorolytic 
cleavage by the bacterial enzyme Escherichia coli purine nucleoside phosphorylase in the gastrointestinal 
tract,51 both of which may lead to enhanced oral bioavailability.  Clofarabine was approved in 
December 2004 by the United States Food and Drug Administration (US FDA) for the treatment of 
pediatric patients with relapsed or refractory acute lymphoblastic leukemia (ALL) after at least 2 prior 
regimens based on the induction of complete responses. 
 
2.2.1 Mechanism of Action 
 
The precise mechanism of action of clofarabine on dividing and non-dividing cells is unknown.  
Like other nucleoside analogues (cytarabine, cladribine, and fludarabine), clofarabine must be 
converted within cells to the 5’-triphosphate form by deoxycytidine kinase (dCK) and mono- and 
di-phosphokinases to be active.  Clofarabine is more efficient as a substrate for purified 
recombinant dCK, exceeding cladribine and the natural substrate, deoxycytidine.52  Evidence 
suggests that the primary cytotoxic effect of clofarabine is due to its inhibition of DNA synthesis 
and repair.  The triphosphate form of clofarabine is an inhibitor of both DNA polymerase  and  
and ribonucleotide reductase.53  These inhibitory effects lead to depletion of intracellular 
deoxynucleotide triphosphate pools and inhibition of elongation of DNA strands during synthesis 
and DNA repair.54  With respect to inhibition of ribonucleotide reductase, clofarabine and 
cladribine are superior to fludarabine.52  With respect to inhibition of DNA polymerase , 
clofarabine and fludarabine are similar and both are superior to cladribine.52  Thus, in comparison 
to cladribine and fludarabine, clofarabine more completely inhibits both ribonucleotide reductase 
and DNA polymerase , versus one or the other. 
 
Unlike fludarabine, clofarabine is active in vitro in non-dividing cells and in cells with a low 
proliferation rate.  Clofarabine can induce the apoptotic pathway as part of its cytotoxic effect on 
cells.51 Clofarabine has been shown to disrupt the integrity of mitochondria in primary chronic 
lymphocytic leukemia (CLL) cells.  The damage leads to release of pro-apoptotic mitochondrial 
factors.55 These effects are postulated to induce apoptosis in indolent, non-dividing CLL cells.  This 
result was not seen with fludarabine and may explain, at least in part, the enhanced cytotoxicity of 
clofarabine,55 although the physiologic and clinical implications of these observations remain 
uncertain and under continued investigation. 
 
2.2.2 Pharmacokinetics and Pharmacology 
 
Pharmacokinetics of Clofarabine in Adult Patients with Acute Myeloid Leukemia (AML) 
 
Pharmacokinetic data were collected from 13 adult patients with refractory or relapsed AML in 
an open-label study in which they were treated with clofarabine 40 mg/m2/day IV infusion over 1 
hour for 5 consecutive days.56  Stationary pharmacokinetics were observed between Days 1 and 5, 
and plasma concentrations declined rapidly thereafter and exhibited biphasic kinetics.  The 
estimated terminal half-life was approximately 6 hours and ranged from 4.1 to 8.6 hours.  
Consistent with this short half-life, pre-dose concentrations on Day 2 were about 10% or less of 
maximal concentrations at the end of infusion.  After 4 days of dosing, pre-dose concentrations 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 16 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
averaged 13.8 ng/mL and ranged from 4.0 to 23.1 ng/mL.  Because of the short half-life of 
clofarabine, there was little-to-negligible accumulation with once daily dosing of clofarabine at 
40 mg/m2 by 1-hour IV infusion. 
 
Pharmacokinetics of Clofarabine in Pediatric Patients with Acute Lymphoblastic Leukemia 
(ALL) 
 
The population pharmacokinetics of clofarabine was studied in 40 pediatric patients aged 2 to 
19 years (21 males/19 females) with relapsed or refractory ALL or AML.  At the given 52 mg/m2 
dose, similar concentrations were obtained over a wide range of body surface areas (BSAs).  
Clofarabine was 47% bound to plasma proteins, predominantly to albumin.  Based on non-
compartmental analysis, systemic clearance and volume of distribution at steady-state were 
estimated to be 28.8 L/h/m2 and 172 L/m2, respectively.  The terminal half-life was estimated to be 
5.2 hours.  No apparent difference in pharmacokinetics was observed between patients with ALL 
and AML or between males and females.  No relationship between clofarabine or clofarabine 
triphosphate exposure and toxicity or response was found in this population.  Based on 24-hour 
urine collections in the pediatric studies, 49-60% of the dose is excreted in the urine unchanged.  In 
vitro studies using isolated human hepatocytes indicate very limited metabolism (0.2%), therefore 
the pathways of non-renal elimination remain unknown.   
 
Although no clinical drug-drug interaction studies have been conducted to date, on the basis of the 
in vitro studies, cytochrome p450 inhibitors and inducers are unlikely to affect the metabolism of 
clofarabine.  The effect of clofarabine on the metabolism of cytochrome p450 substrates has not 
been studied.  The pharmacokinetics of clofarabine have not been evaluated in patients with renal 
or hepatic dysfunction.57 
 
Peripheral blood mononuclear cell (PBMC) clofarabine triphosphate concentrations were assessed 
in selected pediatric patients with relapsed or refractory ALL or AML in the pivotal Phase 2 studies 
of clofarabine (Genzyme Corp. Data on file).58 Triphosphate concentrations were similar in 
magnitude to adults given the same or similar dose.  The half-life of the triphosphate could not be 
adequately characterized but was estimated to be greater than 24 hours.  No correlation between 
triphosphate concentrations and either dose or parent clofarabine concentration was found.  
 
2.3 Rationale for the use of clofarabine in recurrent or refractory LCH 
 
Clofarabine is a second-generation deoxyadenosine analog, designed to improve the efficacy and minimize 
the toxicity of its congeners cladribine and fludarabine. Whereas fludarabine triphosphate primarily 
inhibits DNA polymerases and cladribine triphosphate particularly inhibits ribonucleotide reductase, 
clofarabine triphosphate inhibits both DNA polymerases and ribonucleotidase reductase in addition to 
inducing apoptosis through release of mitochondrial cytochrome C. The cellular retention of 
phosphorylated clofarabine metabolites is longer than that of other purine nucleoside analogues. 
Clofarabine has demonstrated significant activity in ALL, AML, and MDS including patients refractory to 
other deoxyadenosine analogs.59-63 In a Phase I trial of clofarabine in children with refractory hematologic 
malignancies, DLT at 70 mg/m2/day x 5 days was hyperbilirubinemia and skin rash, and MTD was 52 
mg/m2/day for 5 consecutive days. 62 In a subsequent Phase II study using the MTD in children with 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 17 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
recurrent or refractory ALL response rate was 30%. 61 At this dose, toxicity was characterized by 
electrolyte abnormalities (hypokalemia, hypophosphatemia) and mild elevation of liver enzymes and 
bilirubin. Two-thirds of the patients developed severe (≥ grade 3) infectious complications, including 
sepsis and septic shock (20% of patients). 61 
 
Given the good results obtained with cladribine in children with recurrent LCH, there could be a role for 
the use of clofarabine in this population. We recently treated a 2-year-old girl with low-risk multi-system 
LCH with clofarabine. This child was diagnosed at 7 months of age and treated with standard 
vinblastine/prednisone for 12 months. End of therapy evaluation showed residual FDG avid bone lesions 
on PET, and three months after completing therapy the patient had frank clinical and radiological disease 
progression. Treatment with cladribine was started, with symptomatic improvement but lack of complete 
response by PET-CT. Progressive disease was noted after the fourth course of cladribine. Treatment with 
clofarabine was then started at 30 mg/m2/day for 5 days. The patient had marked symptomatic 
improvement, and PET-CT after one course showed complete response, with no areas of abnormal FDG 
uptake for the first time since diagnosis. The patient developed grade 4 neutropenia after the second course, 
and the treatment was subsequently modified to 25 mg/m2/day for 3 days, given in monthly courses for a 
total of 6 courses. The patient remains in remission six months after completing treatment.  A similar 
approach was used to treat a 5-year-old girl with high-risk multi-system LCH that had failed treatment with 
vinblastine/prednisone. This patient subsequently received salvage treatment with methotexate, 
mercaptopurine, etoposide, cladribine (as single agent and in combination with cytarabine), and a 
combination of cyclophosphamide, prednisone, vincristine, and daunomycin. Treatment with clofarabine 
25 mg/m2/day x 5 days was started, and the patient achieved a complete response after 2 courses. These 
two cases demonstrate that clofarabine has activity in refractory LCH and may be a better alternative to 
cladribine for patients with refractory or recurrent disease. 64 Following this initial experience, two other 
small series by investigators associated with this study have confirmed the early findings and suggesting 
that this agent is among the most effective drugs tested against high-risk LCH. 65,66 Additional information 
available through personal experience of the study investigators supports this observation. However, 
prospective studies are needed to define the role of clofarabine.   
 
Rationale for use of Clofarabine in LCH-related disorders 
 
The optimal treatment for patients with RDD, JXG, ECD, HS, and IDCMH is not established.  In particular, 
the prognosis of HS and IDCMH remains poor.  Although there is a reasonable amount of data in the 
literature to support the use of interferon and BRAF inhibitors in ECD, the optimal treatment of ECD 
refractory to these agents and the optimal treatment of HS, JXG, and IDCMH remain to be defined.  
Therefore, given the paucity of data and the activity of clofarabine in LCH, inclusion of these histologies 
in the present trial is justified. 
 
Study and Dose Rationale 
 
The safety profile of clofarabine appears acceptable within the target populations studied to date in the 
clinical studies summarized above, and clofarabine has demonstrated anti-cancer activity through 
inhibition of DNA synthesis and repair, induction of apoptosis, and possibly through other mechanisms.  
Numerous responses have been observed after treatment with clofarabine in heavily pre-treated 
relapsed/refractory patients with ALL or AML.  As documented above, there is also a strong rationale for 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 18 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
the study of clofarabine in refractory LCH, although a less intensive regimen may be effective.  In this 
study, a dose of 25 mg/m2/day will be administered for 5 days. Evaluation of response will be performed 
after 2 cycles, and participants showing response will receive four additional cycles of clofarabine at the 
same dose for the first 5 days in each cycle. The selected dose is significantly lower than the maximum 
tolerated dose of 52 mg/m2/d defined in pediatric phase I trials; this lower dose has been selected based on 
the excellent response rates noted in patients with recurrent or refractory LCH using doses of 25-30 
mg/m2/d. 64,65    
 
3 PARTICIPANT SELECTION 
 
Patients will undergo baseline/screening procedures as defined in Table 2 within 14 days prior to starting 
protocol therapy.  
 
Stratum 1: Recurrent or Refractory LCH 
 
Participants with multi-focal or multi-system disease who have recurred after at least one prior systemic 
chemotherapy regimen. 
 
Stratum 2: LCH-Related Disorders Requiring Systemic Therapy 
 
Participants with LCH-related disorders who require systemic chemotherapy including: Participants with 
RDD who have not responded to or recurred after treatment with corticosteroids. ECD subjects who have 
confirmed presence of BRAF V600E mutation must have not responded to, have recurred after, or be 
unable to receive treatment with a BRAF inhibitor.  
 
Laboratory tests required for eligibility must be completed within 14 days prior to study entry. Baseline 
tumor measurements and other studies must be performed within 30 days of study entry.  
 
3.1 Inclusion Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to participate in the 
study: 
 
1. Prior diagnosis of Langerhans Cell Histiocytosis (stratum 1) or LCH-related disorder (stratum 2) 
established by standard diagnostic criteria and confirmed histologically.  
2. Evidence of active disease (histological confirmation of reactivation or progression is not 
required).  
3. Performance Score > 70% (use Lansky score for age <16 and Karnofsky score for age = >16, see 
Appendix I).  
4. Patients of all ages will be eligible.  
5. Provide signed written informed consent.  
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 19 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
6. In stratum 1, patients must have failed one prior systemic chemotherapy regimen. In stratum 2, 
RDD patients must have failed treatment with corticosteroid. EDC patients who have confirmed 
BRAF V600E mutations must have failed treatment with BRAF inhibitor or are not considered 
to be eligible for such treatment.  
7. There is no limitation of amount or the type of prior therapy or drugs.  
8. Female patents of childbearing potential must have a negative serum pregnancy test within 14 
days prior to enrollment. Male and female patients must use an effective contraceptive method 
during the study and for a minimum of 6 months after study treatment.  
9. Capable of understanding the investigational nature, potential risks and benefits of the study, and 
able to provide valid informed consent.  
10. Participants must have adequate marrow functions as defined below, except those who 
involvement of hematopoietic system for whom these criteria can be waived: 
• Absolute neutrophil count ≥ 750 cells/µL 
• Platelets ≥ 750 cells/µL 
11. Participants must have adequate organ function as defined below:  
• Total bilirubin ≤ 2.5 x institutional upper limit of normal. 
• AST (SGOT)/ALT (SGPT) < 2.5 x institutional upper limit of normal unless it is related to 
involvement by LCH. 
• Pediatric Population (patients < 18 years): Creatinine within normal limits or calculated 
creatine clearance ≥ 90 mL/min/1.73 m2 as calculated by the Schwartz formula for estimated 
glomerular filtration rate (GFR) where GFR (mL/min/1.73 m2) = k x Hight (cm)/serum 
creatinine (mg/dL). k is proportionally constant which varies with age and is a function of 
urinary creatine excretion per unit of body size; 0.45 up to 12 months of age; 0.55 children 
and adolescent girls; and 0.70 adolescent boys.  
• Adult Population (patients >= 18 years): Serum creatinine ≤ 1.0 mg/dL; if serum creatinine 
>1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be > 60 mL/min/1.73 
m2 as calculated by the Modification of Diet in Renal Disease equation where Pediatric 
GFR (mL/min/1.73 m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.203 x (0.74 if 
patient is female) x (1.212 if patient is black), where serum creatinine is measured in mg/dL.  
• Alkaline phosphatase ≤ 2.5 x institutional upper limit of normal. 
 
 
 
 
 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 20 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
3.2 Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible for admission into 
the study. 
 
1. Participants who have had chemotherapy or radiotherapy 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.  Corticosteroid treatment 
is allowed.   
2. Participants may not be receiving any other investigational agents targeting Histiocytosis. 
3. Clofarabine is excreted primarily by the kidneys.  Therefore, drugs with known renal toxicity 
(e.g. vancomycin, amphotericin B, acyclovir, cyclosporin, methotrexate, tacrolimus) should be 
avoided to the extent possible during the 5 days of clofarabine treatment in each cycle or, if 
required, administered cautiously and with close monitoring.   
4. Use of alternative medications (e.g., herbal or botanical that could interfere with clofarabine) is 
not permitted during the entire study period. 
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. 
6. Pregnant women are excluded from this study because clofarabine is a nucleoside analog with 
the potential for teratogenic or abortifacient effects. Because there is an unknown but potential 
risk of adverse events in nursing infants secondary to treatment of the mother with clofarabine, 
breastfeeding should be discontinued if the mother is treated with clofarabine. These potential 
risks may also apply to other agents used in this study.  
7. Individuals with a history of a different malignancy are ineligible except for the following 
circumstances. Individuals with a history of other malignancies are eligible if they have been 
disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence 
of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated 
within the past 5 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the 
skin. 
8. Patients with a history of prior hematopoietic stem cell transplantation (HSCT), elevated 
conjugated serum bilirubin at study entry, uncontrolled systemic fungal, bacterial, or other 
infection, a history of hepatitis B or C infection or a history of cirrhosis.   
9. Individuals who are known to be HIV-positive on combination antiretroviral therapy are 
ineligible because of the potential for pharmacokinetic interactions with clofarabine. In addition, 
these individuals 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. 
 
3.3 Inclusion of Women, Minorities and Other Underrepresented Populations 
 
Individuals of both genders and all ethnic backgrounds are eligible for this study. 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 21 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
4 REGISTRATION PROCEDURES 
   
4.1 General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) OnCore. 
Registrations must occur prior to the initiation of protocol therapy.  
 
An investigator will confirm eligibility criteria and will complete and sign the protocol-specific eligibility 
checklist.  
 
Following registration, participants may begin protocol therapy and should begin protocol therapy within 
7 days. 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. Registration cancellations must be made in OnCore as soon as possible.  
 
4.2 Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research titled Subject Registration (SOP #: 
REGIST-101) must be followed.   
 
4.3 General Guidelines for Other Investigative Sites 
 
Eligible participants will be enrolled on study centrally at the Dana-Farber Cancer Institute by the 
Study Coordinator (or designee). All sites should follow the procedure specified in section 4.4 to 
register participants prior to the initiation of protocol treatment. 
 
Following registration, participants should begin protocol treatment within 7 days. Issues that would 
cause treatment delays should be discussed with the Overall PI.  If a participant does not receive 
protocol therapy following registration, the participant’s registration on the study may be canceled. 
The Study Coordinator should be notified of cancellations as soon as possible. 
 
4.4 Registration Process for Other Investigative Sites 
 
To register a participant, the following forms and source documents should be completed by the 
participating institution, signed, and e-mailed or faxed to the Lead Institution clinical research 
coordinator listed on the first page of this protocol, or faxed to 617-632-3977 (Attention: Victoria 
Koch): 
 
• Signed informed consent document with patient initials and date of birth on every page of the 
consent 
• HIPAA authorization form (if separate from the informed consent document) 
• Completed Eligibility Checklist signed by the site investigator or an attending physician 
whose name is listed in the delegation of responsibility log sheet  
• Documentation of consent and eligibility note 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 22 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
• Copy of a pathology report confirming diagnosis of LCH 
• All required eligibility source documents (as specified in Table 2) 
 
The Lead Institution (DFCI) will review the submitted documents in order to verify eligibility.  To 
complete the registration process, the Lead Institution will: 
 
• Follow DF/HCC Standard Operating Procedure for Human Subject Research titled Subject 
Registration (SOP #: REGIST–101) and register the participant on the protocol. 
• Upon receiving confirmation of registration, the Lead Institution will inform the Participating 
Institution and provide the study specific participant case number, and, if applicable, assigned 
treatment and/or dose level within 2 business days.  
 
Treatment may not begin without confirmation from the Coordinating Center that the 
participant has been registered. 
 
NOTE: Registration can only be conducted during the business hours of 8:00 AM and 5:00 PM 
Eastern Standard Time Monday through Friday. Same day treatment registrations will only be accepted 
with prior notice and discussion with the DF/HCC Lead Institution. 
 
5 TREATMENT PLAN  
 
Each patient can receive a maximum of 6 cycles of study treatment.  Each treatment cycle will last 4 weeks 
(28 days) and a delay up to day 42 is allowed if necessary to meet eligibility criteria for starting subsequent 
cycles. Patients will be stratified into two groups for response analysis purposes:  
 
Table 1: Treatment Plan for all Patients 
INDUCTION 
 
MAINTENANCE 
Cycle 
1 
2 
 
3 
4 
5 
6 
Clofarabine 
 25 mg/m2/day  
Days 1-5 
I.V. 2 hrs +/- 30 min 
Disease  
Evaluation 
Clofarabine 
25 mg/m2/day  
Days 1-5 
I.V. 2 hrs +/- 30 min 
 
Induction: Clofarabine on Days 1-5 of each cycle, administered as I.V. infusion at 25 mg/m2/day. No drug 
treatment from Day 6 to Day 28. This cycle will be repeated once. 
 
Evaluation of disease response (see Section 9) will be performed after 2 cycles of Induction Therapy. In 
the absence of disease progression, participants will be eligible to receive up to 4 cycles of Maintenance 
Therapy, which is identical to the Induction Therapy. 
 
Maintenance: Clofarabine on Days 1-5 of each cycle, administered as I.V. infusion at 25 mg/m2/day. No 
drug treatment from Day 6 to Day 28. Cycle will be repeated for up to three more times every 28 days. 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 23 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Treatment may be administered on an outpatient basis. Expected toxicities and potential risks as well as 
dose modifications for clofarabine is 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. 
 
5.1 Criteria to Proceed with Cycle 1 
 
The following assessment must be completed within 3 days prior to starting Cycle 1. Patients need 
to re-meet lab eligibility criteria as described in section 3.1. 
 
1. Complete physical examination including height, weight and BSA. 
2. Performance status ≥70% (use Lansky score for age < 16 and Karnofsky score for age = 
>16, see Appendix I). 
3. Concurrent medical conditions.   
4. Hematology: CBC with differential and platelet count and peripheral blood smear.  
5. Serum chemistries: Electrolytes (calcium, magnesium, phosphorus, sodium, potassium, 
chloride, and bicarbonate), blood urea nitrogen (BUN), creatinine, and serum glucose. Liver 
function tests (total protein/albumin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin).  
6. Uric Acid as clinically indicated.  
7. Urinalysis. 
8. Baseline adverse event assessment from time of signing informed consent. 
 
5.2 Criteria to Proceed with Subsequent Cycles 
 
A treatment cycle will be repeated every 28 days (or no more than 42 days) if the participant does 
not have disease progression and any non-hematologic toxicities have recovered to grade 1 or 
become a tolerable grade 2, except those grade 3 toxicities specified in section 6.3.2. 
 
The following assessment must be completed within 3 days prior to starting all subsequent cycles. 
Patients need to re-meet lab eligibility criteria as described in section 3.1. 
 
1. Complete physical examination including height, weight and BSA. 
2. Performance status ≥70% (use Lansky score for age < 16 and Karnofsky score for age = 
>16, see Appendix I). 
3. Hematology: CBC with differential and platelet count and peripheral blood smear.  
4. Serum chemistries: Electrolytes (calcium, magnesium, phosphorus, sodium, potassium, 
chloride, and bicarbonate), blood urea nitrogen (BUN), creatinine, and serum glucose. Liver 
function tests (total protein/albumin, aspartate aminotransferase (AST), alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin).  

Clofarabine for Langerhans Cell Histiocytosis 
     Page 24 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
5. Uric Acid as clinically indicated.  
6. Urinalysis. 
7. Concomitant Medications/Transfusions.  
8. Adverse event assessment. 
 
5.3 Drug Administration  
 
Clofarabine should be diluted with NS or D5W prior to administering by IV infusion over 2 hours (+/- 30 
minutes).  The dosage is based on the participant’s body surface area (BSA), calculated using the actual 
height and weight obtained on the day of treatment or at least within three days before the start of each 
cycle. To prevent drug incompatibilities, no other medications should be administered through the same 
IV line. 
 
Participants may receive hydration per institutional standards during clofarabine treatment, giving careful 
consideration to the cardiac and renal function of the participant. Hyperhydration is not required.  
 
5.4 General Concomitant Medication and Supportive Care Guidelines 
 
5.4.1 Prophylactic Steroid Administration 
 
Prophylactic steroid (i.e. hydrocortisone or dexamethasone) has been administered by some 
investigators in investigator sponsored clinical studies with clofarabine and has been reported to 
minimize the occurrence and/or severity of the following potential clofarabine-related toxicities: 
nausea, vomiting, skin rash/desquamation, and capillary leak syndrome.   
 
5.4.2 Management of Capillary Leak Syndrome 
 
In previous studies, during or shortly after IV clofarabine administration a few participants 
developed signs and symptoms consistent with capillary leak syndrome. In these heavily pretreated 
participants, it has been difficult to separate potential drug-related cases of capillary leak syndrome 
from concurrent medical conditions such as infection/sepsis, progressive disease, or other 
underlying problems resulting from prior antileukemic therapies. 
 
For these reasons, during and after each dose of clofarabine, the onset of the following signs or 
symptoms  grade 2 will be assessed: 
− 
Tachypnea or other evidence of respiratory distress; 
− 
Unexplained hypotension; and/or 
− 
Unexplained tachycardia. 
 
If one or more of these signs or symptoms occur during study drug infusion, clofarabine 
administration will be interrupted or held as clinically indicated.  It is recognized that the total 
infusion time for this clofarabine dose in this circumstance may exceed 2 hours.  Thus, if the 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 25 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
participant’s condition stabilizes or improves, clofarabine administration may resume.  
Pretreatment (30-60 minutes prior to clofarabine administration) with steroids (e.g. hydrocortisone 
50-100 mg/m2/day for up to 3 days or its equivalent, or dexamethasone 5-10 mg/m2/day) is 
recommended for all subsequent doses during the remainder of that treatment cycle and for all 
subsequent treatment cycles. 
 
5.4.3 Anti-Emetics 
 
Clofarabine is moderately emetogenic.  Therefore, standard anti-emetic therapy (such as 
prochlorperazine or a 5HT3 antagonist, or/and dexamethasone) should be administered prior to 
therapy. 
 
5.4.4 Blood Products 
 
All blood products are to be irradiated and leukocyte-reduced according to each institution’s 
guidelines.  Also, CMV-negative participants should receive CMV-negative blood products 
according to each institution’s guidelines. 
 
5.4.5 Infection Prophylaxis 
 
The use of prophylactic antibacterial, antifungals, and antiviral agents is recommended according 
to each institution’s guidelines.   
 
5.4.6 Treatment of Fever and Neutropenia  
 
Treatment of fever and neutropenia should follow institutional guidelines.  
 
5.4.7 Colony Stimulating Factors  
 
Participants experiencing prolonged neutropenia (ANC < 500/mm3 for > 7 days) may receive 
myeloid growth factor support (filgrastim or peg-filgrastim). For subsequent cycles, growth factor 
support should be administered starting at least 24 hours after the last dose of clofarabine, and if 
administered daily, until ANC > 1,500/mm3 after expected decrease in neutrophil counts.  
 
5.4.8 Concomitant Therapy 
 
No concomitant cytotoxic therapy or investigational therapy is allowed during the study.  
 
Clofarabine is excreted primarily by the kidneys.  Therefore, drugs with known renal toxicity (e.g. 
vancomycin, amphotericin B, acyclovir, cyclosporin, methotrexate, tacrolimus) should be avoided 
to the extent possible during the 5 days of clofarabine treatment in each cycle or, if required, 
administered cautiously and with close monitoring.  Additionally, the liver is a known target organ 
for clofarabine toxicity.  Therefore, concomitant use of medications known to induce hepatic 
toxicity (e.g., voriconazole, cyclosporine, methotrexate, tacrolimus) should be avoided to the extent 
possible or, if required, administered cautiously and with close monitoring.  Hepatic and renal 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 26 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
function should be assessed prior to and during treatment with clofarabine and it is recommended 
that the participant’s fluid status and hepatic and renal function be carefully monitored during the 
drug administration period.  Use of alternative medications (e.g., herbal or botanical for anticancer 
purposes) is not permitted during the entire study period. 
 
5.5 Duration of Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and tolerance. In 
the absence of treatment delays due to adverse events, treatment may continue for a maximum of 6 cycles 
of study treatment or until one of the criteria for removal from protocol therapy (section 5.7) applies.  
 
5.6 Duration of Follow Up  
 
After completion of protocol therapy or removal from protocol therapy, participants will be followed for 3 
years, or until death, whichever occurs first.  Follow-up studies should be done annually at 12, 24, and 36 
months after therapy (see Table 2 for scheduled tests). 
 
5.7 Criteria for Removal from Protocol Therapy  
 
Participants will be removed from protocol therapy when they have not met eligibility criteria for 
starting subsequent cycles as defined in section 5.2 by end of cycle 2, or if they have met any of the 
criteria listed below:  
 
• Disease progression or death 
o Participants who experience disease progression that requires systemic therapy will 
be followed for survival, disease status and subsequent treatment for 3 years, but 
will not be required to complete any other protocol-defined follow-up assessments. 
• Intercurrent illness that prevents further administration of treatment  
• Second malignancy 
• Unacceptable adverse event(s) 
• Participant demonstrates an inability or unwillingness to comply with the medication 
regimen and/or documentation requirements 
• Participant decides to withdraw from the study 
• General or specific changes in the participant’s condition render the participant unacceptable 
for further treatment in the opinion of the treating investigator.  
• The participant becomes pregnant or fails to use adequate birth control if able to conceive 
 
The reason for removal from protocol therapy and the date the participant is removed must be 
documented in the study-specific case report form (CRF). Alternative care options will be discussed 
with the participant. 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 27 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Documentation of why the patient was removed from treatment and if the patient wishes to continue 
to be followed is required. This documentation needs to be sent to the DFCI Study team within 7 
days of the patient being removed from treatment, if they are coming off treatment early.  
 
For Decentralized Subject Registrations, the research team updates the relevant Off Treatment/Off Study 
information in OnCore.  
 
In the event of unusual or life-threatening complications, or any change of on study status, participating 
investigators must immediately notify the Principal Investigator (or Protocol Chair), Barbara Degar, 
MD at (617) 632-5186 and e-mail the Lead Institution clinical research coordinator listed on the first page 
of this protocol. 
 
5.8 Criteria for Removal from Study 
 
Participants will be removed from the study for the following reasons: 
 
a) Completion of 3-year follow-up period 
b) Death 
c) Lost to follow-up 
d) Withdrawal of consent for data submission 
e) Study completion 
 
6 DOSE DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made using the following recommendations. Toxicity assessments 
will be done using the CTEP Version 4.0 of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) which is identified and located on the CTEP website at: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
If possible, symptoms should be managed symptomatically. In the case of toxicity, appropriate medical 
treatment should be used (including anti-emetics, anti-diarrheas, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first dose of study 
treatment, through the study and up to 30 days from the last dose of treatment. Participants experiencing 
toxicities that are possibly related to the study treatment at the off-study visit will be followed up until the 
conditions resolved or clinically stabilized.  
 
6.1 Anticipated Toxicities  
 
For detailed information on clofarabine toxicology refer to the Investigator’s Brochure for clofarabine.67 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 28 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
6.1.1 Toxicity 
 
Adult Patients  
Drug-related AEs observed in at least 10% of adult participants treated with clofarabine in previous 
clinical trials include myelosuppression, nausea, vomiting, infections, fatigue, headache, diarrhea, 
rigors, dermatitis, anorexia, febrile neutropenia, myalgia, asthenia, petechiae, transient elevated 
liver enzymes, stomatitis, mucositis, pyrexia, flushing, constipation, edema, dehydration, 
nervousness, stomach pain, insomnia, depression, dry skin, back pain, and decreased weight.8   
 
Adverse events reported in 10% of adult participants include tumor lysis syndrome, capillary leak 
syndrome, palmar plantar erythrodysesthesia, pancreatitis, seizures, irregular heartbeat, edema, 
pericardial effusion, multi-organ failure, and death.8 
 
Pediatric Patients 
The most common side effects observed in previous clinical studies of pediatric patients treated 
with clofarabine 52 mg/m2 include vomiting NOS, nausea, febrile neutropenia, diarrhea NOS, 
headache NOS, pruritus NOS, pyrexia, dermatitis NOS, fatigue, rigors, abdominal pain NOS, 
tachycardia NOS, anorexia, petechiae, epistaxis, pain in limb, hypotension NOS, anxiety NEC, 
cough, constipation, erythema NEC, mucosal inflammation NOS, pain NOS, flushing, edema NOS, 
and hematuria.8 
 
Pediatric patients have also experienced increased liver enzymes and increased creatinine.  
Moderate neurological changes have been reported in some patients.  Infections were reported in 
almost half of the patients treated with clofarabine.   
 
Other potential SAEs include pericardial effusion, LVSD, tumor lysis syndrome, SIRS, and 
capillary leak syndrome.8 
 
Sanofi US Services Inc., on behalf of itself, and its affiliate, Genzyme Corporation is conducting a 
Phase I/II study to assess concomitant use of clofarabine, etoposide and cyclophosphamide in 
pediatric patients with acute leukemias.  In the Phase I portion of the study, febrile neutropenia, 
pyrexia and neutropenia were the most commonly reported serious adverse events and were 
reported in 64%, 20%, and 16% of patients, respectively.  There were 10 patient deaths in the trial 
(malignant disease, n=5; adverse events, n=2: infection/micrococcus meningitis, CNS hemorrhage; 
and other causes, n=3: intracranial hemorrhage, multi-organ failure, unknown etiology).  Dose-
limiting toxicities included a grade 3 elevation of lipase, abdominal pain and possible veno-
occlusive disease (VOD) that resolved (cohort 3) and 1 case of prolonged bone marrow aplasia 
(cohort 5).  In the Phase II portion 3 of the 4 first patients treated reported veno-occlusive disease 
(VOD) symptoms including hyperbilirubinemia, hepatomegaly, right upper quadrant pain, ascites 
and/or weight gain.  VOD-like signs and symptoms initially presented within 5 to 12 days of the 
first dose of clofarabine in these patients.  Two of the patients with VOD symptomatology had a 
history of HSCT and total body irradiation (TBI) within the previous 4 to 7 months.3 All 3 patients 
with VOD-like symptoms had ongoing severe infections and/or capillary leak syndrome preceding 
the occurrence of hepatotoxicity.  The fourth patient reported grade 4 hyperbilirubinemia and had 
a history of HSCT and TBI greater than 1 year prior to study entry.  As a result of these safety 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 29 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
findings, the updated protocol now states that patients with a history of prior HSCT, elevated 
conjugated serum bilirubin at study entry, uncontrolled systemic fungal, bacterial, or other 
infection, a history of hepatitis B or C infection or a history of cirrhosis are to be excluded from 
study participation.  The warnings and precautions section of the Clofarabine (Clolar) package 
insert has also been revised to reflect the recent safety findings.8  
 
6.2 Toxicity Management 
 
Please refer to section 5.4 (General Concomitant Medication and Supportive Care Guidelines) for 
management of toxicity. 
 
6.3 Dose Modifications/Delays 
 
6.3.1 Hematologic Toxicity 
 
• Participants who experience prolonged neutropenia (ANC < 500/μL for > 7 days) may 
receive growth factor support (see 5.3.7). If neutropenia persists (ANC < 500/μL) 
despite the addition of growth factor support and in the absence of hematopoietic 
involvement by Histiocytosis, but recovered by day 42 of the cycle, the subsequent cycle 
may start at a reduced dose of clofarabine by 25%. If prolonged neutropenia (ANC < 
500/μL for > 7 days) recurs in subsequent cycles after dose reduction, the participant 
should come off protocol treatment. 
• Participants who experience prolonged thrombocytopenia (platelets < 75,000/μL for > 
7 days) in the absence of hematopoietic involvement by Histiocytosis should have their 
dose of clofarabine reduced by 25% in subsequent cycles. If prolonged 
thrombocytopenia (platelets < 75,000/μL for > 7 days) recurs in subsequent cycles, the 
participant should come off protocol treatment.  
• If ANC or platelets counts are not recovered by day 42 in the absence of hematopoietic 
involvement by Histiocytosis, the participant should be taken off study. 
 
6.3.2 Non-Hematologic Toxicity 
 
• Participants who experience  grade 3 drug-related non-hematologic toxicity or asymptomatic 
grade 2 serum creatinine or serum total bilirubin during any clofarabine administration period 
should have clofarabine held until recovery to baseline or grade  2 before resuming 
treatment at the same dose.  Excluded from this rule are grade 3 skin rash,  grade 3 anorexia, 
transient isolated elevations in hepatic transaminases or alkaline phosphatase, and 
nausea/vomiting, diarrhea, or  grade 3 mucositis that resolves (with or without supportive 
care) to  grade 3 within 48 hours of onset. 
 
 
 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 30 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
7 DRUG FORMULATION AND ADMINISTRATION  
 
Clofarabine Drug Information 
 
7.1 Nomenclature 
 
Chemical Name:  2-chloro-9-(2-deoxy-2-fluoro--D-arabinofuranosyl)-9H-purine-6-amine 
 
Other names: CLOLAR, clofarabine; CAFdA; Cl-F-ara-A;  
 
2-chloro-2-fluoro-deoxy-9- arabinofuranosyladenine  
 
2-chloro-9-(2-deoxy-2-fluoro--D-arabinofuranosyl)adenine (Cl-F-ara-A) 
 
2-chloro-2-arabino-fluoro-2-deoxyadenosine 
 
2-chloro-2-ara-fluorodeoxyadenosine (CAFdA) 
 
2-chloro-2-fluorodeoxyadenosine (CAFdA) 
 
7.2 Molecular Structure 
 
Figure 4-1: 
Molecular Structure 
 
C10H11ClFN5O3 
 
 
7.3 Description 
 
Clofarabine is a white to off-white solid with a melting point of 228C to 230C and a molecular weight 
of 303.5.  The drug substance is very stable in the dry state, and aqueous solutions are stable to heat 
treatment.  Clofarabine is freely soluble in water (1.5 mg/mL) or buffered solutions at room temperature.  
Clofarabine is not less than 97% pure on a dried basis by high performance liquid chromatography (HPLC) 
analysis. 
 
7.4 Form 
 
Clofarabine is formulated at a concentration of 1 mg/mL.  Clofarabine is supplied in 1 vial size: a 20-mL 
clear, glass vial with gray stopper and blue flip off seal.  The 20-mL vials contain 20 mL (20 mg) of sterile 
solution.  The pH range of the solution is 4.5 to 7.5.  The solution is clear and practically colorless, 
preservative free, and free from foreign matter. 
 
N
N
N
N
Cl
H2N
O
HO
OH
F

Clofarabine for Langerhans Cell Histiocytosis 
     Page 31 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
7.5 Storage and Handling 
 
Vials containing undiluted clofarabine for injection should be stored at controlled room temperature.  The 
current commercial expiry period for Clolar (clofarabine) is 24 months at room temperature.  Ongoing 
stability studies will continue to confirm the appropriate quality of drug product used for clinical trials 
beyond 24 months. 
 
7.6 Preparation 
 
Clofarabine should be filtered through a sterile 0.2 micron syringe filter and then diluted with 5% Dextrose 
or 0.9% Sodium Chloride prior to intravenous infusion to a final concentration between 0.15mg/ml and 
0.4mg/ml. Clofarabine for injection should be diluted with 0.9% sodium chloride injection USP or 
European Pharmacopeia (EP) normal saline (NS) or 5% dextrose injection (D5W) USP or EP prior to IV  
infusion.  The resulting admixture may be stored at room temperature but must be used within 24 hours of 
preparation.  The dosage is based on the participant’s body surface area (BSA), calculated using the actual 
height and weight before the start of each cycle and should not be adjusted downward to “ideal” weight.  
To prevent drug incompatibilities, no other medications should be infused concurrently through the same 
IV lines as clofarabine.  Also, no blood products should be administered at the same time as clofarabine. 
 
7.7 Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and the 
environment, should undertake the preparation, handling, and safe disposal of the chemotherapeutic agent 
in a self-contained and protective environment. 
 
7.8 Availability 
 
Clofarabine is an investigational agent in this study and will be supplied free-of-charge from Sanofi US 
Services Inc., on behalf of itself, and its affiliate, Genzyme Corporation  
 
7.9 Administration 
 
Clofarabine should be administered as I.V. infusion via peripheral or central access over 2-hours in a 
window of 1.5 to 2.5 hours.  
 
7.10 
Ordering 
 
Clofarabine will be supplied by Sanofi US Services Inc., on behalf of itself, and its affiliate, Genzyme 
Corporation free of charge. The Coordinating Center will order the drug directly from Sanofi US Services 
Inc., on behalf of itself, and its affiliate, Genzyme Corporation. Each participating site will submit drug 
order requests using a specific drug order form supplied by the Coordinating Center. The completed form 
should be sent to: Victoria_koch@dfci.harvard.edu. 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 32 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
For US sites, allow 5-7 business days for initial drug orders and 3-5 business days for drug re-orders from 
the acknowledgement of order receipt to the date of delivery. For Canadian sites, allow 7-10 business days 
for initial and re-orders from the acknowledgement of order receipt to the date of delivery. There are no 
weekend, Monday, or Holiday deliveries. For questions regarding shipments, please contact Jigisha Patel 
via email at Jigisha.patel@sanofi.com. 
 
7.11 
Accountability 
 
Participating pharmacies will be required to submit Drug Accountability Logs at the time of monitoring 
documenting receipt and shipment of drug supply, dispensing/ordering of supply, and destruction of 
unused study medication and/or damaged or expired drug. 
 
7.12 
Destruction and Return 
 
At the end of the study, unused supplies of clofarabine should be destroyed according to institutional 
policies. Destruction will be documented in the Drug Accountability Record Form. 
 
8 STUDY CALENDAR 
 
Baseline laboratory tests are to be conducted within 14 days prior to start of protocol therapy. Other 
evaluations (scans, pathology, EKG, etc.) must be done within 30 days of study entry. 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. 
 
All assessments must be performed prior to administration of any study medication. All study 
assessments and medications should be administered within + 3 days of the protocol-specified 
date, unless otherwise noted.  
 
All follow-up assessments must be performed 12, 24, and 36 months from the off-treatment date 
(i.e. Day 28 of last administered cycle) +/- 31 days.  
 
A calendar for the time points when the required study data should be obtained is provided below.  
 
 
 
 
 
 
 
 
 
 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 33 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Table 2: Required Data / Study Calendar 
Assessments 
Baseline/ 
Screening 
(within 14 
days) 
Before 
Starting 
Each Cycle 
(within 3 
days) 
During 
Each 
Cycle  
End of 
Cycle 25  
End of 
Treatment 
(+/- 7 days 
from day 28 
of Cycle 6) 
Follow-
up7  
(+/- 31 
days) 
Informed Consent 
X1 
 
 
 
 
 
Medical History 
    Concurrent Condition 
    Concomitant Medications/    
    Transfusions 
X 
 
 
 
 
 
Height 
 
X 
 
 
X 
 
Weight 
 
X 
 
 
X 
 
BSA 
 
X 
 
 
X 
 
Physical exam/Vital Signs 
X 
X 
 
 
X 
 
Performance Status 
X1 
X 
 
 
X 
 
Hematology (CBC/Diff/Plts) 
X1 
X 
Weekly4 
 
X 
X2 
Electrolytes including Ca++, PO4, 
Mg++ 
X 
X 
Weekly4 
 
X 
X2 
Creatinine, BUN, Serum glucose 
X1 
X 
Weekly4 
 
X 
X2 
LFTs (Total Protein/Alb., ALT, 
AST, ALP, Billi.) 
X1 
X 
Weekly4 
 
X 
X2 
Uric acid 
X 
X2 
 
 
X2 
 
Serum -HCG3 
X1 
 
 
 
X 
 
EKG 
X 
 
 
 
X2 
 
Urinalysis 
X 
X 
 
 
X 
 
Bone Marrow Biopsy, Aspirate 
and Smear 
X2 
(within 30 
days) 
 
 
X2 
X2 
X2 
Disease Assessment/ Response 
Documentation (CT/MRI/ Bone 
Scan/ PET, as clinically indicated) 
X1 
(within 30 
days) 
 
 
X 
X6 
X8 
Chest X-Ray PA and L 
X 
 
 
 
X 
 
Skeletal survey (stratum 1 only) 
X 
 
 
X 
X6 
X8 
Clofarabine Administration 
 
 
Days 1-5 
 
 
 
Adverse Event Assessment 
X 
X 
Weekly4 
 
X 
 
1 Source documents are required for eligibility review before registration. 
2 As clinically indicated.  
3 For females of childbearing potential. 
4 Weekly assessments are recommended as clinically indicated, to be completed every 7 days, +/- 3 days. 
5 End of Cycle 2 assessments must be completed on Day 28 of Cycle 2 +/- 7 days, and prior to starting Cycle 3. 
6 End of treatment disease assessment imaging window +/- 14 days from day 28 of Cycle 6.  
7All Follow-Up Assessments to be performed 12, 24, and 36 months from the off-treatment date (i.e. Day 
28 of last administered cycle) +/- 31 days.  
8 12, 24, and 36 months after completion of therapy (i.e. Day 28 of last administered cycle)  

Clofarabine for Langerhans Cell Histiocytosis 
     Page 34 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
9 CRITERIA FOR RESPONSE – STRATUM 1 
 
In contrast to leukemia or other malignancies the terms “remission” or “relapse” should be avoided. In 
accordance with the nature of Histiocytosis 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.68 
 
Table 3: Definition of Disease State 
Main Category 
Sub-categories 
Definition 
Non-active Disease (NAD) 
Resolution of all signs/symptoms  
(no evidence of disease) 
Active Disease 
(AD) 
Regressive Disease (Better) 
Regression of signs/symptoms, and no new 
lesions. 
Stable Disease (Stable) 
Persistence of signs or symptoms, and no new 
lesions. 
Progressive Disease* (Worse) 
Progression of signs/symptoms and/or appearance 
of new lesions. 
* Progression of skeletal lesions is defined as unequivocal enlargement of the size of existing lesions and/or 
appearance of new lesions. 
 
9.1 Definition of Response Criteria 
Table 4: Three Categories of Response 
Response Category 
Definition 
Better 
• Complete disease resolution (NAD) 
• Regression (AD better) 
Intermediate 
• Stable (unchanged) 
Worse 
• Progression* 
* Progression of skeletal lesions is defined as unequivocal enlargement of the size of existing lesions and/or 
appearance of new lesions. In patients with risk organ involvement the overall response (and hence therapeutic 
decision) depends on response in risk organs. 
 
9.2 CRITERIA FOR RESPONSE – STRATUM 2  
 
For PET-based assessments, a clinical response of progressive metabolic disease (PMD), no metabolic 
response (NMR), partial metabolic response (PMR), or complete metabolic response (CMR) will be 
determined. PMD/PD includes radiological evidence of progression per Lugano Classification Revised 
Staging System for malignant lymphoma69. The PET scan metabolic uptake will be graded using the 
Deauville 5-point scale, with a score of   considered to represent a CMR. 
 
Deauville 5-point scale: 1 = no uptake above background; 2 = uptake ≤ mediastinum; 3 = uptake > 
mediastinum but ≤ liver; 4 = uptake moderately > liver; 5 = uptake markedly higher than liver and/or 
new lesions; X = new areas of uptake unlikely to be related to lymphoma.  

Clofarabine for Langerhans Cell Histiocytosis 
     Page 35 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Table 5: CMR / CR 
Response/Site 
FDG PET-CT-Based (Complete Metabolic 
Response) 
CT-Based (CR)a 
All of the following:  
 
 
Lymph nodes and 
extralymphatic sites 
Score 1, 2 or 3 with or without a 
residual mass on 5-Point-Scale. It is recognized 
that in Waldeyer’s ring or extranodal sites with 
high physiologic uptake or with activation 
within spleen or marrow (eg, with 
chemotherapy or myeloid colony-stimulating 
factors), uptake may be greater than normal 
mediastinum and/or liver. In this circumstance, 
complete metabolic response may be inferred if 
uptake at sites of initial involvement is no 
greater than surrounding normal tissue even if 
the tissue has high physiologic uptake. 
 
 
Target nodes/nodal masses 
must regress to  1.5cm in 
LDi 
 
No extra lymphatic sites of 
disease 
Non-measured lesion 
Not applicable 
Absent 
Organ enlargement 
Not applicable 
Regress to normal 
New lesions 
None 
None 
Bone marrowb 
No evidence of FDG-avid disease in marrow 
Normal by morphology; if 
indeterminate, IHC 
negative 
a CT-Based could also apply to MRI-based 
b Only if bone marrow involvement at diagnosis 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 36 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Table 6: PMR / PR 
Response/Site 
FDG PET-CT-Based (Complete 
Metabolic Response) 
CT-Based (CR)a 
All of the following: 
Target nodes/nodal 
masses, extranodal 
lesions 
Score 4 or 5 with reduced uptake 
compared with baseline and residual 
mass(es) of any size 
 
At interim, these findings suggest 
responding disease 
 
At end of treatment, these findings 
suggest residual disease 
 50% decrease in SPD of up to 6 
target measurable nodes and extranodal 
sites 
 
When a lesion is too small to measure 
on CT, assign 5mm X 5mm as the 
default value; when no longer visible, 0 
X 0mm; for a node > 5mm X 5mm, but 
smaller than normal, use actual 
measurement for calculation 
Non-measured 
lesion 
Not applicable 
Absent/normal, regressed, but no 
increase 
Organ enlargement 
Not applicable 
Spleen must have regressed by >50% 
in length beyond normal 
New lesions 
None 
None 
Bone marrowb 
Residual uptake higher than uptake in 
normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes from chemotherapy 
allowed). If there are persistent focal 
changes in the marrow in the context 
of a nodal response, consideration 
should be given to further evaluation 
with MRI or biopsy or an interval 
scan. 
Not applicable 
a CT-Based could also apply to MRI-based 
b Only if bone marrow involvement at diagnosis 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 37 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Table 7: NMR/ SD 
Response/Site 
FDG PET-CT-Based (Complete 
Metabolic Response) 
CT-Based (CR)a 
All of the following: 
Lymph nodes and 
extralymphatic sites 
 
Score 4 or 5 with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment 
< 50% decrease in SPD of up to 6 
target measurable nodes and extranodal 
sites; no criteria for Progressive 
Disease met 
 
Non-measured lesion 
Not applicable 
No increase consistent with 
Progression 
Organ enlargement 
Not applicable 
No increase consistent with 
Progression 
New lesions 
None 
None 
Bone marrowb 
No change from baseline 
Not applicable 
a CT-Based could also apply to MRI-based 
b Only if bone marrow involvement at diagnosis  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 38 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Table 8: PMD / PD 
Response/Site 
FDG PET-CT-Based (Complete 
Metabolic Response) 
CT-Based (CR)a 
All of the following: 
 
 
 
 
Individual target 
nodes/nodal masses 
 
Extranodal lesions  
 
 
 
 
 
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or new FDG-avid foci 
consistent with lymphoma at 
interim or end-of-treatment 
assesssment 
An individual node/lesion must be 
abnormal with: 
 
LDi > 1.5 cm & 
Increase by  50% from PPD nadir & 
An increase in LDi or SDi from nadir 
     0.5 cm for lesions  2cm 
     1.0 cm for lesions > 2cm 
 
In the setting of splenomegaly, the 
splenic length must increase by > 50% 
of the extent of its prior increase 
beyond baseline (eg, a 15cm spleen 
must increase to 16cm). If no prior 
splenomegaly, must increase by at least 
2cm from baseline.  
 
New or recurrent splenomegaly 
Non-measured lesion 
None 
New or clear progression of preexisting 
nonmeasured lesions 
 
 
 
New lesions 
New FDG-avid foci consistent with 
lymphoma rather than another 
etiology (e.g., infection, 
inflammation). 
 
If uncertain regarding etiology of 
new lesions, biopsy or interval scan 
may be considered. 
Regrowth of previously resolved 
lesions 
 
A new node > 1.5cm in any axis 
 
A new extranodal site > 1.0cm in any 
axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and must 
be attributable to lymphoma. 
Assessable disease of any size 
unequivocally attributable to 
lymphoma. 
Bone marrowb 
New or recurrent FDG-avid foci 
New or recurrent involvement 
a CT-Based could also apply to MRI-based 
b Only if bone marrow involvement at diagnosis 
 
9.3 Other Response Parameters 
 
Response should be maintained for 8 weeks. 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 39 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
10 ADVERSE EVENT REPORTING REQUIREMENTS 
 
All adverse events that occur after the initial dose of study treatment, during treatment, or within 30 days 
of the last study intervention need to be captured. Adverse events will be followed for 30 days after the 
last study intervention if a participant discontinues protocol treatment early. All AEs need to be followed 
until resolution.  
 
10.1 
Adverse Event (AE) Characteristics, Collection and Routine Reporting 
 
An adverse event (AE) is any undesirable sign, symptom or medical condition or experience that develops 
or worsens in severity after starting the first dose of study treatment or any procedure specified in the 
protocol, even if the event is not considered to be related to the study.  
 
All AEs (grades 1-5) whether reported by the participant, discovered during questioning, directly 
observed, or detected by physical examination, laboratory test or other means, will be recorded in the 
participant’s medical record and on the appropriate study-specific case report forms.  
• NOTE: Abnormal laboratory values or diagnostic test results constitute adverse events only if they 
are clinically significant (i.e. cause a cycle to be delayed, induce clinical signs or symptoms or 
require treatment or further diagnostic tests).  
 
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.  
 
Attribution is the relationship between an adverse event and the study treatment. Attribution will be 
assigned as follows: 
 
• 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. 
 
Adverse events can be 'Expected' or 'Unexpected.' 
• Expected adverse events are those that have been previously identified as resulting from 
administration of the agent. For the purposes of this study, an adverse event is considered expected 
when it appears in the current adverse event list (see Section 6.1), the Investigator’s Brochure, the 
package insert or is included in the informed consent document as a potential risk.  
• Unexpected adverse events are an adverse reaction, the nature or severity of which is not 
consistent with the applicable product information (e.g., Investigator's Brochure for an unapproved 
investigational medicinal product or package insert/summary of product characteristics for an 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 40 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
approved product). An expected ADR with a fatal outcome should be considered unexpected unless 
the local/regional product labeling specifically states that the Adverse Drug Reaction (ADR) might 
be associated with a fatal outcome. 
 
Reportable Adverse Events must be reported in routine study data submissions to the Overall PI on the 
adverse events case report forms (i.e. in InForm). 
 
10.2 
Serious Adverse Events (SAE) and Expedited Reporting 
 
A serious adverse event (SAE) is any adverse event, occurring at any dose and regardless of causality that:  
• Results in death (Grade 5) 
• Is life-threatening. Life-threatening means that the person was at immediate risk of death from the 
reaction as it occurred, i.e., it does not include a reaction which hypothetically might have caused 
death had it occurred in a more severe form. 
• Requires intensive inpatient medical interventions, including mechanical ventilation, pressor 
support, and/or fluid resuscitation, or emergent surgical operations. Unplanned hospital admission 
for febrile neutropenia, bacteremia or other documented infections, seizure, pancreatitis, 
thrombosis, nausea/vomiting, diarrhea, and other expected toxicities from the study treatment will 
not be considered a serious adverse event unless the severity of the condition is considered life-
threatening and/or lead to intensive medical interventions or surgical procedure. 
• Hospitalization admissions and/or surgical operations scheduled to occur during the study period, 
but planned prior to study entry are not considered SAEs if the illness or disease existed before the 
person was enrolled in the trial, provided that it did not deteriorate in an unexpected manner during 
the trial (e.g., surgery performed earlier than planned). 
• Results in persistent or significant disability/incapacity. Disability is defined as a substantial 
disruption of a person’s ability to conduct normal life functions. 
• Is a congenital anomaly or birth defect; or 
• Is an important medical event when, based upon appropriate medical judgment, it may jeopardize 
the participant and require medical or surgical intervention to prevent one of the outcomes listed 
above. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
• Per DFCI’s Expedited Reporting requirements, the following events also require expedited (SAE) 
reporting:  
o Unexpected Grade 2 (moderate) and Grade 3 (severe) events that are possibly, probably or 
definitely related/associated with the intervention. 
o Unexpected Grade 4 (life-threatening or disabling) events regardless of attribution.  
o All Grade 5 (fatal) Events – When the participant is enrolled and actively participating in 
the trial OR when the event occurs within 30 days of the last study intervention.  
▪ Note: If the participant is in long term follow up, report the death at the time of 
continuing review.  
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 41 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Events not considered to be serious adverse events are hospitalizations for: 
• Routine treatment or monitoring of the studied indication, not associated with any deterioration in 
condition, or for elective procedures 
• Elective or pre-planned treatment for a pre-existing condition that did not worsen 
• Emergency outpatient treatment for an event not fulfilling the serious criteria outlined above and 
not resulting in inpatient admission 
• Respite care 
 
The Overall Principal Investigator/Sponsor (Dr. Barbara Degar) and the study team at the lead institution 
should be informed within 1 business day, by email or phone of all SAEs that occur after the initial dose 
of study treatment, during treatment, or within 30 days after the last study intervention. In the event that 
the participating investigator does not become aware of the SAE immediately (e.g., participant sought 
treatment elsewhere), the participating investigator is to report the event within 24 business hours after 
learning of it and document the time of his or her first awareness of the event. Report serious adverse 
events by telephone, email or facsimile: 
 
Barbara Degar, MD 
Pediatric Oncology 
Dana-Farber Cancer Institute 
450 Brookline Ave  
Boston, MA 02215 
Phone: 617-632-5186 
Email: Barbara_Degar@dfci.harvard.edu 
Fax: 617-632-4811 
 
At the same time, an e-mail should also be sent to the Lead Site clinical research coordinator listed 
on page one of this protocol.  
 
Within the following 24-48 business hours, the participating investigator should relay follow-up 
information to the PI and study team as necessary.  
 
10.3 
AESI: An adverse event of special interest: 
 
AESI is an adverse event (serious or non-serious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and rapid communication by the Investigator 
to the Sponsor may be appropriate. Such events may require further investigation in order to characterize 
and understand them. AESIs may be added or removed during a study by protocol amendment. 
 
10.4 
New safety finding:  
 
Any (other than reportable individual case safety report (ICSR)) safety issue that may require expedited 
reporting because providing information that may lead to a change in the known risk-benefit balance for 
the  product and as mentioned, but not limited to, in the following regulatory texts: Europe: Volume 9A of 
the Rules Governing Medicinal products in the European Union (September 2008) Section 4.1; and US: 
FDA: 21 CFR Parts 312 Investigational New Drug Application- Section 312.32, (c) (1) IND safety reports. 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 42 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
10.5 
Reporting to the Institutional Review Board (IRB) 
 
Investigative sites within DF/HCC will report all serious adverse events directly to the DFCI Office for 
Human Research Studies (OHRS). 
 
Each investigative site will be responsible to report SAEs that occur at that institution to their respective 
IRB per their local IRB’s policies and procedures in reporting adverse events. These sites will also 
complete a DF/HCC AE Reporting form and submit to the Overall PI and DFCI study team.  The Overall 
PI and DFCI study team will then submit the DF/HCC AE Reporting form from outside institutions to 
the DFCI OHRS according to DFCI IRB policies and procedures in reporting adverse events. 
 
10.6 
Reporting to Regulatory Agencies 
 
For multi-site trials where a DF/HCC investigator is serving as the principal investigator, each participating 
investigator is required to abide by the reporting requirements set by the DF/HCC. The study must be 
conducted in compliance with FDA regulations, local safety reporting requirements, and reporting 
requirements of the principal investigator.  
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA and Health 
Canada. The Overall PI will report to the FDA and Health Canada, regardless of the site of occurrence, 
any serious adverse event that meets the FDA and Health Canada’s criteria for expedited reporting 
following the reporting requirements and timelines set by the FDA and Health Canada. 
 
10.7 
Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any subject safety reports or 
sentinel events that require reporting according to institutional policy. 
 
10.8 
Pharmacovigilance Specifications and reporting to Sanofi 
 
The sponsor-investigator Barbara Degar, M.D. of the Investigator-Sponsored Trial/Study (IST/ISS) will 
report the following information in English to the Sanofi Global Pharmacovigilance contact, E-mail: CL-
CPV-Receipt@sanofi.com or Fax: +33 (0)1.60.49.77.77 or Fax: 1-908 -203-7783 
 
1. Routine transmission of all Serious Adverse Events (SAEs) including pregnancy, overdose and 
Adverse Events of Special Interest (AESI), if any. These events must be transmitted within 1 
business day of the ISS sponsor’s awareness or identification of the event, for Pre-marketing IST 
and post-marketing ISS with recently approved products.  
2. Routine transmission of SAEs related to the use of the Sanofi product must be transmitted within 1 
business day of the ISS sponsor’s awareness or identification of the event for all other approved 
products. 
3. The reference safety information to be used by the ISS sponsor for evaluation of expectedness of 
adverse events shall be the current approved product label available in the country (for an approved 
indication)/ the Investigator Brochure.  

Clofarabine for Langerhans Cell Histiocytosis 
     Page 43 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
4. Any Periodic reports (e.g. Development Safety Update Report (DSUR)), submitted to Regulatory 
Authority must be transmitted to Sanofi at the time of submission. 
5. New Safety Findings in a study pertaining to safety of product must be transmitted within 1 business 
day. (e.g., Data Safety Monitoring Board recommendations) 
6. The study reports of any ISS must contain a section describing safety review and conclusion and 
must be reviewed by Sanofi before finalization. 
 
11 DATA AND SAFETY MONITORING 
 
11.1 
Data Reporting 
 
11.1.1 Method 
 
The ODQ will collect, manage, and perform quality checks on the data for this study.  
 
11.1.2 Data Submission 
 
Sites are responsible for submitting data and/or data forms to the ODQ according to the schedule 
set by the ODQ.  
 
11.2 
Safety Meetings 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and 
accrual data from this trial. 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 Principal Investigator and the Lead Site study team. 
The DSMC will meet quarterly and/or as often as necessary, as determined by the DSMC, if required to 
review toxicity and accrual data.  Information to be provided to the committee may include:  up-to-date 
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 within 30 days for Phase I or II 
protocols; for gene transfer 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.  
 
11.3 
Monitoring  
 
Involvement in this study as a participating investigator implies acceptance of potential audits or 
inspections, including source data verification, by representatives designated by the DF/HCC Overall 
Principal Investigator (or Protocol Chair) or DF/HCC. The purpose of these audits or inspections is to 
examine study-related activities and documents to determine whether these activities were conducted and 
data were recorded, analyzed, and accurately reported in accordance with the protocol, institutional 
policy, Good Clinical Practice (GCP), and any applicable regulatory requirements.  
 
All data will be monitored for timeliness of submission, completeness, and adherence to protocol 
requirements. Monitoring will begin at the time of participant registration and will continue during 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 44 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
protocol performance and completion.  
 
Please refer to section 17 Appendix II for more details. 
 
12 REGULATORY CONSIDERATIONS 
 
12.1 
Protocol Review and Amendments 
 
This protocol, the proposed informed consent and all forms of participant information related to the 
study (e.g., advertisements used to recruit participants) and any other necessary documents must be 
submitted, reviewed and approved by a properly constituted IRB governing each study location.  
 
Any changes made to the protocol must be submitted as amendments and must be approved by the IRB 
prior to implementation. Any changes in study conduct must be reported to the IRB. The DF/HCC 
Overall Principal Investigator (or Protocol Chair) or his designee will disseminate protocol amendment 
information to all participating investigators.  
 
All decisions of the IRB concerning the conduct of the study must be made in writing. 
 
12.2 
Informed Consent 
 
All participants must be provided a consent form describing this study and providing sufficient 
information for participants to make an informed decision about their participation in this study. The 
formal consent of a participant, using the IRB approved consent form, must be obtained before the 
participant is involved in any study-related procedure. The consent form must be signed and dated by 
the participant or the participant’s legally authorized representative, and by the person obtaining the 
consent. The participant must be given a copy of the signed and dated consent document. The original 
signed copy of the consent document must be retained in the medical record or research file.  
 
12.3 
Ethics 
 
This study is to be conducted according to the following considerations, which represent good and 
sound research practice: 
 
• 
US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html  

Clofarabine for Langerhans Cell Histiocytosis 
     Page 45 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
o Title 21 Part 312 – Investigational New Drug Application 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr312_02.html  
• 
State laws 
• 
DF/HCC research policies and procedures       
http://www.dfhcc.harvard.edu/clinical-research-support/clinical-research-unit-cru/policies-
and-procedures/  
 
It is understood that deviations from the protocol should be avoided, except when necessary to 
eliminate an immediate hazard to a research participant. In such case, the deviation must be reported 
to the IRB according to the local reporting policy.  
 
12.4 
Study Documentation 
 
The investigator must prepare and maintain adequate and accurate case histories designed to record all 
observations and other data pertinent to the study for each research participant. This information enables 
the study to be fully documented and the study data to be subsequently verified. 
 
Original source documents supporting entries in the case report forms include but are not limited to hospital 
records, clinical charts, laboratory and pharmacy records, recorded data from automated instruments, 
microfiches, photographic negatives, microfilm or magnetic media, and/or x-rays.  
 
12.5 
Records Retention 
 
All study-related documents must be retained for the maximum period required by applicable federal 
regulations and guidelines or institutional policies.  
 
12.6 
Multi-Center Guidelines 
 
This protocol will adhere to the policies and requirements of the Dana-Farber/Harvard Cancer Center. 
The specific responsibilities of the DF/HCC Overall Principal Investigator (or Protocol Chair), 
Coordinating Center, and Participating Institutions are presented in the Dana-Farber/Harvard Cancer 
Center Multi-Center Data and Safety Monitoring Plan (see Appendix II). 
 
• 
The DF/HCC Overall Principal Investigator/Coordinating Center is responsible for 
distributing all IND Action Letters or Safety Reports to all participating institutions for 
submission to their individual IRBs for action as required. 
• 
Mechanisms will be in place to ensure quality assurance, protocol compliance, and adverse 
event reporting at each site.  
• 
Except in very unusual circumstances, each participating institution will order the agent(s) 
directly from the supplier. A participating site may order the agent(s) only after the initial IRB 
approval for the site has been forwarded to the Coordinating Center.  
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 46 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
13 STATISTICAL CONSIDERATIONS  
 
13.1 
Overview 
 
This is a prospective study of clofarabine treatment for Histiocytosis patients. All patients will receive the 
same treatment with the standard dose of clofarabine (25 mg/m2/d). A single-arm design test will be used 
to estimate the response rate in Stratum 1. In addition, in an exploratory fashion, we will estimate the rates 
of response and toxicity in patients with LCH-related disorders (Stratum 2). Stratum 2 is a heterogeneous 
group of patients, and we wish to gather data in order to generate hypotheses about the response rates of 
the subgroups of Stratum 2 which could be tested in a future protocol. 
  
13.2 
Sample Size/Accrual Rate 
 
Twenty evaluable participants in Stratum 1 will be required in order to have sufficient power to address 
the study’s primary objective. To account for participants who enroll and are subsequently determined to 
be ineligible or unevaluable, a total of up to 25 participants may be enrolled in order to obtain 20 evaluable 
patients.  At an estimated accrual rate of 10 participants per year, the accrual goal of 20 evaluable 
participants can be achieved in less than 4 years. It is estimated that up to 10 patients per year meeting the 
eligibility criteria for Stratum 2 are seen across all study sites (personal communication from Drs. Degar 
and Jacobsen).  Therefore, the estimated accrual rate of Stratum 2 patients is up to 5 patients per year,  
which allows for up to 20 patients in Stratum 2, though realistically, fewer of these rare patients are 
anticipated to be enrolled.  We estimate a total study accrual of up to 45 patients (25 in Stratum 1, and 20 
in Stratum 2).  
   
Once the accrual goal of eligible patients for a given stratum is reached (with a 5-patient overage to account 
for potentially ineligible patients), that stratum will be closed to accrual.  Once the accrual goal of evaluable 
patients is met within Stratum 1, the overall study will be closed even if fewer than 20 patients have been 
enrolled in Stratum 2.  In the unlikely event that 20 patients are enrolled on Stratum 2 before Stratum 1 has 
met its accrual goal, Stratum 2 will be closed to accrual.  
 
13.3 
Study Design/Endpoints 
 
The primary endpoint within each stratum will be the proportion of responders.  A responder is defined as 
an eligible, evaluable participant who achieves either complete resolution or regression of disease, i.e., 
their disease gets “Better” per section 9.1, as the best overall response at any time up to and including the 
End of Cycle 2 assessment, which must be completed on Day 28 of Cycle 2 +/- 7 days, and must be 
completed prior to starting Cycle 3. 
 
Secondary endpoints are: 
 
a) 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; 
b) Overall survival (OS), calculated as the time from enrollment until death or last contact; 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 47 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
c) Feasibility, which is assessed by the proportion of patients who experience a toxicity-event.  
Participants who have clofarabine stopped because of toxicity concerns will be considered to have 
experienced a toxicity-event. Otherwise, participants who complete therapy or who are removed 
from protocol therapy for reasons related to disease progression, second malignancy or death 
unrelated to protocol therapy will be considered to have successfully tolerated treatment; and, 
d) The proportion of participants reporting grades 3-4 toxicity, for each CTCAE v4.0 toxicity code. 
 
13.4 
 Evaluability 
 
To be evaluable for inclusion in the analysis of response and toxicity, a patient must be eligible and have 
received at least one dose of protocol therapy.  All evaluable participants must be assessed for response 
and toxicity to treatment, even if there are major protocol treatment deviations. Each participant should be 
assigned a category of response according to section 9 of the protocol. 
 
13.5 
 Monitoring Rules 
 
The study will be referred to the DSMC for review of dosing and toxicity at the first occurrence of a toxic 
death. 
 
A Simon’s two-stage group sequential design will be used to determine if there is sufficient evidence of 
efficacy to warrant further investigation of clofarabine.  
 
Rule A - Two-stage stopping rule for response in Stratum 1 
 
Stage 1:  Accrue 13 evaluable participants.  If 7 or fewer respond, then there is insufficient evidence to 
support further study of clofarabine in this cohort, and the study will be closed to further accrual. We would 
also close the trial if it became apparent prior to the accrual of all 13 that we would never achieve the 8 
responders. If 8 or more out of 13 are responders, then proceed to stage 2. 
 
Stage 2: A total of 20 evaluable patients will be studied.  If 13 or fewer respond, then there is insufficient 
evidence to support further study of clofarabine in this cohort. If 14 or more are responders, then there is 
sufficient evidence to warrant further investigation of clofarabine within this cohort. 
 
This rule has 91% power to detect a 27% difference (53% under the null to 80% under the alternative), 
with alpha = 0.093.  If the response rates were actually higher, there would be even greater power to detect 
a 27% difference, for example 63% versus 90%. 
 
Rules for monitoring for toxicity associated with chemotherapy 
 
The study will be monitored to ensure the therapy can be delivered as planned (‘chemotherapy feasibility’). 
Toxicities will be graded according to CTCAE version 4.0. Unacceptable toxicity will be defined as grade 
5 toxicity and Grade 3 or 4 non-hematological toxicity that are possibly, probably, or definitely related to 
Clofarabine, with the specific exceptions of the following Grade 3 toxicities: anorexia, weight loss, nausea, 
vomiting, fatigue, mucositis, diarrhea, fever, electrolyte/metabolic abnormalities, menorrhagia, and 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 48 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
infection. Because all patients, regardless of stratum, receive the same treatment with the standard dose of 
clofarabine (25 mg/m2/d), the stopping rule for toxicity will be applied to the overall cohort, i.e., combining 
Stratum 1 and Stratum 2.  The toxicity monitoring rule will be applied to the first 25 evaluable participants, 
as this will provide sufficient evidence of safety/feasibility for the balance of the trial’s accrual. 
 
Rule B – Three-stage stopping rule for toxicity events 
 
Stage 1:  Accrue 7 evaluable participants.  If at any time 2 or more participants experience a toxicity-event, 
enrollment will be suspended for DSMB review of dosage modifications or stopping the trial.  If 1 or fewer 
have a toxicity-event, then proceed to stage 2. 
 
Stage 2:  Accrue an additional 8 evaluable participants for a total of 15.  If at any time 3 or more participants 
experience a toxicity-event, enrollment will be suspended for DSMB review of dosage modifications or 
stopping the trial.  If 2 or fewer have a toxicity-event, then proceed to stage 3. 
 
Stage 3: Accrue an additional 10 evaluable participants for a total of 25. If  7 or more participants 
experience a toxicity-event, then there is insufficient evidence to support chemotherapy feasibility. If 6 or 
fewer have a toxicity-event, then there is sufficient evidence that the therapy can be delivered as planned, 
and this evidence supports continuation until the accrual goal for this trial is reached. 
If all 25 participants are evaluated and the true toxicity-event rate is 5%, the therapy will be considered 
tolerable with a probability of 0.94. If all 25 participants are evaluated and true toxicity-event rate is 30%, 
the therapy will be considered tolerable with a probability of 0.1. 
 
13.6 
 Statistical Methods to Address Objectives 
 
Objective 1.3 - Monitoring Rule A will be used to address primary objective 1.3. The analysis will include 
all evaluable Stratum 1 participants.  In addition, a 95% confidence interval will be placed on the response 
rate. 
 
Secondary Objective 1.4.a – Descriptive analyses using the methods of Kaplan and Meier (with standard 
errors per Peto) will be performed to calculate the PFS and OS within each stratum and overall.  Lifetables 
will also be constructed. 
 
Secondary Objective 1.4.b – Monitoring Rule B will be used to address secondary objectives 1.4.b and 
1.4.c. In addition, a descriptive tabulation of the proportion of participants reporting grade 3 and higher 
toxicity, separately by stratum (1 and 2) and by CTC toxicity code, will be generated for all evaluable 
patients.  A given participant will be counted only one time per toxicity code at the maximum grade 
regardless of the number of times that participant experienced the toxicity. 
 
Secondary Objective 1.4.c – Within Stratum 2 and within subgroups of Stratum 2, we will calculate the 
proportion of evaluable patients who are responders, and place 95% confidence intervals on these 
proportions.  A descriptive tabulation of the proportion of participants reporting grade 3 and higher toxicity, 
by CTC toxicity code, will be generated for Stratum 2 patients.  A given participant will be counted only 
one time per toxicity code at the maximum grade regardless of the number of times that participant 
experienced the toxicity. 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 49 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
14 PUBLICATION PLAN 
 
A final report will be written regardless of the outcome of the study, within 24 months of its completion. 
The writing committee will be formed by all the study investigators; timing of the publication(s) and 
presentation to national and international meetings will be decided by the committee.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 50 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
15 REFERENCES 
 
1. 
Arico M, Egeler RM. Clinical aspects of Langerhans cell histiocytosis. Hematol Oncol Clin North 
Am 1998;12:247-58. 
2. 
Schmitz L, Favara BE. Nosology and pathology of Langerhans cell histiocytosis. Hematol Oncol 
Clin North Am 1998;12:221-46. 
3. 
Willman CL, Busque L, Griffith BB, et al. Langerhans' cell histiocytosis (histiocytosis X) - a 
clonal proliferative disease. N Engl J Med 1994;331:154-60. 
4. 
Broadbent V, Pritchard J, Davies EG. Spontaneous remission of multisystem histiocytosis X. 
Lancet 1984;1:253-4. 
5. 
Kannourakis G, Abbas A. The role of cytokines in the pathogenesis of Langerhans cell 
histiocytosis. Br J Cancer 1994;70 (Suppl. 23):S37-S40. 
6. 
Lahey ME. Histiocytosis X: An analysis of prognostic factors. J Pediatr 1975;87:184-9. 
7. 
Komp DM, Herson J, Starling KA, Vietti TJ, Hvizdala E. A staging system for Histiocytosis X: A 
Southwest Oncology Group Study. Cancer 1981;47:798-800. 
8. 
Ceci A, de Terlizzi M, Colella R, et al. Langerhans cell histiocytosis in childhood: Results from 
the Italian cooperative. Med Pediatr Oncol 1993;21:259-64. 
9. 
Gadner H, Heiger A, Grois N, Gatterer-Menz I, Ladisch S. Treatment strategy for disseminated 
Langerhans cell histiocytosis. Med Pediatr Oncol 1994;23:72-80. 
10. 
Broadbent V, Gadner H. Current therapy for Langerhans cell histiocytosis. Hematol Oncol Clin 
North Am 1998;12:327-38. 
11. 
Gadner H, Grois N, Arico M, et al. A randomized trial of treatment for multisystem Langerhans' 
cell histiocytosis.  J Pediatr2001:728-34. 
12. 
Gadner H, Grois N, P”tschger U, et al. Improved outcome in multisystem Langerhans cell 
histiocytosis is associated with therapy intensification.  Blood2008:2556-62. 
13. 
Womer RB, Anunciato KR, Chehrenama M. Oral methotrexate and alternate-day prednisone for 
low-risk Langerhans cell histiocytosis. Med Pediatr Oncol 1995;25:70-3. 
14. 
Munn SE, Olliver L, Broadbent V, Pritchard J. Use of indomethacin in Langerhans cell 
histiocytosis.  Med Pediatr Oncol1999:247-9. 
15. 
Farran RP, Zaretski E, Egeler RM. Treatment of Langerhans cell histiocytosis with pamidronate.  
J Pediatr Hematol Oncol2001:54-6. 
16. 
Rodriguez-Galindo C, Kelly P, Jeng M, Presbury GG, Rieman M, Wang W. Treatment of 
children with Langerhans Cell Histiocytosis with 2-Chlorodeoxyadenosine.  Am J Hematol2002:179-84. 
17. 
Bernard F, Thomas C, Bertrand Y, et al. Multicentre pilot study of 2-chlorodeoxyadenosine and 
cytosine arabinoside combined chemotherapy in refractory Langerhans cell histiocytosis with 
hematological dysfunction.  Eur J Cancer2005:2682-9. 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 51 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
18. 
Choi SW, Bangaru BS, Wu CD, Finlay JL. Gastrointestinal involvement in disseminated 
Langerhans cell histiocytosis with durable complete response to 2-chlorodeoxyadenosine and high-dose 
cytarabine.  J Pediatr Hematol Oncol2003:503-6. 
19. 
Steiner M, Mathes-Martin S, Attarbaschi A, et al. Improved outcome of treatment-resistant high-
risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity 
conditioning.  Bone Marrow Transplant2005:215-25. 
20. 
Guchelaar HJ, Richel DJ, Schaafsma MR. Clinical and toxicological aspects of the antineoplastic 
drug cladribine: a review. Ann Hematol 1994;69:223-30. 
21. 
Avery TL, Rehg JE, Lumm WC, Harwood FC, Santana VM, Blakley RL. Biochemical 
pharmacology of 2-chlorodeoxyadenosine in malignant human hematopoietic cell lines and therapeutic 
effects of 2-bromodeoxyadenosine in drug combinations in mice. Cancer Res 1989;49:4972-8. 
22. 
Robertson LE, Chubb S, Meyn RE, et al. Induction of apoptotic cell death in chronic lymphocytic 
leukemia by 2-chloro-2'-deoxyadenosine and 9-á-D-arabinosyl-2-fluoroadenine. Blood 1993;81:143-50. 
23. 
Santana VM, Mirro J, Kearns C, Schell M, Crom W, Blakley RL. 2-chlorodeoxyadenosine 
produces a high rate of complete hematologic remission in relapsed acute myeloid leukemia. J Clin 
Oncol 1992;10:364-70. 
24. 
Spasokoukotskaja T, Arner ES, Brosjo O, et al. Expression of deoxycytidine kinase and 
phosphorylation of 2-chlorodeoxyadenosine in human and tumour cells and tissues 
Eur J Cancer 1995;31A:202-8. 
25. 
Carrera CJ, Terai C, Lotz M, et al. Potent toxicity of 2-chlorodeoxyadenosine toward human 
monocytes in vitro and in vivo. J Clin Invest 1990;86:1480-8. 
26. 
Saven A, Burian C. Cladribine activity in adult Langerhans-cell histiocytosis. Blood 
1999;93:4125-30. 
27. 
Mottl H, Stary J, Chanova M, Nekolna M, Drahokoupilova E, Smelhaus V. Treatment of 
recurrent Langerhans cell histiocytosis in children with 2-chlorodeoxyadenosine.  Leuk 
Lymphoma2006:1881-4. 
28. 
Weitzman S, Wayne AS, Arceci R, Lipton JM, Whitlock JA, De Rossi G. Nucleoside analogues 
in the therapy of Langerhans cell histiocytosis: a survey of members of the Histiocyte Society and review 
of the literature. Med Pediatr Oncol 1999;33:476-81. 
29. 
Stine KC, Saylors RL, Saccente S, McClain KL, Becton DL. Efficacy of continuous infusion 2-
CDA (cladribine) in pediatric patients with Langerhans cell histiocytosis.  Pediatr Blood Cancer2004:81-4. 
30. 
Ottaviano F, Finlay JL. Diabetes insipidus and Langerhans cell histiocytosis: A case report of 
reversibility with 2-chlorodeoxyadenosine.  J Pediatr Hematol Oncol2003:575-7. 
31. 
Buchler T, Cervinek L, Belohavek O, et al. Langerhans cell histiocytosis with central nervous 
system involvement: Follow-up by FDG-PET during treatment with cladribine.  Pediatr Blood 
Cancer2005:286-8. 
32. 
Choi EK, Park SR, Lee JH, et al. Induction of apoptosis by carboplatin and hyperthermia alone or 
combined in WERI human retinoblastoma cells.  Int J Hyperthermia2003:431-43. 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 52 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
33. 
Konca C, Ozkurt ZN, Deger M, Aki Z, Yagci M. Extranodal multifocal Rosai-Dorfman disease: 
response to 2-chlorodeoxyadenosine treatment. International journal of hematology 2009;89:58-62. 
34. 
Simko SJ, Tran HD, Jones J, et al. Clofarabine salvage therapy in refractory multifocal histiocytic 
disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai-Dorfman 
disease. Pediatric blood & cancer 2014;61:479-87. 
35. 
Stover DG, Alapati S, Regueira O, Turner C, Whitlock JA. Treatment of juvenile 
xanthogranuloma. Pediatric blood & cancer 2008;51:130-3. 
36. 
Rajendra B, Duncan A, Parslew R, Pizer BL. Successful treatment of central nervous system 
juvenile xanthogranulomatosis with cladribine. Pediatric blood & cancer 2009;52:413-5. 
37. 
Gong L, He XL, Li YH, Ren KK, et al. Clonocal status and clinicopathological feature of 
erdheim-chester disease. Pathology, Research and Practice 2009;205:601-7. 
38. 
Haroche J, Charlotte F, Arnaud L. High prevalence of BRAF V600E mutations in erdheim-
chester disease but not in other non-langerhans cell histiocytoses. Blood 2012;120:2700-3. 
39. 
Haroche J, F C-A, J E. Dramatic efficacy of vemurafenib in both multisystemic and refractory 
erdhem-chester disease and langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood 
2013;121:1495-500. 
40. 
Emile JF, Diamond EL, Helias-Rodzewicz Z, et al. Recurrent RAS and PIK3CA mutations in 
Erdheim-Chester disease. Blood 2014;124:3016-9. 
41. 
Arnaud L, Hervier B, Neel A, et al. CNS involvement and treatment with interferon-alpha are 
independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients. 
Blood 2011;117:2778-82. 
42. 
Myra C, Sloper L, Tighe PJ, et al. Treatment of Erdheim-Chester disease with cladribine: a 
rational approach. The British journal of ophthalmology 2004;88:844-7. 
43. 
Bourke SC, Nicholson AG, Gibson GJ. Erdheim-chester disease: pilmonary inflitration 
responsing to cyclophosphamide and prednisolone. Thorax 2003;58:1004-5. 
44. 
Pileri SA, Grogan TM, Harris NL, et al. Tumours of histiocytes and accessory dendritic cells: am 
immunohistochemical approach to classification from the international lymphoma study group based on 
61 cases. Histopathology 2002;41:1-29. 
45. 
Grounder M, Desai V, Kuk D, et al. Impact of surgery, radiation and system therapy on the 
outcome of patients with dendritic cell and histiocytic sarcomas. European journal of cancer 
2015;51:2413-22. 
46. 
Tsujimura H, Miyaki T, Yamada S, et al. Successful treatment of histiocytic sarcoma with 
induction chemotherapy consisting of dose-escalated CHOP plus etoposide and upfront consolidation 
auto-transplantation. International journal of hematology 2014;100:507-10. 
47. 
Tomlin J, Orosco RK, Boles S, et al. Successful Treatment of Multifocal Histiocytic Sarcoma 
Occurring after Renal Transplantation with Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone 
(CLAG-M) Followed by Allogeneic Hematopoietic Stem Cell Transplantation. Case reports in 
hematology 2015;2015:728260. 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 53 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
48. 
Shukla N, Kobos R, Renaud T, et al. Successful treatment of refractory metastatic histiocytic 
sarcoma with almetuzumab. Cancer 2012;118:3719-24. 
49. 
Saygin C, Uzunaslan D, Ozguroglu M, et al. Dentritic cell sarcoma: a pooles analysis including 
462 cases with presentation of our case series. Crit Rev Oncol Hematol 2013;88:253-71. 
50. 
Reichelova V, Liliemark J, Albertioni F. Liquid chromatographic study of acid stability of 2-
chloro-2'-arabino-fluoro-2'-deoxyadenosine, 2-chloro-2'-deoxyadenosine and related analogues. Journal 
of Pharmaceutical and Biomedical Analysis 1995;13:711-4. 
51. 
Carson DA, Wasson DB, Esparza LM, Carrera CJ, Kipps TJ, Cottam HB. Oral antilymphocyte 
activity and induction of apoptosis by 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine. Proceedings of the 
National Academy of Sciences of the United States of America 1992;89:2970-4. 
52. 
Lotfi K, Mansson E, Spasokoukotskaja T, et al. Biochemical Pharmacology and Resistance to 2-
Chloro-2'-arabino-fluoro-2'-deoxyadenosine, a Novel Analogue of Cladribine in Human Leukemic Cells. 
Clinical Cancer Research 1999;5:2438-44. 
53. 
Parker WB, Shaddix SC, Chang CH, et al. Effects of 2-chloro-9-(2-deoxy-2-fluoro-beta-D-
arabinofuranosyl)adenine on K562 cellular metabolism and the inhibition of human ribonucleotide 
reductase and DNA polymerases by its 5'-triphosphate.  Cancer Res1991:2386-94. 
54. 
Xie KC, Plunkett W. Deoxynucleotide pool depletion and sustained inhibition of ribonucleotide 
reductase and DNA synthesis after treatment of human lymphoblastoid cells with 2-chloro-9-(2-deoxy-2-
fluoro- ƒ -D-arabinofuranosyl) adenine.  Cancer Res1996:3030-7. 
55. 
Genini D, Adachi S, Chao Q, et al. Deoxyadenosine analogs induce programmed cell death in 
chronic lymphocytic leukemia cells by damaging the DNA and by directly affecting the mitochondria. 
Blood 2000;96:3537-43. 
56. 
Clinical Report - Protocol CLO-221: A Phase II, open-label study of clofarabine in adult patients 
with refractory or relapsed acute myelogenous leukemia. San Antonio, TX:ILEX Products, Inc. Final 
report dated 13 February 2004. 
57. 
Clolar (clofarabine) Package Insert. San Antonio, TX: Genzyme Corporation. Final dated 
February 2008. 
58. 
A five day intravenous, a five day oral, and a 21-day oral comparative hematological toxicity 
study of clofarabine in male Fisher 344 rats (Study No. 0658-07156). Mt Vernon, IN: BASi Evansville. 
Final report dated 15 November 2007. 
59. 
Gandhi V, Plunkett W. Clofarabine and nelarabine: two new purine nucleoside analogs.  Curr 
Opin Oncol2006:584-90. 
60. 
Bonate PL, Arthaud L, Cantrell WR, Stephenson K, Secrist JA, Weitman S. Discovery and 
development of clofarabine: a nucleoside analogue for treating cancer.  Nat Rev Drug Discov2006:855-63. 
61. 
Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with 
refractory or relapsed acute lymphoblastic leukemia.  J Clin Oncol2006:1917-23. 
62. 
Jeha S, Gandhi V, Chan K, et al. Clofarabine, a novel nucleoside analog, is active in pediatric 
patients with advanced leukemia.  Blood2004:784-9. 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 54 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
63. 
Kantarjian HM, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of 
clofarabine in patients with solid and hematologic cancers.  J Clin Oncol2003:1167-73. 
64. 
Rodriguez-Galindo C, Jeng M, Khuu P, McCarville MB, Jeha S. Clofarabine in refractory 
Langerhans cell histiocytosis. Pediatric Blood & Cancer 2008;51:703-6. 
65. 
Abraham A, Alsultan A, Jeng M, Rodriguez-Galindo C, Campbell PK. Clofarabine salvage 
therapy for refractory high-risk langerhans cell histiocytosis. Pediatric Blood & Cancer 2013;60:E19-
E22. 
66. 
Simko SJ, Tran HD, Jones J, et al. Clofarabine salvage therapy in refractory multifocal histiocytic 
disorders, including Langerhans cell histiocytosis, juvenile xanthogranuloma and Rosai–Dorfman 
disease. Pediatric Blood & Cancer 2014;61:479-87. 
67. 
Clofarabine Investigator's Brochure. 6th ed. San Antonio, TX: Genzyme Corp. Final report dated 
15 March 2007. 
68. 
Gadner H, Minkov M, Grois N, et al. Therapy prolongation improves outcome in multisystem 
Langerhans cell histiocytosis. Blood 2013;121:5006-14. 
69. 
Cheson BD FR, Barrington SF, et al. Recommendations for initial evaluation, staging, and 
response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol 
2014:3059-68. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 55 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
16 APPENDIX I: Performance Status Criteria 
 
Table 1: Performance Status Criteria   
Percentage 
Description 
 
Lansky Performance Scale  
(< 16 yrs) 
Karnofsky Performance Scale  
(> = 16 yrs) 
100 
Fully active, normal. 
Normal, no complaints, no evidence of 
disease. 
90 
Minor 
restrictions 
in 
physically 
strenuous activity. 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 
Active, but tires more quickly. 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Both greater restriction of and less time 
spent in play activity. 
Cares for self, unable to carry on normal 
activity or to do active work. 
60 
Up and around, but minimal active play; 
keeps busy with quieter activities. 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Gets dressed but lies around much of the 
day, no active play but able to participate 
in all quiet play and activities. 
Requires considerable assistance and 
frequent medical care. 
40 
Mostly in bed; participates in quiet 
activities. 
Disabled, requires special care and 
assistance. 
30 
In bed; needs assistance even for quiet 
play. 
Severely 
disabled, 
hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely limited to 
very passive activities. 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
No play; does not get out of bed. 
Moribund, fatal processes progressing 
rapidly. 
0 
Unresponsive. 
Dead. 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 56 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
17 APPENDIX II: Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring 
Plan 
 
17.1 
Introduction 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan (DF/HCC 
DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research protocol. The DF/HCC 
DSMP should serve as a reference for any sites external to DF/HCC that will be participating in the 
research protocol. 
 
17.1.1 Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-Center 
protocol will comply with Federal Regulations, Health Insurance Portability and Accountability 
Act (HIPAA) requirements and applicable DF/HCC Standard Operating Procedures.       
  
17.1.2 Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol:  A research protocol in which one or more outside institutions 
are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC investigator is the 
sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) Network Clinical Trial 
Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members (Dana-
Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth Israel Deaconess 
Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham and Women’s Hospital 
(BWH)) responsible for the coordination, development, submission, and approval of a protocol as 
well as its subsequent amendments per the DFCI IRB and applicable regulatory guidelines (CTEP, 
Food and Drug Administration (FDA), Office of Biotechnology Activities (OBA) etc.).  The Lead 
Institution is typically the home of the DF/HCC Sponsor. The Lead Institution also typically serves 
as the Coordinating Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol.  Within DF/HCC, 
this person is the Overall Principal Investigator who takes responsibility for initiation, management 
and conduct of the protocol at all research locations. In applicable protocols, the DF/HCC Sponsor 
will serve as the single liaison with any regulatory agencies.  The DF/HCC Sponsor has ultimate 
authority over the protocol and is responsible for the conduct of the study at DF/HCC and all 
Participating Institutions. In most cases the DF/HCC Sponsor is the same person as the DF/HCC 
Overall Principal Investigator; however, both roles can be filled by two different people.  
 
Participating Institution:  An institution that is outside the DF/HCC consortium that is 
collaborating with DF/HCC on a protocol where the sponsor is a DF/HCC Investigator.  The 
Participating Institution acknowledges the DF/HCC Sponsor as having the ultimate authority and 
responsibility for the overall conduct of the study.    
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 57 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract Research 
Organization (CRO), etc) that provides administrative support to the DF/HCC Sponsor in order that 
he/she may fulfill the responsibilities outlined in the protocol document and DSMP, and as 
specified in applicable regulatory guidelines (i.e. CTEP Multi-Center Guidelines). In general, the 
Lead Institution is the Coordinating Center for the DF/HCC Multi-Center Protocol. Should the 
DF/HCC Sponsor decide to use a CRO, the CRO will be deemed the Coordinating Center.   
 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring high-
quality standards are used for data collection and the ongoing management of clinical trials, 
auditing, and data and safety monitoring. QACT also coordinates quality assurance efforts related 
to multi-center clinical research. 
 
DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within DF/HCC 
responsible for providing a comprehensive data management platform for managing clinical trial 
data. 
 
17.2 
General Roles and Responsibilities 
 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and the Participating 
Institutions are expected to adhere to the following general responsibilities:  
 
17.2.1 DFCI/HCC Sponsor  
 
The DF/HCC Sponsor, Barbara Degar, MD will accept responsibility for all aspects of conducting 
a DF/HCC Multi-Center protocol which includes but is not limited to:  
 
• Oversee the coordination, development, submission, and approval of the protocol as well 
as subsequent amendments.  
• Ensure that the investigators, study team members, and Participating Institutions are 
qualified and appropriately resourced to conduct the protocol.   
• Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the protocol. 
• Ensure all Participating Institutions are using the correct version of the protocol. 
• Ensure that each participating investigator and study team member receives adequate 
protocol training and/or a Site Initiation Visit prior to enrolling participants and throughout 
trial’s conduct as needed. 
• Ensure the protocol will be provided to each participating site in a language understandable 
to all applicable site personnel when English is not the primary language.  
• Monitor progress and overall conduct of the study at all Participating Institutions.  
• Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable reporting 
requirements are met.  
• Review data and maintain timely submission of data for study analysis.  

Clofarabine for Langerhans Cell Histiocytosis 
     Page 58 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
• Act as the single liaison with FDA. 
• Ensure compliance with all requirements as set forth in the Code of Federal Regulations, 
applicable DF/HCC requirements, HIPAA requirements, and the approved protocol. 
• Commit to the provision that the protocol will not be rewritten or modified by anyone other 
than the DF/HCC Sponsor. 
• Identify and qualify Participating Institutions and obtain accrual commitments prior to 
extending the protocol to that site. 
• Monitor accrual and address Participating Institutions that are not meeting their accrual 
requirements.  
 
17.2.2 Coordinating Center 
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
 
• Assist in protocol development.  
• Maintain FDA correspondence, as applicable. 
• Review registration materials for eligibility and register participants from Participating 
Institutions in the DF/HCC clinical trial management system (CTMS). 
• Distribute protocol and informed consent document updates to Participating Institutions as 
needed. 
• Oversee the data collection process from Participating Institutions. 
• Maintain documentation of Serious Adverse Event (SAE) reports and deviations/violation 
submitted by Participating Institutions and provide to the DF/HCC Sponsor for timely 
review.   
• Distribute serious adverse events reported to the DF/HCC Sponsor that fall under the DFCI 
IRB Adverse Event Reporting Policy to all Participating Institutions. 
• Provide Participating Institutions with information regarding DF/HCC requirements that 
they will be expected to comply with. 
 
• Carry out plan to monitor Participating Institutions either by on-site or remote monitoring.  
• Maintain Regulatory documents of all Participating Institutions which includes but is not 
limited to the following: local IRB approvals/notifications from all Participating 
Institutions, confirmation of Federal wide Assurances (FWAs) for all sites, all SAE 
submissions, Screening Logs for all sites, IRB approved consents for all sites 
Conduct regular communications with all Participating Institutions (conference calls, 
emails, etc) and maintain documentation all relevant communications. 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 59 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
17.2.3 Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations and 
DF/HCC requirements, the protocol and HIPAA requirements.  
 
The general responsibilities for each Participating Institution may include but are not limited to: 
 
• Document the delegation of research specific activities to study personnel. 
• Commit to the accrual of participants to the protocol. 
• Submit protocol and/or amendments to their local IRB. 
• Maintain regulatory files as per sponsor requirements. 
• Provide the Coordinating Center with regulatory documents or source documents as 
requested. 
• Participate in protocol training prior to enrolling participants and throughout the trial as 
required (i.e. teleconferences). 
• Update Coordinating Center with research staff changes on a timely basis. 
• Register participants through the Coordinating Center prior to beginning research related 
activities.  
• Submit Serious Adverse Event (SAE) reports to local IRB per institutional requirements 
and to the Coordinating Center, in accordance with DF/HCC requirements. 
• Submit protocol deviations and violations to local IRB per local requirements and to the 
DF/HCC Sponsor in accordance with DF/HCC requirements. 
• Order, store and dispense investigational agents and/or other protocol mandated drugs per 
federal guidelines and protocol requirements. 
• Have office space, office equipment, and internet access that meet HIPAA standards. 
• Participate in any quality assurance activities and meet with monitors or auditors at the 
conclusion of a visit to review findings. 
• Promptly provide follow-up and/or corrective action plans for any monitoring queries or 
audit findings. 
 
17.3 
DF/HCC Requirements for Multi-Center Protocols 
 
The following section will clarify DF/HCC Requirements and further detail the expectations for 
participating in a DF/HCC Multi-Center protocol.  
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 60 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
17.3.1 Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any subsequent 
amended protocols to all Participating Institutions.    
 
17.3.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures from the 
Coordinating Center.  It is the individual Participating Institution’s responsibility to notify its IRB 
of these revisions. 
 
• Non life-threatening revisions: Participating Institutions will receive written notification 
of protocol revisions regarding non life-threatening events from the Coordinating Center. 
Non-life-threatening protocol revisions must be IRB approved and implemented within 90 
days from receipt of the notification. 
• Revisions for life-threatening causes: Participating Institutions will receive immediate 
notification from the Coordinating Center concerning protocol revisions required to protect 
lives with follow-up by fax, mail, e-mail, etc.  Life-threatening protocol revisions will be 
implemented immediately followed by IRB request for approval. 
• Protocol closures and temporary holds: Participating Institutions will receive notification 
of protocol closures and temporary holds from the Coordinating Center. Closures and holds 
will be effective immediately.  In addition, the Coordinating Center, will update the 
Participating Institutions on an ongoing basis about protocol accrual data so that they will 
be aware of imminent protocol closures. 
 
17.3.3 Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the informed 
consent for Participating Institutions. The Participating Institution consent form must follow the 
consent template as closely as possible and should adhere to specifications outlined in the DF/HCC 
Guidance Document on Model Consent Language for PI-Initiated Multi-Center Protocols.  This 
document will be provided separately to each Participating Institution. 
 
Participating Institutions are to send their version of the informed consent document and HIPAA 
authorization, if a separate document, to the Coordinating Center for review and approval prior to 
submission to their local IRB. The approved consent form must also be submitted to the 
Coordinating Center after approval by the local IRB for all consent versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician members 
of the study team who will be obtaining consent and signing the consent form for therapeutic 
protocols. Participating institutions must follow the DF/HCC requirement that for all interventional 
drug, biologic, or device research, only attending physicians may obtain initial informed consent 
and any re-consent that requires a full revised consent form. 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 61 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
17.3.4 IRB Documentation 
 
The following must be on file with the Coordinating Center: 
 
• Initial approval letter of the Participating Institution's IRB.  
• Copy of the Informed Consent Form(s) approved by the Participating Institution’s IRB.  
• Participating Institution’s IRB approval for all amendments. 
• Annual approval letters by the Participating Institution's IRB. 
 
17.3.5 IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to continue 
research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received from 
the Participating Institution on or before the anniversary of the previous approval date.   
 
17.3.6 Participant Confidentially and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information known as 
the Health Insurance Portability and Accountability Act (HIPAA). Any information, related to the 
physical or mental health of an individual is called Protected Health Information (PHI). HIPAA 
outlines how and under what circumstances PHI can be used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the course of a 
study, the study participant must sign an authorization statement.  This authorization statement may 
or may not be separate from the informed consent document.  The Coordinating Center, with the 
approval from the DFCI IRB, will provide a consent template, with information regarding 
authorization for the disclosure of protected health information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in its trials. 
However, because of the nature of these trials, certain protected health information must be 
collected. DF/HCC has chosen to use authorizations, signed by the participant in the trial, rather 
than limited data sets with data use agreements. 
 
17.3.6.1 
DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center should 
be de-identified. It is recommended that the assigned protocol case number (as described 
below) be used for all participant specific documents. Participant initials may be included 
or retained for cross verification of identification.  

Clofarabine for Langerhans Cell Histiocytosis 
     Page 62 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
17.3.7 DF/HCC Multi-Center Protocol Registration Policy  
 
17.3.7.1 
Initiation of Therapy 
 
Participants must be registered with the DF/HCC CTMS before receiving treatment.  
Treatment may not be initiated until the Participating Institution receives confirmation of 
the participant’s registration from the Coordinating Center. The DF/HCC Sponsor and 
DFCI IRB must be notified of any violations to this policy. Please see section 4.4 of the 
protocol for more information regarding registration procedures. 
 
17.3.7.2 
Eligibility Exceptions 
 
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval will 
be permitted. All Participating Institutions are required to fully comply with this 
requirement. The process for requesting an eligibility exception is defined below. 
 
17.3.8 DF/HCC Protocol Case Number  
 
At the time of registration, the following identifiers for all subjects: initials, date of birth, gender, 
race and ethnicity. Once eligibility has been established and the participant successfully registered, 
the participant is assigned a unique protocol case number.  Participating Institutions should submit 
all de-identified subsequent communication and documents to the Coordinating Center, using this 
case number to identify the subject.   
 
17.3.8.1 
Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review and 
approval, except when necessary to eliminate apparent immediate hazards to the participant. 
DF/HCC requires all departures from the defined procedures set forth in the IRB approved 
protocol to be reported to the DF/HCC Sponsor, who in turn is responsible for reporting to 
the DFCI IRB. 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional policy 
for reporting to their local IRB. 
 
17.3.8.2 
Definitions 
 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 63 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Protocol Violation: Any protocol deviation that was not prospectively approved by the IRB 
prior to its initiation or implementation.  
 
 
17.3.8.3 
Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all protocol 
violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original submission. 
The deviation may not be implemented without all required approvals.  
 
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of 
violations. 
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines.  
 
17.3.9 Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, rights and 
well-being of study participants. Recording and reporting of adverse events that occur during the 
course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated treatment will be 
evaluated for safety. The safety parameters include all laboratory tests and hematological 
abnormalities, physical examination findings, and spontaneous reports of adverse events reported 
by participants.  All toxicities encountered during the study will be evaluated according to the 
NCI criteria specified in the protocol. Life-threatening toxicities must be reported immediately to 
the DF/HCC Sponsor via the Coordinating Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 64 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
17.3.9.1 
Guidelines for Reporting Serious Adverse Events 
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol section 10. 
 
 
 
 
 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Adverse Event Reporting Policy.  
 
The Coordinating Center will review documentation of all Participating Institution Adverse 
Event reports and be responsible for communicating to all participating investigators, any 
observations reportable under the DFCI IRB Reporting Requirements.   
 
Participating Institutions will review and submit to their IRB according to their institutional 
policies and procedures. 
 
17.3.9.2 
Guidelines for Processing IND Safety Reports  
 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions. Participating Institutions will review 
and submit to their IRB according to their institutional policies and procedures. 
 
17.3.10  Data Management 
 
DF/HCC CTRIO develops case report forms (CRF/eCRFs), for use with the protocol.  These forms 
are designed to collect data for each study. DF/HCC CTRIO provides a web based training for 
eCRF users. 
 
17.3.10.1 
Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. 
Participating Institutions are notified of their data submission delinquencies in accordance 
with the following: 
 
Incomplete or Questionable Data 
If study forms are received with missing or questionable data, the submitting institution will 
receive a written or electronic query from the DF/HCC Office of Data Quality, Coordinating 
Center or designee. 
 
Responses to all queries should be completed and submitted within 14 calendar days.   
 
Responses may be returned on the written query or on an amended paper case report form, 
or in the case of electronic queries, within the electronic data capture (eDC) system. In the 
case of a written query for data submitted on a paper case report form, the query must be 
attached to the specific data being re-submitted in response.   
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 65 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Missing Forms 
If study forms are not submitted on schedule, the Participating Institution will periodically 
receive a Missing Form Report from the Coordinating Center noting the missing forms.  
These reports are compiled by the DF/HCC Office of Data Quality and distributed on a 
monthly basis.  
 
17.4 
Requisitioning Investigational Drug 
 
The ordering of investigational agent is specified in the protocol section 7.10. 
 
Ensure that the pharmacy will be able to receive and store the agent according to state and federal 
requirements. The local IRB should be kept informed of who will supply the agent (Sanofi) so that any 
regulatory responsibilities can be met in a timely fashion.  
 
17.5 
Monitoring: Quality Control  
 
The quality control process for a clinical trial requires verification of protocol compliance and data 
accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data Quality, provides quality 
control oversight for the protocol. 
 
17.5.1 Ongoing Monitoring of Protocol Compliance  
 
17.5.1.1 
Site Qualification 
 
Sites are invited to participate in this protocol if they are familiar with and have participated 
in prior Phase I studies, have an appropriate volume of patients to be able to contribute to 
study enrollment goals, and have appropriate resources, including IRB support, 
investigational pharmacists, clinical research coordinators, research nurses, and 
experienced physician investigators to conduct Phase II research.  DF/HCC Site/Protocol 
Feasibility Questionnaires must be completed by each site.  The Sponsor will assess that the 
investigators, study team members, and Participating Institutions are qualified and 
appropriately resourced to conduct the protocol.  The DF/HCC Sponsor will have final 
approval of any and all participating sites on this trial. 
 
17.5.1.2 
Regulatory Documents 
 
DFCI will collect all required regulatory documentation prior to study activation.  This 
includes but, is not limited to 1572, Site PI and Co-Investigator CVs, Financial Disclosure 
Forms, IRB approval documentation. The study team will work with all participating sites 
to ensure all updated / revised regulatory documentation is maintained at each site and 
forwarded to DFCI and maintained in the Trials Master File. 
 
Once a proposed Participating Institution receives institutional IRB approval, all approval 
documentation and IRB-approved related documents will be emailed to the Coordinating 
Center study staff and an amendment to add a site will be submitted to the DF/HCC IRB.   

Clofarabine for Langerhans Cell Histiocytosis 
     Page 66 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
Once approval is received to add the Participating Institution study materials will be sent to 
the Participating Institution.  Study materials will include, but are not limited to, regulatory 
documents and participant tracking forms.  
 
All Participating Institutions must maintain and update all essential regulatory documents 
in a regulatory binder.  A designated member of the DF/HCC Lead Institution will be 
responsible for maintaining the Trial Master File which will include copied of all regulatory 
documentation for the Lead Site and all Participating Institutions.   
 
All Participating Institutions are required to submit all institutional IRB correspondences 
and approvals to be retained in the Trial Master File at the Lead Institution.  The Lead 
Institution will review all working study documents and ensure that most current IRB-
approved protocol and study documents are being used by the Participating Institutions.  
 
17.5.1.3 
Site Initiation Visit 
 
A Site Initiation Visit (SIV) will be conducted with all participating sites via 
teleconference/webinar prior to enrolling participants.  The SIV will cover study objectives 
and rationale, history of LCH-CLO, study design, eligibility, registration, required data, 
treatment schedule, side effects/AEs, SAE reporting, and dose modification.  It will be led 
by the Coordinating Center and it is expected that the Site PI and all study staff will attend.   
 
17.5.1.4 
Delegation of Authority/Responsibility 
 
Participating Institutions will be instructed to complete a Delegation of Responsibility/ 
Authority Log which will be reviewed/approved by the DF/HCC Sponsor.  A copy of this 
document will be retained in the Trial Master File.  Participating Institutions will be 
instructed to inform the Coordinating Center immediately should there be a change in 
personnel.  An updated training and Delegation of Authority/Responsibility log will need 
to be completed as soon as possible.  
 
17.5.1.5 
Monitoring 
 
The Participating Institutions will be required to submit participant source documents to the 
Coordinating Center for monitoring. Participating Institution may also be subject to on-site 
monitoring conducted by the Coordinating Center.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety. Monitoring will occur before the clinical phase of the 
protocol begins, continue during protocol performance and through study completion. 
Additional monitoring practices may include but are not limited to; source verification, 
review and analysis of the following: eligibility requirements of all participants, informed 
consent procedures, adverse events and all associated documentation, study drug 
administration/treatment, regulatory files, protocol deviations, pharmacy records, response  

Clofarabine for Langerhans Cell Histiocytosis 
     Page 67 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
assessments, and data management.  
 
A study monitor will be available for monitoring all participating sites. All monitoring 
reports and ongoing progress reports for all participating sites will be provided to the 
DF/HCC Sponsor.  Any major monitoring findings will be communicated to the DF/HCC 
Sponsor immediately. 
Virtual Monitoring  
The monitor will be responsible for on-going virtual monitoring of regulatory documents 
and data entered by participating sites.  Participating sites will be responsible for providing 
necessary source documentation for virtual monitoring.    
 
All eligibility source documentation from all participating sites will be reviewed by the 
Coordinating Center prior to registering participants on protocol. At the time of registration, 
all points of eligibility must be found in either source documentation or if eligibility points 
cannot be found in source documentation (i.e. lab reports etc.), they must be included in 
an MD note.   
 
Registration documents (consent form and eligibility checklist) will also be reviewed via 
virtual monitoring at the time of registration.  At the time of registration, the eligibility 
checklist(s) and all pages of the consent form(s) must be faxed or emailed to the DFCI Study 
Team for review (refer to protocol section 4 for participant registration process).  The DFCI 
Study Team will review each consent form to ensure 1) it is the most appropriate and current 
version, 2) that the participant information is included on all pages of the consent and that 
all pages of the consent have been submitted, 3) that the participant has signed and dated 
the consent form, 4) that a physician has reviewed and signed the consent form on the same 
day/time as the participant, and that 5) all appropriate items have been completed.     
 
Additional source documents that will be reviewed virtually include, but are not limited to: 
 
• All results of the Required Assessments (Protocol Table 2).  
• Any extra source documentation (i.e. admission notes, scans, culture results) 
pertaining to a serious adverse event (SAE). 
 
In addition to enrollment documents, a subset of participants will have all data reviewed via 
virtual monitoring.  This will occur once the participants complete cycle 1 of this study.  
 
A list of items required to be virtually monitored will be provided to participating sites.   
 
Virtual monitoring will be performed on an ongoing basis.  The monitor will query within 
the Electronic Data Capture system.  The DF/HCC Sponsor will be notified on an ongoing 
basis on the status of virtual monitoring, including which patients and what data has been 
virtually monitored.  As part of virtual monitoring, if any significant non-compliance (i.e. 
if a patient is ineligible) is found during virtual monitoring this will be reported to the 
DF/HCC Sponsor immediately.   

Clofarabine for Langerhans Cell Histiocytosis 
     Page 68 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
On-Site Monitoring 
On-site monitoring may occur if sub-standard performance is discovered during virtual 
monitoring.  
 
If sub-standard performance is discovered during routine monitoring (virtual or on-site) or 
auditing, more frequent on-site monitoring visits and/or audits will be made. Sub-standard 
performance includes, but is not limited to, data not entered on time, unreported adverse 
events, or enrolling ineligible participants. Participating Institutions that fail to meet the 
performance goals of accrual, submission of timely accurate data, adherence to protocol 
requirements, and compliance with state, federal, and Good Clinical Practice guidelines, 
will be recommended for a six- month probation period. Such institutions must respond 
with a corrective action plan and must demonstrate during the probation period that 
deficiencies have been corrected, as evidenced by the improved performance measures. 
Participating Institutions that fail to demonstrate significant improvement will be 
considered by the Sponsor for revocation of participation.  
 
All submitted data will be monitored for timeliness of submission, completeness, and 
adherence to protocol requirements. The Coordinating Center and if applicable, ODQ Data 
Analysts assigned to the protocol, will perform the ongoing protocol data compliance 
monitoring. 
 
17.5.1.6 
Adverse Event Reporting 
 
Documentation of all adverse events must be included as part of source documentation.  
Documentation that a physician determined attribution of each event must also be included.  
AEs and SAEs must be reported as instructed in the protocol with the log serving as record  
 
for all events at each Participating Institution.  The DF/HCC Sponsor, Barbara Degar, MD, 
will be notified/report all AEs and SAEs as per protocol.  Each Participating Institution will 
be instructed to keep an SAE log and submit it to the DF/HCC Lead Institution prior to each 
monthly teleconference.  The DF/HCC Lead Institution will maintain a master SAE list.   
 
17.5.1.7 
Drug Accountability 
 
Participating pharmacies will be required to submit Drug Accountability Logs at the time 
of monitoring documenting receipt and shipment of drug supply, dispensing/ordering of 
supply, and destruction of unused study medication and/or damaged or expired drug.  
Participating Institutional Pharmacies should destroy drug as per their institutional policy.   
 
17.5.1.8 
Ongoing Communication 
 
Participating institutions will be required to participate in monthly Coordinating Center 
initiated teleconferences. This will be a forum to discuss study related issues not limited 
to the following: study accrual, SAE’s/AE’s, clinical response, deviations/violations, and 
monitoring A log of all SAEs and minor/major deviation/violation that have occurred on 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 69 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
study will be reviewed during each conference call. An agenda will be sent prior to each 
conference call and minutes will be taken.  Calls will be held more or less regularly as 
needed based upon study accrual, necessary study updates or Sponsor request.   
 
17.5.2 Monitoring Reports   
 
The DF/HCC Sponsor will review all monitoring reports for on-site and remote monitoring of 
Participating Institutions to ensure protocol compliance. The DF/HCC Sponsor may increase the 
monitoring activities at Participating Institutions that are unable to comply with the protocol, 
DF/HCC Sponsor requirements or federal and local regulations. Participating Institutions may also 
be subject to an audit as determined by the DF/HCC Sponsor. 
 
17.5.3 Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish accrual 
requirements for each participating institution. Accrual will be monitored for each participating 
institution by the DF/HCC Sponsor or designee. Sites that are not meeting their accrual expectations 
may be subject to termination.  The minimum accrual requirement is at least 1 patient per site 
annually. 
 
17.6 
Auditing: Quality Assurance  
 
Auditing is a method of Quality Assurance. Its main focus is to measure whether standards and procedures 
were followed. Auditing is the systematic and independent examination of all trial related activities and 
documents.  Audits determine if evaluated activities were appropriately conducted and whether data was 
generated, recorded and analyzed, and accurately reported per the protocol, Standard Operating Procedures 
(SOPs), and the Code of Federal Regulations (CFR). 
 
17.6.1 Audit Plan: DF/HCC Sponsored Trials 
 
All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality (ODQ). 
Typically, approximately 3-4 participants would be audited at the site over a 2-day period.  If 
violations which impact participant safety or the integrity of the study are found, more participant 
records may be audited. 
 
17.6.2 Audit Notifications 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all scheduled 
audit dates (internal or NCI) and re-audit dates (if applicable), which involve this protocol. All 
institutions will forward a copy of final audit and/or re-audit reports and corrective action plans (if 
applicable) to the Coordinating Center, within 12 weeks after the audit date.  
 
 
 

Clofarabine for Langerhans Cell Histiocytosis 
     Page 70 of 70 
June 12, 2019 
 
 
 
 
CONFIDENTIAL 
This document is confidential. Do not disclose or use except as authorized. 
17.6.3 Audit Reports 
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans if applicable. 
The Coordinating Center, must forward these reports to the DF/HCC ODQ per DF/HCC policy for 
review by the DF/HCC Audit Committee. Based upon the audit assessments the DF/HCC Audit 
Committee could accept or conditionally accept the audit rating and final report. Conditional 
approval could require the DF/HCC Sponsor to implement recommendations or require further 
follow-up.  For unacceptable audits, the DF/HCC Audit Committee would forward the final audit 
report and corrective action plan to the DFCI IRB as applicable. 
 
17.6.4 Participating Institution Performance 
 
The DF/HCC Sponsor, DFCI IRB, is charged with considering the totality of an institution’s 
performance in considering institutional participation in the protocol. 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of timely 
and accurate data, adherence to protocol requirements, and compliance with state and federal 
regulations, may be recommended for a six-month probation period. Such institutions must respond 
with a corrective action plan and must demonstrate during the probation period that deficiencies 
have been corrected, as evidenced by the improved performance measures. Participating 
Institutions that fail to demonstrate significant improvement will be considered by the DF/HCC 
Sponsor for revocation of participation. A DF/HCC Sponsor and/or the DFCI IRB may terminate 
a site’s participation if it is determined that a site is not fulfilling its responsibilities as described 
above.