Clinical trial NCT04463615
Conditions: Recurrent Lymphoproliferative Disorder Refractory Lymphoproliferative Disorder
Sponsor: City of Hope Medical Center
Start date: 2021-05-05; Completion date: 2021-07-28
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This trial studies how well leflunomide works for the treatment of patients with CD30+ lymphoproliferative disorders that have come back (relapsed) or do not respond to treatment (refractory). Leflunomide may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed description:
PRIMARY OBJECTIVE:

I. To evaluate overall response rate of leflunomide treatment.

SECONDARY OBJECTIVES:

I. To assess complete response rate and duration of response of leflunomide treatment.

II. To assess toxicities of leflunomide treatment. III. To assess disease status by the CAILS (composite assessment of index lesion severity).

EXPLORATORY OBJECTIVE:

I. To generate a preliminary ribonucleic acid (RNA) signature associated with response of CD30+ lymphoproliferative disorders (LYPDs) cells to leflunomide.

OUTLINE:

Patients receive leflunomide orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 12 months.

Arms: arm 1: Patients receive leflunomide PO QD on days 1-28. Treatment repeats every 28 days for up to 13 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Leflunomide
Intervention descriptions: intervention 1: Given PO

Protocol documents:
Prot_SAP_000.pdf: 
 
IRB #: 19606 
 
 
Version: 02 
 
07/08/2021 
CITY OF HOPE 
1500 E. DUARTE ROAD 
DUARTE, CA 91010 
 
DEPARTMENT OF HEMATOLOGY AND HEMATOPOIETIC CELL TRANSPLANTATION                            
 
TITLE: Pilot Trial of Leflunomide in Patients with CD30+ Lymphoproliferative Disorders 
 
CITY OF HOPE PROTOCOL NUMBER: 
IRB # 19606  
 
Protocol Date: 07/08/2021 
 
Initial Submission  
 
Protocol dated 10/04/2019 
 
 
 
 
Version: 00 
COH Amendment 01 
Protocol dated 07/08/2021 (PI change) 
Packet: 01 
COH Amendment 02 
Protocol dated 07/08/2021 (TP) 
Packet: 02 
 
SITE:  
 
 
 
 
 
 
STAGE (If applicable): 
 
 
 
 
 
MODALITY:  
 
 
 
 
 
 
TYPE:  
 
 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
 
 
Christiane Querfeld, M.D., Ph.D. 
 
 
COLLABORATING INVESTIGATORS: 
 
Stephen Rosen, M.D. 
Jasmine Zain, M.D. 
 
PARTICIPATING CLINICIANS: 
Elizabeth Budde, M.D., Ph.D. 
Matthew Mei, M.D. 
Liana Nikolaenko, M.D. 
Leslie Popplewell, M.D. 
Tanya Siddiqi, M.D. 
Swetha Kambhampati, M.D. 
John Baird, M.D. 
 


This document is confidential and for research purposes only. Do not copy, redistribute, disclose or use except as 
authorized.  
 
 
City of Hope National Medical Center 
1500 E. Duarte Road 
Duarte, CA 91010 
Clinical Trial Protocol 
Pilot Trial of Leflunomide in Patients with Cutaneous CD30+ Lymphoproliferative 
Disorders 
Version Date: 07/08/2021 
Protocol Version: 01 
City of Hope #: 19606 
Agents: Leflunomide, commercially available ... 
IND Number: Exempt 
Sponsor/IND Holder: Exempt 
Funding Support: Pending  
Funding Support/Industry Partner: Pending 
NCT Number: Pending 
Participating Sites: City of Hope (Duarte) 
Short Title Leflunomide Pilot for CD30+ LYPD 
 
 
Principal Investigator 
Christiane Querfeld, MD, PhD 
City of Hope National Medical Center 
Dept. of Pathology 
T: (626)-256-4673 ext 82405 
Email: cquerfeld@coh.org 
Coordinating Center 
Data Coordinating Center 
City of Hope National Medical Center 
T: (626)-218-7904 
Email: DCC@coh.org 
. 
 


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PROTOCOL TEAM 
Biostatistician 
Lu Chen, PhD 
City of Hope National Medical Center 
Dept. of Computational and 
Quantitative Medicine 
T: 626-218-6626 
Email: lchen@coh.org 
Protocol Development Scientist 
D. Lynne Smith, PhD 
City of Hope National Medical Center 
Toni Stephenson Lymphoma Center 
T: 626 218-1134 
Email: lysmith@coh.org 
  
 
Co-Investigator 
Xiwei Wu, PhD 
City of Hope National Medical Center 
Dept. of Molecular and Cellular 
Biology 
T: 626 218-5071 
Email: xwu@coh.org 
 
 
 
Co-Investigator 
Steven Rosen, MD 
Director, Comprehensive Cancer 
Center and Beckman Research 
Institute 
City of Hope National Medical Center 
T: (626)-218-9150 
Email: srosen@coh.org 
Co-Investigator 
Jasmine Zain, MD 
City of Hope National Medical Center 
Dept. of Hematology 
T: (626)-256-4673 ext 82405 
Email: jazain@coh.org 
 
 


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STUDY SCHEMA 
 
*Initial biopsy prior to first dose of leflunomide on C1D1 
†On C2D1, C5D1, and end of therapy if lesions are present, and at disease progression. 
 
 


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PROTOCOL SYNOPSIS 
Protocol Title 
Pilot Trial of Leflunomide in Patients with Cutaneous CD30+ Lymphoproliferative Disorders 
Study Detail 
Population/Indication(s): 
Patients with cutaneous CD30+ lymphoproliferative disorders 
Phase: 
Pilot study 
Sample Size: 
Expected: 12, Maximum: 14 
Estimated Accrual Duration: 
3 years 
Estimated Study Duration 
Up to 5 years 
Participant Duration: 
Up to 24 months (12 months of treatment + 12 months of follow-up). 
Participating Sites: 
 City of Hope Duarte, CA 
Study Agents: 
Leflunomide, commercially available ... 
Sponsor: 
City of Hope 
Industry Partner:  PendingPendingPendingPendingPendingPendingPending 
 
 
 
 
Rationale for this Study 
Cutaneous CD30 lymphoproliferative disorders include lymphomatoid papulosis and primary cutaneous anaplastic large 
cell lymphoma.  Systemic therapies for widespread cutaneous disease include methotrexate, radiation therapy, and 
brentuximab vedotin, all of which have poor side effect profiles for a group of diseases that have a relatively indolent 
course. Leflunomide is a commercially available oral immunosuppressive agent that has been FDA approved since 1998 
for the treatment of rheumatoid arthritis (RA). The primary mechanism of action of leflunomide is inhibition of de novo 
pyrimidine synthesis by targeting dihydroorotate dehydrogenase (DHODH), resulting in anti-proliferative effects in B- and 
T-lymphocytes. Leflunomide has been investigated for its anti-neoplastic potential in a variety of pre-clinical tumor 
models. Recent pre-clinical studies have demonstrated significant anti-neoplastic activity in CD30+ lymphoproliferative 
disorders. In addition, limited clinical experience is suggestive of a beneficial response when leflunomide is used to treat 
CD30+ lymphoproliferative disorders (CD30+LYPD). Considering the favorable toxicity profile and extensive clinical 
experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for therapy CD30 
LYPDs. 
Treatment Description 
Leflunomide will be administered orally at a dose of 20 mg/day following a loading dose of 100 mg/day for the first three 
days of administration. Patients will be treated in planned 28-day treatment cycles. Patients may continue to receive 
cycles of treatment on study (maximum 13 cycles) until disease progression or unacceptable toxicity, or other criteria for 
removal from study treatment are satisfied. While on active treatment patients will undergo  evaluation for response 
after every cycle. At the time of terminating leflunomide, all participants will receive 11 days of oral cholestyramine 
treatment (8 g three times daily) to reduce the plasma leflunomide levels. Patient will be followed for 1 year after 
terminating leflunomide treatment, or until disease progression, whichever is earlier. 
Objectives 
Primary Objective 
 To evaluate overall response rate of leflunomide treatment 
Secondary Objectives 
 To assess complete response rate and duration of response of leflunomide treatment 
 To assess toxicities of leflunomide treatment 
 To assess disease status by the CAILS (composite assesment of index lesion severity) 
Exploratory Ex-vivo and Molecular Objectives 


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 
To generate a preliminary RNA signature associated with response of CD30+LYPD to leflunomide 
Study Design 
This study will be conducted as a single center, single agent pilot study. 
Evaluation Criteria and Endpoints 
Primary Endpoint(s): 
 
The primary endpoint is overall response (CR + PR). Response will be categorized by mSWAT. The response 
categories and criteria are summarized in Table 11.2 of the protocol.  
Statistical Considerations 
Sample size: This study will accrue 12 response evaluable patients, with a maximum accrual of 14 patients. Because this is 
a rare disease that has not been systematically studied in a prospective clinical trial, there is a lack of historical data on the 
response rate (and by modified severity weighted assessment tool [mSWAT]) in this patient population. The sample size 
for this pilot study was chosen based on feasibility considerations, and not based on any definitive statistical criterion. 
With 12 patients, the 95% exact binomial confidence interval for the overall response rate will have a width of 55% (33% 
response rate, with 4 responders), 57% (42% response rate, with 5 responders), 58% (50% response rate, with 6 
responders), 57% (58% response rate, with 7 responders), 55% (67% response rate, with 8 responders), 52% (75% 
response rate, with 9 responders), and 46% (83% response rate, 10 responders) respectively. For any AE with a true 
incidence of 15% or higher, with 12 patients there is at least an 86% chance of observing 1+ patients with such AE. 
We project to accrue approximately one patient every 3 months. The projected study accrual duration is therefore 3 
years. 
Analysis: Observed toxicities will be summarized in terms of type (organ affected or laboratory determination), severity, 
attribution, time of onset, duration, serum concentration of the active leflunomide metabolite, probable association with 
the study treatment and reversibility or outcome. Baseline information (e.g. the extent/type of prior therapy) and 
demographic information will be presented as well to describe the patients treated in this study. 
Rates and 95% Clopper Pearson binomial confidence interval (CI) will be calculated for overall response rate (patients 
that have confirmed CR or PR) and clinical benefit rate (patients that have confirmed CR/PR/MR or SD). In addition, sub-
analyses will be performed where participants will be considered evaluable for response if they are confirmed eligible, 
receive at least 75% of leflunomide during the first cycle of therapy and have their disease re-evaluated. Response rates 
will also be explored based on number/type of prior therapy(ies) and serum concentration of the leflunomide metabolite 
(µg/mL). Time to response and survival will be estimated using the product-limit method of Kaplan and Meier. 
Preliminary molecular profiles for mRNA will be derived from skin biopsies. These profiles will be used to identify 
molecular correlates of therapeutic response using pathway identification and supervised principal components analysis. 
Abbreviated Eligibility Criteria 
Main Inclusion Criteria 
 
Adult patients with a diagnosis of CD30+LYPD with life expectancy of > 3 months 
 
ECOG  ≤2 
 
Relapsed or refractory to at least 1 prior line of therapy 
 
Platelet count > 50,000/µL, ANC ≥ 1000/mm3, AST and ALT < 2.0 x ULN, total bilirubin < 1.5 x ULN 
Main Exclusion Criteria 
 
Prior treatment with lenflunomide 
 
Prior diagnosis of rheumatoid arthritis 
 
Prior allogeneic transplant 
 
Acute active infection, known HIV, HBV, HCV infection 
 
Preexisting liver disease 


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 
History of allergic reactions attributed to compounds of similar chemical or biologic composition to leflunomide 
or cholestyramine. 
 
Non-hematologic malignancy within the past 3 years aside from the following exceptions:  
o 
adequately treated basal cell or squamous cell skin cancer 
o 
carcinoma in situ of the cervix 
o 
prostate cancer < Gleason Grade 6 with a stable PSA 
o 
successfully treated in situ carcinoma of the breast 
 
Investigational Product Dosage and Administration 
Leflunomide will be administered orally at a dose of 20 mg/day following a loading dose of 100 mg/day for the first three 
days of administration.  
Clinical Observations and Tests to be Performed 
 
Clinical observations will include tolerance as well as response to treatment. 
 
Baseline studies will include: history and physical, skin biopsies (the skin biopsy will be used for clinical 
assessment and leftover samples will be used for correlative laboratory studies), as well as a laboratory 
evaluation to include CBC with differential, comprehensive chemistry panel (to include LDH, magnesium, 
phosphorus and uric acid). 
 
Clinical observation of response will take place on day 1 of each 28-day cycle. Subjects will be evaluated 
through clinic visits and physical exams as well as laboratory tests to include CBC with differential, 
comprehensive chemistry panel. Blood tests will be performed at a minimum of every 28 days but may be 
done more frequently as clinically indicated.  
 
Skin biopsy will be performed at the baseline, after 1 month, 4 months of Leflunomide therapy and at end 
of therapy (if lesions are present), and at disease progression. 
 
Patients will undergo toxicity assessment every two weeks for the first three cycles following initiation 
with leflunomide and will undergo, at a minimum, monthly toxicity assessments thereafter. 
 
 


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TABLE OF CONTENTS 
SECTION ....................................................................................................................................................................... PAGE 
Protocol Team ..................................................................................................................................................................... 2 
Study Schema ...................................................................................................................................................................... 3 
Protocol Synopsis ................................................................................................................................................................ 4 
Table of Contents ................................................................................................................................................................ 7 
Abbreviations ...................................................................................................................................................................... 9 
1.0 
Objectives ............................................................................................................................................................ 10 
1.1 
Primary Objective 
10 
o 
To evaluate overall response rate of leflunomide treatment 
10 
1.2 
Secondary Objectives 
10 
1.3 
Exploratory Objectives 
10 
2.0 
Background .......................................................................................................................................................... 10 
2.1 
Introduction/Rationale for Development 
10 
2.2 
Leflunomide 
10 
2.3 
Preclinical Studies of Leflunomide as an antineoplastic agent 
11 
2.4 
Background for Correlative Studies 
12 
2.5 
Overview and Rationale of Study Design 
12 
3.0 
Eligibility Criteria .................................................................................................................................................. 14 
3.1 
Inclusion Criteria 
14 
3.2 
Exclusion Criteria 
15 
3.3 
Inclusion of Women and Minorities 
16 
4.0 
Participant Enrollment ......................................................................................................................................... 17 
4.1 
Pre-Enrollment Informed Consent and Screening Procedures 
17 
4.2 
Participant Enrollment 
17 
4.3 
Screen Failures and Registered Participants Who Do Not begin Study Treatment 
18 
5.0 
Treatment Program ............................................................................................................................................. 18 
5.1 
Treatment Program Overview 
18 
5.2 
Cycle Definition 
18 
5.3 
Agent Administration 
18 
5.4 
Assessments and Special Monitoring 
18 
5.5 
End of Treatment Evaluations and Leflunomide Detoxification 
19 
5.6 
Duration of Therapy and Criteria for Removal from Protocol Therapy 
19 
5.7 
Active Follow-Up 
19 
5.8 
Duration of Study Participation 
19 
5.9 
Prohibited and Concomitant Therapies/Medications 
20 
5.10 
Supportive care 
20 
6.0 
Anticipated Adverse Event List ............................................................................................................................. 20 
6.1 
Leflunomide 
20 
6.2 
Cholestyramine 
21 
7.0 
Dose Delay/Modification Guidelines.................................................................................................................... 22 
7.1 
Dose Modifications for Leflunomide 
22 
7.2 
Dose Modifications of Cholestyramine 
25 
8.0 
Agent Information ............................................................................................................................................... 25 
8.1 
Leflunomide 
25 
8.2 
Cholestyramine 
26 
9.0 
Correlative/ Special Studies ................................................................................................................................. 27 
9.1 
Central Pathology Review 
27 
9.2 
Skin Biopsies 
27 
10.0 
Study Calendar ..................................................................................................................................................... 30 
11.0 
Endpoint Definitions/Measurement of Effect ...................................................................................................... 33 


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11.1 
Safety Endpoints 
33 
11.2 
Efficacy Endpoints 
33 
11.3 
Exploratory Endpoints 
33 
12.0 
Statistical Considerations ..................................................................................................................................... 33 
12.1 
Study Design 
33 
12.2 
Sample Size and Accrual Rate 
33 
12.3 
Evaluable Participants and Participant Replacement 
34 
12.4 
Statistical Analysis Plan 
34 
13.0 
Data Handling, Data Management, Record Keeping ............................................................................................ 34 
13.1 
Source Documents 
34 
13.2 
Data Capture Methods and Management 
34 
13.3 
Case Report Forms/Data Submission Schedule 
35 
13.4 
Regulatory Records 
35 
14.0 
Reporting of Adverse Events, Unanticipated Problems & Other Events of Interest .............................................. 35 
14.1 
Assessment of Adverse Events 
35 
14.3 
Expedited Reporting 
36 
14.4 
Adverse Events of Special Interest (AESI) Requiring Expedited Reporting 
37 
15.0 
Adherence to the Protocol & Reporting of Protocol Deviations ........................................................................... 37 
16.0 
Study Oversight, Quality Assurance, & Data and Safety Monitoring .................................................................... 38 
16.1 
All Investigator Responsibilities 
38 
16.2 
Study PI Responsibilities 
38 
16.3 
Protocol Management Team (PMT) 
38 
16.4 
Auditing & Quality Assurance 
38 
16.5 
Risk Determination 
38 
16.6 
City of Hope Data and Safety Monitoring Committee (DSMC) 
38 
17.0 
Ethical and Regulatory Considerations ................................................................................................................. 38 
17.1 
Ethical Standard 
38 
17.2 
Regulatory Compliance 
39 
17.3 
Institutional Review Board 
39 
17.4 
Informed Consent 
39 
17.5 
Participant Withdrawal 
40 
17.6 
Special and Vulnerable Populations 
40 
17.7 
Participant Confidentiality 
41 
17.8 
Use of Unused (Leftover) Specimens Collected for this Trial 
42 
17.9 
Conflict of Interest 
42 
17.10 
Financial Obligations, Compensation, and Reimbursement of Participants 
42 
17.11 
Publication/ Data Sharing 
42 
18.0 
References ........................................................................................................................................................... 44 
Appendix A: ECOG Performance Status Scale .................................................................................................................... 46 
Appendix B: ISCL/EORTC tNM Classification of cutaneous Lymphoma other than MF/SS .................................................. 47 
Appendix C: Modified Severity Weighted Assessment Tool (MSWAT) ............................................................................... 49 
appendix E: Composite Assessment of Index Lesion Severity (CAILS) ................................................................................ 53 
 
 


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ABBREVIATIONS  
Abbreviation 
Meaning 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
COH 
City of Hope 
CR 
Complete Response 
CRC 
Clinical Research Coordinator  
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
DLCO 
Carbon Monoxide Diffusing Capacity 
DLT 
DHODH 
Dose Limiting Toxicity 
Dihydroorotate Dehydrogenase  
DSMC 
Data Safety Monitoring Committee 
EOT 
End of Treatment 
FDA 
Food and Drug Administration 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICG 
Integrated Genomics Core 
IDS 
Investigational Drug Service 
IND 
Investigational New Drug  
IRB 
LYPDs 
MNC 
MR 
Institutional Review Board 
Lymphoproliferative Disorders  
Mononuclear Cells 
Minimal Response 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
PD 
Progressive Disease 
PI 
Principal Investigator 
PMT 
Protocol Monitoring Team 
PR 
RP2D 
RA 
Partial Response 
Recommended Phase II Dose 
Rheumatoid Arthritis 
SAE 
Serious Adverse Event 
sCR 
SD 
Stringent Complete Response 
Stable Disease 


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1.0 OBJECTIVES 
In patients with CD30+ Lymphoproliferative Disorders (CD30+LYPDs) 
1.1 Primary Objective 
o 
To evaluate overall response rate of leflunomide treatment 
1.2 Secondary Objectives 
o 
To assess complete response rate and duration of response of leflunomide treatment 
o 
To assess toxicities of leflunomide treatment 
o To assess disease status by the CAILS (composite assessment of index lesion severity). 
1.3 Exploratory Objectives 
o 
To generate a preliminary RNA signature associated with response of CD30+LYPDs cells to leflunomide. 
2.0 BACKGROUND 
2.1 Introduction/Rationale for Development 
The term “CD30+ T-cell lymphoproliferative disorders” (CD30+LYPDs) describes a group of diverse diseases of the 
skin.[1] Primary cutaneous CD30+ T cell lymphoproliferative disorders (pcCD30+ T cell LPDs) are the second most 
common type of cutaneous T cell lymphomas (CTCL), after mycosis fungoides (MF), accounting for 30% of all 
primary cutaneous lymphomas [2, 3]. CD30+LYPD includes primary cutaneous anaplastic large cell lymphoma 
(pCALCL) and lymphomatoid papulosis (LyP).  Their diagnostic hallmark is CD30 expression by the atypical 
lymphocytes, in the same typical membranous and golgi pattern observed in systemic anaplastic large cell 
lymphoma (sALCL) [4]. The treatment and prognosis of cutaneous CD30+ T cell LPDs differ significantly from those 
of systemic lymphomas, emphasizing the importance of a clinical pathological correlation and thorough workup 
to ensure an accurate diagnosis [5]. 
For both LyP and pcALCL, treatments are determined by the extent of disease. In LyP, topical treatments such as 
corticosteroids and nitrogen mustard are not effective in changing the overall course of disease.  Current therapies 
treat only current existing lesions and associated symptoms, such as pruritus [6, 7]. Patients with diffuse disease 
are treated with phototherapy or methotrexate [8]. Both therapies cannot be continued indefinitely due to the 
risk of long term side effects. Once these therapies are discontinued, lesions usually recur with the same intensity. 
In pcALCL, for single or localized lesions the main effective treatments are surgical excision or radiotherapy.  For 
multifocal or recurrent pcALCL, systemic therapies are used such as methotrexate, bexarotene or Brentuximab 
Vedotin [9].  Treatment decision making is particularly challenging, given the toxic nature of available agents for 
a relatively indolent lymphoma. 
2.2 Leflunomide 
Leflunomide is a commercially available oral immunosuppressive agent that has been FDA approved since 1998 
for the treatment of rheumatoid arthritis (RA) as a single agent or in combination with methotrexate. It has been 
used in over 300,000 patients worldwide for RA treatment. Leflunomide is generally well-tolerated and may be 
taken over a long period of time.  
The in vitro and in vivo mechanisms of leflunomide are not completely defined. The primary clinical mechanism 
of action is inhibiting de novo pyrimidine synthesis by targeting dihydroorotate dehydrogenase (DHODH), and 
thus achieving anti-proliferative effect in B- and T-lymphocytes. A secondary mechanism of action is inhibition of 
cytokine and growth factor receptor associated tyrosine kinase activity [10].  


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Leflunomide (the pro-drug) is rapidly converted to its active primary metabolite teriflunomide (A77 1726), which 
mediates leflunomide’s pharmacologic activity. Teriflunomide serum concentrations show wide inter-patient 
variability; in one study, the mean serum teriflunomide concentration in patients receiving 20 mg/ daily was 42 
mg/l with a range from 3-150 mg/l and a standard deviation of 35 mg/l [11]. Of note, the serum concentration of 
this metabolite was shown to predict RA response [11].  
The FDA approved dose in adults for the treatment of RA is a loading dose of 100 mg orally (PO) once daily for 3 
days, followed by a maintenance dose of 10-20 mg PO once daily. Leflunomide has been used at up to 40 mg/day 
in patients with Wegner’s granulomatosis with a safety profile similar to the 20mg/day dose used in RA [12, 13]. 
Doses up to 60 mg/day have been safely used for the treatment of allograft polyoma BK virus in renal allograft 
patients to achieve a targeted blood level of teriflunomide (A77 1726) of 50-100 micrograms/mL [14]; the targeted 
blood level was frequently achieved with a dose of 40mg/ day with no increase in toxicity reported [14].  
In addition to studies that demonstrate the serum concentration of the metabolite may predict response, recent 
work demonstrates that polymorphisms in the gene encoding DHODH may be associated with leflunomide 
treatment outcome in RA patients[15, 16].  
The long half-life of the metabolite (about 2 weeks) affects management of patients taking leflunomide. A loading 
dose of 100 mg for 3 days is used to facilitate rapid attainment of steady state levels of M1. Without a loading 
dose, it is estimated that attainment of steady state concentrations would require nearly two months of dosing 
[17]. To eliminate the metabolite, a drug elimination procedure using cholestyramine is recommended. 
Cholestyramine, a bile acid sequestrant, fixes the metabolite, preventing reabsorption and expediting drug 
elimination. Without the drug elimination procedure, it may take up to 2 years to reach non-detectable plasma 
levels after stopping treatment with leflunomide [17] 
2.3 Preclinical Studies of Leflunomide as an antineoplastic agent 
Leflunomide has been investigated for its anti-neoplastic potential in a variety of pre-clinical tumor models. The 
first reports of anti-tumor activity in mouse xenograft models of glioma indicate that inhibition of pyrimidine 
synthesis is not sufficient for anti-tumor activity and concomitant inhibition of tyrosine phosphorylation may also 
play a role[18]. In chronic lymphocytic leukemia (CLL), leflunomide has been shown to inhibit the cell cycle 
progression in primary leukemic cells in vitro [19]. Dietrich et al showed that teriflunomide (A77 1726) affects 
proliferation of CLL by blocking DHODH at very low concentration (3-5 µg/ml) and by additionally inhibiting 
JAK/STAT pathway at intermediate concentrations (>10 µg/ml)[20]. The metabolite is also effective in fludarabine-
refractory cells [20]. In addition, pre-clinical anti-tumor activity of leflunomide has been reported for melanoma 
[21] and prostate cancer [22].  
Recent pre-clinical studies of teriflunomide (A77 1726) have demonstrated significant antineoplastic activity in 
myeloma [23]. Teriflunomide inhibits cell growth and induces apoptosis in common myeloma cell lines at clinically 
achievable concentrations (50-200 µmol/L) in a time- and dose-dependent manner. The stimulatory effect of 
conditioned medium of HS-5 bone marrow stromal cells on multiple myeloma cell growth is completely abrogated 
by teriflunomide. In addition, studies revealed additive effects when teriflunomide was combined with the 
genotoxic agents melphalan and doxorubicin and synergistic effects when combined with bortezomib and 
treosulfan[23]. Finally, the Rosen laboratory has found leflunomide to be active in both glucocorticoid sensitive 
and resistant myeloma cell lines (Steven Rosen, personal communication).  
 
With respect to cutaneous lymphoma, the Querfeld laboratory has found the active metabolite 
teriflunomide to be effective at 48-72 hours in inducing apoptosis in mycosis fungoides, sezary syndrome, and 
CD30+LYPD cell lines.  In particular, the apoptosis was achievable at the 50-200umol/L concentration. 
 


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2.4 Background for Correlative Studies 
Leflunomide is rapidly converted to its active primary metabolite teriflunomide (A77 1726), which mediates 
leflunomide’s pharmacologic activity. Previous population-based PK studies in patients with RA have 
demonstrated a high degree of intersubject variability in measured steady-state total (free + albumin-bound) 
teriflunomide serum concentrations, resulting in coefficients of variation in CL/F estimates of >50% [29, 30]. 
Teriflunomide is >99% bound to serum albumin and free drug concentrations have also been reported to be highly 
variable, with a median of 55.8 μg/l and a range of 27.9-148.4 μg/l [31]. Moreover, measured total and free 
teriflunomide levels have been shown to predict response and toxicity in RA patients, leading some investigators 
to suggest a role for therapeutic drug monitoring and dose optimization of leflunomide [16]. It has also been 
reported that genetic polymorphisms in CYP1A2 and CYP2C19, the hepatic enzymes responsible for leflunomide 
metabolism, and DHODH, a key enzyme in the de novo synthesis of pyrimidines and the main target of 
teriflunomide, can all influence the risk of leflunomide-associated toxicity in RA patients [32-34]. 
Transcriptomic diversity exists within the clonal tumor cells that comprise cutaneous lymphomas as noted by 
recent work in mycosis fungoides and Sézary Syndrome [24, 25].  This correlates with the clinical experience of 
many experts that monotherapy alone is unable to produce response rates higher than 30-40% or meaningful 
durations of response in these patients as well.  In addition, it is not only the tumor heterogeneity but also the 
response to the tumor in the microenvironment in the form of T-cell exhaustion that contributes to a lack of higher 
response rates [26].  For these reasons, it is important to assess the heterogeneity of gene expression of tumor 
cells and the cells of the microenvironment that likely exists within CD30+LYPDs. Single-cell RNA analysis provides 
a view of all involved cellular components simultaneously and their individual gene expression states. Utilizing 
single cell mRNA sequencing will not only allow us to note the multiple mutations and the molecular signature of 
this group of diseases for the first time by assessing the baseline biopsies, but also will help us to explore the 
mechanism by which the leflunomide suppresses the growth of the CD30+LYPDs as noted in work conducted on 
CTCL lines by the Querfeld group. In addition, this will contribute to determining what future combination 
therapies can be utilized for better clinical and durable response as well as for tailoring patient-specific treatment.  
The parallel assessment of immunohistochemistry will allow us to correlate the new single cell data with what is 
seen/noted pathologically. Tumor cells in CD30+LYPD will be characterized utilizing a standard 
immunohistochemistry panel which includes CD3, CD4, CD8, CD30, BF1, Gamma, TRAF1, MUM1, perforin, 
granzyme, TIA-1 [27].  Current work in this area has noted that the predominant cells in the tumor 
microenvironment of CD30+LYPDs include a large percentage of CD163+ macrophages (M2) (44.7% in LyP vs. 35% 
in pcALCL).  However, there are a number of tumor infiltrating CD8+ lymphocytes, FOXP3+ T-regulatory cells 
(Tregs) and only a few programmed cell death (PD1) lymphocytes [28].  We would like to examine the effect 
leflunomide has on the changing microenvironment as well. 
2.5 Overview and Rationale of Study Design 
Teriflunomide, the active metabolite of leflunomide, is approved for treatment of multiple sclerosis [15]. The “on 
target” effect of leflunomide and teriflunomide, which occurs at low doses, is mediated through inhibition of the 
cellular dihydroorotate dehydrogenase (DHODH) enzyme [16]. DHODH is required for de novo pyrimidine 
synthesis (but not for pyrimidine synthesis mediated by the salvage pathway), and “on target” effects of the 
leflunomide/teriflunomideare is reversed in vitro by supplementing the media with uridine, which restores de 
novo pyrimidine synthesis. Lymphocytes are particularly dependent upon de novopyrimidine synthesis for their 
proliferation [17], and the major “on target” immunosuppressive effect of leflunomide/teriflunomide is thought 
to be due to decreased T cell proliferation. In addition to decreasing the amount of pyrimidine-based nucleotides 
available for DNA/RNA synthesis, drugs that inhibit DHODH activity globally decrease the level of O-linked 
GlcNAcylate-modified proteins through an “on-target” effect [18]. Diffuse large B-cell lymphoma (DLBCL) cell lines 
and primary DLBCL tumor cells have higher levels of nuclear O-GlcNAcylate-modified proteins than do normal B-
cells, and the levels of these proteins correlate with DLBCL cell growth and survival [19]. With respect to cutaneous 
lymphoma the Querfeld laboratory has found the active metabolite teriflunomide to be effective at 48-72 hours 


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in inducing apoptosis in mycosis fungoides, Sézary cell, and CD30+LYPD cell lines.  In particular, the apoptosis was 
achievable at the 50-200umol/L concentration. 
These pre-clinical data, and the relatively low toxicity profile seen with prolonged administration in the 
rheumatoid arthritis population as well as the multiple myeloma population, in total provide evidence to support 
the investigation of leflunomide as an anti-CD30+ agent.  
While the standard dose of leflunomide (20mg daily), following a loading dose of 100mg daily for 3 days, is FDA 
approved for continuous treatment of rheumatoid arthritis, leflunomide has been administered without an 
increase in the type, frequency or severity of adverse events at doses up to 40 mg/day in patients with Wegner’s 
granulomatosis, and up to 60mg/day in a subset of patients with polyoma BK neuropathy to achieve targeted 
therapeutic levels [12, 13].  
Because the current dosing guideline for patients with rheumatoid arthritis do not to exceed 20 mg daily 
maintenance doses [17], the 20mg/day dose is selected as the safe starting dose.  In addition, in personal 
communications, Miles Prince has used leflunomide at doses of 10-20mg daily for 6 weeks in patients who have 
failed methotrexate with report of minimal side effects.  
Patients will be treated in planned 28-day treatment cycles. Patients may continue to receive cycles of treatment 
on study until disease progression or unacceptable toxicity, or other criteria for removal from study treatment are 
satisfied. While on active treatment patients will undergo monthly evaluation for response by mSWAT and the 
CAILs (composite assessment of index lesion severity) [29, 30]. Following the decision to end leflunomide 
treatment, all patients will undergo 11 days of treatment with cholestyramine, which fixes the metabolite, 
preventing re-absorption and effectively lowering drug levels. Cholestyramine has been shown to decrease plasma 
levels of teriflunomide (A77 1726) in healthy volunteers by approximately 40% in 24 hours and by 49-65% in 48 
hours [17]. 
In addition, molecular correlates and ex vivo responses will be evaluated using skin specimens, which will be 
collected from patients before treatment, after one cycle, four cycles of leflunomide treatment, end of therapy (if 
lesions are still present), and at disease progression. Molecular correlate analysis of leflunomide response will 
include single cell RNA sequencing. Specimens derived from before and after leflunomide treatment (after 1 
month and at progression or complete response, if possible) will be analyzed, as well as pre-treatment specimens 
exposed to teriflunomide ex vivo.  
 
 


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3.0 ELIGIBILITY CRITERIA 
Patient MRN (COH Only) 
Patient Initials (F, M, L): 
Participants must meet all of the following criteria on screening examination to be eligible to participate in the 
study:  
3.1 Inclusion Criteria 
Informed Consent 
__1. Documented informed consent of the participant and/or legally authorized representative. 
 
Assent, when appropriate, will be obtained per institutional guidelines 
Age Criteria, Performance status 
__2. Age:≥ 18  years 
__3. Patients must have a life expectancy of > 3 months 
__4. ECOG ≤ 2 
Nature of Illness and Illness Related Criteria 
__5. Patients must have a diagnosis of cutaneous CD30+LYPD 
__6. Patients must be relapsed or are refractory to at least 1 prior line of therapy 
__7. At least 2 weeks from prior therapy to time of start of treatment. Prior therapy includes steroids (except 
prednisone or equivalent – up to 10 mg/day is allowed). 
Clinical Laboratory and Organ Function Criteria (To be performed within 21 days prior to Day 1 of protocol therapy unless 
otherwise stated [see Section 10.0]) 
__8. ANC ≥ 1000/mm3 
NOTE: Growth factor is not permitted within 14 days of ANC 
assessment unless cytopenia is secondary to disease 
involvement. 
ANC: 
Date: 
__9. Platelets ≥ 50,000/mm3 
NOTE: Platelet transfusions are not permitted within 14 days of 
platelet assessment unless cytopenia is secondary to disease 
involvement. 
Plts: 
 
Date: 
__10. __10. Total bilirubin ≤ 1.5 X ULN (unless has Gilbert’s disease) 
ULN: 
Bil: 
Date: 
__11. AST ≤ 2.0 x ULN 
ULN: 
AST: 
Date: 
__12. ALT ≤ 2.0 x ULN 
ULN: 
ALT: 
Date: 
__13. Creatinine clearance of ≥ 30 mL/min per 24 hour urine test or the 
Cockcroft-Gault formula or  
 
Serum Cr: 
 
Cr Clearance: 
Date: 


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__14. Seronegative for HIV Ag/Ab combo, HCV*, active HBV (Surface 
Antigen Negative) *If positive, Hepatitis C RNA quantitation 
must be performed. 
__15. Meets other institutional and federal requirements for 
infectious disease titer requirements 
Note Infectious disease testing to be performed within 28 days 
prior to Day 1 of protocol therapy. 
HIV: 
HCV: 
HBV: 
Syphilis: 
 
Date: 
__16. Negative for tuberculosis antigen (e.g. T-Spot test). 
 
Date: 
__17. Women of childbearing potential (WOCBP): negative urine or 
serum pregnancy test  
If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required 
Urine: 
Serum: 
Date: 
 
 
 
 
 
 
 
Contraception 
__18. Agreement by females and males of childbearing potential* to use an effective method of birth control 
(hormonal or barrier method of birth control or abstinence) or abstain from heterosexual activity for the course 
of the study through at least three months after the last dose of protocol therapy. The effects of study 
treatment on a developing fetus have the potential for teratogenic or abortifacient effects. Should a woman 
become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating 
physician immediately. 
* Childbearing potential defined as not being surgically sterilized (men and women) or have not 
been free from menses for > 2 years (women only).  
3.2 Exclusion Criteria 
Prospective participants who meet any of the following criteria will not be eligible for admission into the study: 
Concomitant medications 
__1.  Current or planned use of other investigational agents, or concurrent biological, chemotherapy, or 
radiation therapy during the study treatment period. (See inclusion criterion #7 for washout times). 
__2.  Current or planned growth factor or transfusion support. If growth factor or transfusion support is 
provided between screening and start of treatment, the participant will no longer be eligible.  
Other illnesses or conditions 
__3.  Prior Allogeneic transplant. 
__4.  Acute active infection requiring systemic therapy within 2 weeks prior to enrollment. 
__5.  Known history of hepatitis B or hepatitis C infection 
__6.  Known HIV infection. 
__7.  History of allergic reactions attributed to compounds of similar chemical or biologic composition to 
leflunomide or cholestyramine. 
__8.  Non-hematologic malignancy within the past 3 years aside from the following exceptions:  
o 
adequately treated basal cell or squamous cell skin cancer 
o 
carcinoma in situ of the cervix 
o 
prostate cancer < Gleason Grade 6 with a stable PSA 
o 
successfully treated in situ carcinoma of the breast 


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__9.  Clinically significant medical disease or condition that, in the investigator’s opinion, may interfere with 
protocol adherence or the patient’s ability to give informed consent.  
__10.  Pregnant women and women who are lactating. Leflunomide has potential for teratogenic or 
abortifacient effects. Because there is a potential risk for adverse events in nursing infants secondary to 
treatment of the mother with these agents, breastfeeding should be discontinued if the mother is enrolled on 
this study.  
__11.  Any other condition that would, in the Investigator’s judgment, contraindicate the patient’s participation 
in the clinical study due to safety concerns or compliance with clinical study procedures, e.g., 
infection/inflammation, intestinal obstruction, unable to swallow medication, social/ psychological issues, etc. 
Noncompliance 
__12.  Prospective participants who, in the opinion of the investigator, may not be able to comply with all study 
procedures (including compliance issues related to feasibility/logistics). 
Eligibility Confirmed* by 
(Choose as applicable): 
Print Name 
Signature 
Date 
 Site PI 
 
 
 
 Authorized study MD 
 
 
 
 Study Nurse 
 
 
 
 Study CRA/ CRC 
 
 
 
Other:______________ 
 
 
 
*Eligibility should be confirmed per institutional policies. 
3.3 Inclusion of Women and Minorities 
The study is open anyone regardless of gender or race/ethnicity. Efforts will be made to extend the accrual to a 
representative population. However, a balance must be struck between subject safety considerations and 
limitations on the number of individuals exposed to potentially toxic or ineffective treatments on the one hand 
and the need to explore gender, racial, and ethnic aspects of clinical research on the other. If differences in 
outcome that correlate to gender, racial, or ethnic identity are noted, accrual may be expanded or additional 
studies may be performed to investigate those differences more fully. 
 
 


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4.0 PARTICIPANT ENROLLMENT 
4.1 Pre-Enrollment Informed Consent and Screening Procedures 
Diagnostic or laboratory studies performed exclusively to determine eligibility will be done only after obtaining 
written informed consent. Studies or procedures that are performed for clinical indications (not exclusively to 
determine study eligibility) may be used for baseline values and/or to determine pre-eligibility, even if the studies 
were done before informed consent was obtained. The informed consent process is to be fully documented (see 
Section 17.4), and the prospective participant must receive a copy of the signed informed consent document. 
Screening procedures are listed in Section 10.0 (Study Calendar). 
4.2 Participant Enrollment 
4.2.1 
COH DCC Availability and Contact Information 
Eligible participants will be registered on the study centrally by the Data Coordinating Center (DCC) at City of Hope.   
DCC staff are available between the hours of 8.00 am and 5.00 pm PST, Monday through Friday (except holidays).  
o Phone: (626) 218-7904 
o E-mail: DCC@coh.org 
4.2.2 
Slot verification and reservation 
Designated study staff should call or email the DCC to verify current slot availability, and to reserve a slot for a 
specific prospective subject (provide DCC with subject initials). Slots can only be held for a limited time. 
The DCC should be notified of cancellations of prospective participants holding slots as soon as possible.   
4.2.3 
Registration Process  
To register a participant the subsequent procedure is to be followed: 
1. The study team (data manager/coordinator/research nurse) should contact the DCC via telephone or 
email to provide notification regarding the pending registration and communicate desired timeline of the 
registration, especially if it must be completed promptly to meet the registration window.  
2. The data manager/coordinator/research nurse will email a copy of the following documents to the DCC: 
o Completed eligibility checklist (printed from Section 3.0 of the protocol) 
o Source documentation to support eligibility criteria**  
o Signed Informed Consent  
o Signed subject’s bill of Rights  
o Signed HIPAA authorization form (if separate from informed consent) 
** It is NOT acceptable to submit emails as source documentation  
3. After having received all transferred documentation, the DCC will complete the review of the documents 
to verify eligibility, working with the study team as needed to resolve any missing required source 
elements. A participant failing to meet all protocol eligibility requirements will not be registered. 
4. Once eligibility is confirmed, DCC staff will send a Confirmation of Registration Form and signed Eligibility 
Checklist within 24 hours, including the participant study number and cohort assignment (dose level or 
expansion cohort) to:  
o The study team: Principal Investigator, treating physician, protocol statistician, protocol nurse, 
CRC and COH IDS Pharmacy. 
o the COH sponsor team designees, including Study PI 


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5. Upon receipt of the Confirmation of Registration email from the DCC, COH study team will register the 
patient in OnCore. 
4.3 Screen Failures and Registered Participants Who Do Not begin Study Treatment 
Notify the DCC if the participant screen fails after registration or if the participant does not start treatment. 
Issues that would cause treatment delays should be discussed with the Principal Investigator. 
5.0 TREATMENT PROGRAM 
5.1 Treatment Program Overview 
Treatment on study will be in the outpatient setting and will consist of daily treatment with leflunomide; patients 
will be treated in planned 28-day treatment cycles for up to 13 cycles (approximately 1 year) until meeting any 
off-protocol treatment criteria (Section 5.6). After the decision to end study treatment has been made, 
participants will receive treatment with cholestyramine (Section 5.5) to eliminate leflunomide. Participants who 
end study treatment for reasons other than disease progression will undergo active follow-up (Section 5.7) until 
disease progression or 12 months of active follow-up, whichever is earlier. For a detailed tabular view of the 
treatment, monitoring, and follow-up schedule, see the Study Calendar in Section 10.0.  
5.2 Cycle Definition 
The planned cycle length is 28 days. Leflunomide will be taken orally once daily. Missed or held doses will not be 
made up. The day count continues despite a hold in agent administration. Day 1 safety assessments must be 
reviewed prior to the initiation of the cycle. For a cycle to commence, the participant must be actively taking 
study agent. Windows for procedures are detailed in Section 10.0. 
5.3 Agent Administration 
5.3.1 
Leflunomide 
Participants will be instructed to take each dose of leflunomide orally, once a day, at approximately the same time 
each day. They may take it with or without food. If a patient forgets or misses a dose for whatever reason, it should 
not be replaced or made up. Participants will be given a study calendar (pill diary, see Appendix D) to document 
each dose of leflunomide that is taken or missed.  
Leflunomide is administered with a loading dose of 100 mg/day for the first three doses (first three days) in Cycle 
1. Starting day 4 in Cycle 1 and for all later cycles, it will be administered at 20 mg/day (or 10 mg/day if dose 
reduced due to toxicities).   
There will be no intra-patient dose escalation; patients will undergo dose modification due to toxicity per Section 
7.2. 
5.3.2 
Cholestyramine 
Cholestyramine is not a study agent but is required for the elimination of the study agent leflunomide. See Section 
5.5 for cholestyramine administration details. 
5.4 Assessments and Special Monitoring 
For a detailed list of all study procedures including timing and windows, see Section 10.0.  


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5.5 End of Treatment Evaluations and Leflunomide Detoxification 
All participants will be followed until resolution or stabilization of any serious adverse events occurring during 
treatment and completion of the Day 30 End of Treatment assessments. See Section 10 for a list of all assessments 
and windows. 
Because of the ability of leflunomide to be reabsorbed through the colon, resulting in a very long half-life, all 
participants will be treated with cholestyramine to prevent re-absorption of leflunomide after the decision to end 
study treatment has been made.  
Participants removed from study treatment will undergo oral administration of cholestyramine 8 grams oral 
suspension three times daily for 11 days. It will not be a deviation if an administration of cholestyramine is delayed 
or if the 11 days are not consecutive. Cholestyramine administration may be adjusted per the discretion of the 
treating investigator. After the treatment with cholestyramine, clinical laboratory testing will be performed to 
verify plasma levels less than 0.02 mg/L or 0.02µg/mL by two separate tests at least 14 days apart. If plasma levels 
are higher than 0.02 mg/L or 0.02µg/mL, additional cholestyramine treatment will be considered. See Section 10 
for a tabular view of cholestyramine administration and metabolite testing windows and days of administration. 
Note: Cholestyramine can affect the absorption of other oral medications. Such medications should be taken 1 
hour before administration of cholestyramine on any day or per other guidance in the package insert. Watch for 
bleeding abnormalities due to vitamin K deficiency for which intravenous vitamin K may be administered. 
5.6 Duration of Therapy and Criteria for Removal from Protocol Therapy 
Patients will receive study treatment for a maximum of 13 cycles until disease progression, unacceptable toxicity 
or other criteria for removal from study treatment are satisfied. Participants may be removed from treatment for 
any of the following reasons: 
o Evidence of disease progression per mSWAT (see Appendix C) 
o Participant receives 13 cycles (~ 12 months of protocol therapy) 
o Patient is deemed intolerant to study treatment because of toxicity, despite dose modification/delay 
o Participant withdraws from the treatment phase of the study  
o General or specific changes in the participant's condition, including non-compliance, which renders the 
participant unacceptable for further treatment in the opinion of the treating investigator. 
Documentation of the reason for discontinuing therapy and the date effective should be made in the medical 
record and appropriate eCRF. The participant should then proceed to off-treatment procedures for safety 
monitoring, leflunomide elimination and follow-up procedures. The participant’s status is to be modified in the 
OnCore system once the off-treatment period is completed. Alternative care options will be discussed with the 
participant. 
5.7 Active Follow-Up 
Participants who do not progress while on treatment (regardless of whether the patient finished 13 cycles or 
terminated treatment early) will be in Active Follow Up, for 12 months after the end of the protocol treatment, 
where they will continue to undergo  response assessment every 3 months, until disease progression or otherwise 
meeting an criteria for removal from study participation as detailed in Section 5.8. 
The schedule and windows for assessments and data collection points are further detailed in Table 10. 
Assessment time points and windows are detailed in Section 10.0. 
5.8 Duration of Study Participation 
Participants may be removed from the study as a whole at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral or administrative reasons. The reason(s) for 
discontinuing study participation should be documented and may include: 


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o Completion of 12 months of active follow up after the end of protocol treatment 
o Disease progression per mSWAT, after completing the End of Treatment assessments 
o Disease progression per mSWAT during active follow-up  
o Withdrawal of consent  
o Participant is lost to follow-up. All attempts to contact the participant must be documented. 
o At the discretion of the investigator for safety, behavioral, study termination or administrative reasons 
Documentation of the reason for discontinuing study participation and the date effective should be made in the 
Electronic Health Record/medical record and appropriate eCRF 
5.9 Prohibited and Concomitant Therapies/Medications  
5.9.1 
Allowed concomitant medications 
Concomitant medications and treatments that are permitted while on study treatment include allopurinol, anti-
emetics, anti-diarrheals, FDA-approved bisphosphonates, erythropoietin, transfusions (as necessary), and 
palliative radiation. 
Concurrent treatment with any other anti-neoplastic therapies will not be permitted while on study treatment. 
Concurrent administration of live vaccines will not be permitted while on study treatment. 
During cycle 1 only: Transfusions are not permitted unless platelets <25,000/mm3 or platelets < 50,000/ mm3 
accompanied by bleeding. Growth factors are not permitted unless ANC <500/ mm3. 
If concomitant therapy must be added or changed, including over-the-counter medications or alternative 
therapies, the reason and name of the agent/therapy should be recorded in the eCRF and documented in the 
Electronic Health Record/medical record. 
5.9.2 
Prohibited medications 
o Exposure to any new immunosuppressive medication in the 4 weeks prior to enrollment. 
o Patients may not be receiving any other parenteral investigational agents. Oral chemotherapeutic agents 
or biologics –for example ruxolitinib, rituxan, ibrutinib therapy (either past or current exposure) - is 
allowed. 
o The use of medication that are CYP1A2 inducers and CYP2C8 inhibitors and vitamin K antagonists are 
prohibited. 
5.10 Supportive care 
With the exception of prohibited therapies, participants should receive prophylactic or supportive as clinically 
indicated per institutional policies. 
6.0 ANTICIPATED ADVERSE EVENT LIST 
6.1 Leflunomide 
Per the package insert for leflunomide, the expected toxicities for leflunomide follow, where the asterisk (*) 
signifies a common event (10%-30% of patients), unmarked items are infrequent events (1-3% of patients), a 
double asterisk (**) signifies a rare but possibly serious event, and a triple asterisk (***) signifies an event that 
may become serious and occurs in up to 10% of patients:  
Blood and lymphatic system 
anemia (including iron deficiency anemia), ecchymosis, pancytopenia**, 
agranulocytosis**, neutropenia**, thrombocytopenia**, leukopenia** 
Cardiac 
angina pectoris, migraine, palpitation, tachycardia, vasodilatation 


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Endocrine 
diabetes mellitus, hyperthyroidism 
Eye 
blurred vision, cataract, conjunctivitis, eye disorder 
Gastrointestinal 
diarrhea*, abdominal pain, dyspepsia, nausea, vomiting, oral ulceration, 
anorexia, pancreatitis**, constipation, esophagitis, flatulence, gastritis, 
gingivitis, melena, oral moniliasis, pharyngitis, salivary gland enlarged, 
stomatitis (or aphthous stomatitis), tooth disorder 
Hepatobillary 
cirrhosis**, hepatitis**, hepatic failure**, acute hepatic necrosis**, 
cholelithiasis**, cholestasis**, elevated hepatic enzymes (primarily ALT and 
AST) 
Immune system 
allergic reactions, anaphylactoid reactions** 
Infections 
respiratory infection*, infections (including bronchitis, rhinitis, sinusitis, 
pharyngitis, pneumonia, and urinary tract infections, oral or vaginal 
candidiasis, herpes simplex, herpes zoster, and fungal dermatitis), 
opportunistic and/or severe infections** including sepsis, that may be fatal 
(especially Pneumocystis jiroveci pneumonia, tuberculosis, aspergillosis) 
Metabolism and nutrition 
hyperglycemia, creatine phosphokinase increased, hyperlipidemia 
Musculoskeletal and connective 
tissue 
arthrosis, bone necrosis, bone pain, bursitis, muscle cramps, myalgia, tendon 
rupture 
Neoplasms 
secondary malignancy**, cyst 
Nervous system 
headache*, peripheral neuropathy* (including peripheral numbness, tingling, 
burning, severe pain, cold sensation in the distal extremities, or extremity 
weakness), paresthesias, taste perversion (dysgeusia), anxiety, depression, 
dry mouth, insomnia, neuralgia, neuritis, sleep disorder, sweating increased, 
vertigo, migraine 
Renal and urinary 
albuminuria, cystitis, dysuria, hematuria, hypophosphaturia, hyperuricemia, 
increased urinary frequency 
Reproductive 
menstrual irregularity/disorder, menstrual disorder, vaginal moniliasis 
vaginal moniliasis, prostate disorder 
Respiratory 
interstitial lung disease** (sometimes fatal), interstitial pneumonitis**, 
pulmonary fibrosis**, asthma, dyspnea, epistaxis, lung disorder 
Skin and subcutaneous tissue 
maculopapular rash*, dry skin*, alopecia*, hair discoloration*, Stevens-
Johnson syndrome**, toxic epidermal necrolysis**, erythema multiforme**, 
cutaneous lupus erythematosus**, acne, contact dermatitis, fungal 
dermatitis, hematoma, nail disorder, skin discoloration, skin disorder, skin 
nodule, subcutaneous nodule, skin ulcer 
Vascular 
varicose veins, hypertension***, vasculitis, cutaneous necrotizing vasculitis** 
Miscellaneous 
weight loss*, leg cramps*, jaundice**, allergy related angioedema**, fever, 
peripheral edema, hernia, neck pain, pelvic pain, pain, abscess, malaise 
6.2 Cholestyramine 
Per the package insert for cholestyramine, the expected toxicities for cholestyramine follow, where the double 
asterisk (**) signifies a common event, and a single asterisk (*) signifies a less common event, and remaining 
unmarked items are less likely: 
Blood and lymphatic system 
anemia, ecchymosis, prolonged prothrombin time, hypoprothrombinemia 
Ear and labyrinth 
tinnitus, vertigo 
Eye 
uveitis 
Gastrointestinal 
constipation**, abdominal pain*, anorexia*, nausea*, vomiting*, diarrhea*, 
flatulence*, diarrhea*, eructation,* steatorrhea,* diverticulitis, bleeding 
from known duodenal ulcer, dysphagia, gastrointestinal hemorrhage, 
hemorrhoidal bleeding, hiccups, intestinal obstruction (rare), melena, 
pancreatitis, rectal pain, tongue irritation, tooth enamel damage (dental 
erosion), dental bleeding, dental caries, dental discoloration 


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Hepatobillary 
abnormal hepatic function tests, biliary colic, gallbladder calcification 
Immune system 
hypersensitivity reaction 
Infections 
 
Metabolism and nutrition 
hyperchloremic metabolic acidosis 
Musculoskeletal and connective 
tissue 
arthralgia, arthritis, backache, myalgia, osteoporosis associated with vitamin 
D deficiency 
Nervous system 
anxiety, dizziness, drowsiness, dysgeusia, fatigue, headache, neuralgia, 
paresthesia, syncope 
Renal and urinary 
hematuria, dysuria, burnt odor to urine, diuresis 
Respiratory 
asthma dyspnea and wheezing associated with hypersensitivity reaction 
Skin and subcutaneous tissue 
perianal skin irritation, skin irritation, skin rash, urticaria 
Miscellaneous 
adenopathy, increased libido, edema, bleeding tendencies due to vitamin K 
deficiency, vitamin deficiency (A, D, E, K), weight loss, weight gain, 
hematoma, hemorrhage, femoral nerve pain 
 
7.0 DOSE DELAY/MODIFICATION GUIDELINES 
7.1 Dose Modifications for Leflunomide 
7.1.1 
General Information 
a. The study will use the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 to 
grade toxicities. A copy of the version 5.0 can be downloaded from: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
b. Rules for dose modification are found in Table 7.1.1. 
c. Baseline values are from the last values obtained prior to treatment.  
d. For holds due to toxicities related to study agent, if the participant does not meet criteria to resume 
treatment within 14 days, the participant must permanently discontinue study treatment.  
7.1.2 
Dose Modifications 
The tables below detail the specific dose modifications for toxicities on single agent leflunomide (Table 7.1.1) and 
are to be used in agreement with the information in Section 7.1.1. 
Table 7.1.1 Dose Modifications for Leflunomide Treatment 
Adverse Event 
Treatment modification 
Hematological Toxicities:  
Febrile Neutropenia Grade 3 
(ANC: <1.0 x109/L with a single 
temperature of >38.3 ◦C or a 
sustained temperature ≥ 38.0◦C for 
more than one hour. 
At 20 mg: 
o 
Hold study agent. 
o 
If resolves to ANC ≥ 1.0 x 109/L and temperature < 38.0◦C within 14 
days, resume study agent at 10 mg. 
o 
If does not resolve within 14 days, permanently discontinue study 
agent. 
At 10 mg: Permanently discontinue study agent 
Febrile Neutropenia Grade 4 
Life threatening consequences; 
urgent intervention needed. 
Permanently discontinue study agent.  
Neutropenia (ANC) Grade 1 
(1.5x 109/L -<LLN) 
Maintain study agent. 


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Neutropenia (ANC) Grade 2 
(1.0 –<1.5x 109/L) 
Maintain study agent.  
Neutropenia (ANC) Grade 3 
(0.5 –< 1.0x 109/L) 
Maintain study agent. Growth factor recommended after cycle 1. 
Neutropenia (ANC) Grade 4 
(<0.5x 109/L) 
At 20 mg: 
o 
Hold study agent and provide supportive care. 
o 
If ANC does not resolve to ≤ grade 3 (ANC ≥ 0.5 x 109/L) in 5 days, 
permanently discontinue study agent. Otherwise proceed as follows: 
o 
If resolves to ≤ grade 2 (ANC ≥ 1.0 x 109/L) in ≤ 14 days, resume study 
agent at 10 mg. 
o 
If ANC does not resolve to ≤ grade 2 (ANC ≥ 1.0 x 109/L) by 14 days, 
permanently discontinue study agent. 
At 10 mg: Permanently discontinue study agent. 
Thrombocytopenia Grade 1 
(75 x 109/L -<LLN) 
Maintain study agent 
Thrombocytopenia Grade 2 
(50 – <75 x 109/L) 
Maintain study agent 
Thrombocytopenia Grade 3 without 
bleeding  
(25 – <50 x 109/L) 
Maintain study agent.  
Thrombocytopenia Grade 3 with 
bleeding 
(25 – <50 x 109/L) 
At 20 mg:  
o 
Hold study agent and provide supportive care. 
o 
If bleeding does not resolve in 5 days, permanently discontinue study 
agent. Otherwise proceed as follows: 
o 
If bleeding resolves within 5 days and platelets resolve to ≤ grade 2 
(platelets ≥ 50 x 109/L) in ≤ 14 days, resume study agent 10 mg. 
o 
If bleeding resolves within 5 days but thrombocytopenia does not 
resolve to ≤ grade 2 (platelets ≥ 50 x 109/L) by 14 days, permanently 
discontinue study agent. 
At 10 mg: Permanently discontinue study agent. 
Thrombocytopenia Grade 4 
(<25 x 109/L) 
At 20 mg: 
o 
Hold study agent and provide supportive care. 
o 
If platelets do not resolve to ≤ grade 3 (platelets ≥ 25 x 109/L) in 5 days, 
permanently discontinue study agent. Otherwise proceed as follows: 
o 
If resolves to ≤ grade 2 (platelets ≥ 50 x 109/L) in ≤ 14 days, resume 
study agent 10 mg. 
o 
If thrombocytopenia does not resolve to ≤ grade 2 (platelets ≥ 50 x 
109/L) by 14 days, permanently discontinue study agent. 
At 10 mg: permanently discontinue study agent. 
Gastrointestinal 
Diarrhea Grade 1 
(2-3 stools/day >baseline) 
Maintain treatment. 
Diarrhea Grade 2 
(4-6 stools/day > baseline) 
Maintain study agent. 
Diarrhea Grade 3 
(7-9 stools/day > baseline) 
 
At 20 mg: 
Hold study agent and provide optimal anti-diarrheal therapy. 
First Occurrence:  
If resolves to ≤ grade 1 in ≤ 7 days, resume at 20 mg.  
If resolves to ≤ grade 1 in 8-14 days, resume study agent at 10 mg.  
If does not resolve within 14 days, permanently discontinue study agent. 
Recurrence: 
If resolves to ≤ grade 1 in ≤ 14 days, resume at 10 mg. 
If does not resolve within 14 days, permanently discontinue study agent. 
At 10 mg: Permanently discontinue study agent. 


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Diarrhea Grade 4 
(≥10 stools/day > baseline) 
 
At 20 mg: 
Hold study agent and provide optimal anti-diarrheal therapy.  
If does not resolve to Grade 3 within 48 hours, permanently discontinue study 
agent.  
If resolves to Grade 3 within 48 hours, then: 
First Occurrence:  
Hold until resolution to ≤ grade 1.  
If resolved in ≤ 7 days, resume at pre-hold dose.  
If resolved in 8-14 days, resume study agent at 10 mg. 
If not resolved within 14 days, permanently discontinue study agent. 
Recurrence: 
Hold until resolution to ≤ grade 1. 
If resolved in ≤ 14 days, resume study agent at 10 mg. 
     If not resolved within 14 days, permanently discontinue study agent. 
At 10 mg: Permanently discontinue study agent. 
Vomiting or Nausea Grade 1 
Maintain study agent. 
Vomiting or Nausea Grade 2  
Maintain study agent. 
Vomiting or Nausea Grade 3 
At 20 mg: 
Hold study agent and provide optimal supportive care/therapy. 
First Occurrence:  
If resolves to ≤ grade 1 in ≤ 7 days, resume at pre-hold dose.  
If resolves to ≤ grade 1 in 8-14 days, resume study agent at 10 mg.  
If does not resolve within 14 days, permanently discontinue study agent. 
Recurrence: 
If resolves to ≤ grade 1 in ≤ 14 days, resume at 10 mg. 
If does not resolve within 14 days, permanently discontinue study agent. 
At 10 mg: Permanently discontinue study agent. 
Vomiting Grade 4 
At 20 mg: 
Hold study agent and provide optimal supportive care/therapy.  
If does not resolve to Grade 3 within 48 hours, permanently discontinue study 
agent.  
If resolves to Grade 3 within 48 hours, then: 
First Occurrence:  
Hold until resolution to ≤ grade 1.  
If resolved in ≤ 7 days, resume at pre-hold dose.  
If resolved in 8-14 days, resume study agent at 10 mg.  
If not resolved within 14 days, permanently discontinue study agent. 
Recurrence: 
Hold until resolution to ≤ grade 1. 
If resolved in ≤ 14 days, resume study agent at 10 mg. 
      If not resolved within 14 days, permanently discontinue study agent. 
At 10 mg: Permanently discontinue study agent. 
Hepatic investigations 
ALT (SGPT) or AST (SGOT)  
< 3.0 x ULN or TBili < 1.5 x ULN 
Maintain study agent. 
ALT (SGPT) or AST (SGOT)   
>3.0 - 5.0 x ULN or TBili >1.5 - > 3.0 
x ULN 
 First Occurrence:  
Hold until resolution to < 3.0 x ULN for ALT or AST or < 1.5 for TBili.  Resume 
at pre-hold dose if resolved within 14 days. If does not resolve within 14 
days, permanently discontinue study agent. 
Recurrence: 
Hold until resolution to < 3.0 x ULN for ALT or AST or <1.5 for TBili. Resume 
at 10 mg if resolved within 14 days. If does not resolve within 14 days, 
permanently discontinue study agent. 


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ALT (SGPT) or AST (SGOT)  
> 5.0 x ULN or TBili > 3.0 x ULN 
 
Permanently discontinue study agent. 
 
Electrolyte/metabolic toxicity 
Electrolyte/metabolic Grade 3 
Provide support care. Maintain study agent per investigator discretion.  
 
If alteration persists despite aggressive replacement therapy, then dose reduce 
or permanently discontinue (per investigator discretion with PI consultation). 
Electrolyte/metabolic Grade 4 
Provide support care. Maintain study agent per investigator discretion. 
 
If resolves to Grade 1 or baseline within 48: for first event, maintain at pre-hold 
dose; for recurrent event, dose reduce or permanently discontinue (per 
investigator discretion with PI consultation). 
 
If does not resolve to Grade 1 or baseline within 48 hours, permanently 
discontinue study agent. 
Other unspecified Non-Hem toxicities considered related to leflunomide 
Grade 1 
Maintain study agent. 
Grade 2  
Maintain study agent. 
Grade 3 
First Occurrence:  
Hold until resolution to ≤ Grade 2. Resume at pre-hold dose if resolved 
within 7 days. If does not resolve within 7 days, permanently discontinue 
study agent. 
Recurrence: 
Hold until resolution to ≤ Grade 1. Resume at 10 mg if resolved within 14 
days. If does not resolve within 14 days, permanently discontinue study 
agent. 
Grade 4 
Permanently discontinue study agent. 
Other unspecified Non-Hem Toxicities considered UNRELATED to study agent 
Other unspecified events of any 
grade considered unlikely to be 
related or not related to study 
agents. 
Maintain treatment with study agents. Interruption of study agent or dose de-
escalation is permitted if the investigator consults with the Principal Investigator 
to determine that this is in the best interest of the participant.  
7.2 Dose Modifications of Cholestyramine 
Cholestyramine will be administered and dose modified per the discretion of the treating investigator in 
agreement with standard administration practices.  
 
8.0 AGENT INFORMATION 
8.1 Leflunomide 
Leflunomide is an FDA approved agent for the treatment of rheumatoid arthritis. Please refer to the Package Insert 
for additional details not provided in this section. 
8.1.1 
Description and classification 
The chemical name for leflunomide is N-(4’-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide. It has a 
molecular formula C H F N O, a molecular weight of 270.2. Leflunomide is a pyrimidine synthesis inhibitor. 


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8.1.2 
Mode of action 
Leflunomide is an isoxazole immunomodulatory agent which inhibits dihydroorotate dehydrogenase (an enzyme 
involved in de novo pyrimidine synthesis) and has antiproliferative activity. Several in vivo and in vitro 
experimental models have demonstrated an anti-inflammatory effect. 
8.1.3 
Toxicology 
See Section 6.1 
8.1.4 
Pharmacology 
Following oral administration, leflunomide is metabolized to an active metabolite teriflunomide (A77 1726) which 
is responsible for essentially all of its activity in vivo. Following oral administration, peak levels of the active 
metabolite occurred between 6 to 12 hours after dosing. Due to the very long half-life of teriflunomide (~2 weeks), 
a loading dose of 100 mg for 3 days was used in clinical studies to facilitate the rapid attainment of steady-state 
levels of teriflunomide. Without a loading dose, it is estimated that attainment of steady-state plasma 
concentrations would require nearly two months of dosing. Biliary recycling is a major contributor to the long 
elimination half-life of teriflunomide. The active metabolite of leflunomide is eliminated slowly from the plasma. 
Use of a drug elimination procedure (cholestyramine or activated charcoal) is used to reduce the drug 
concentration more rapidly after stopping leflunomide therapy. 
8.1.5 
Storage and stability 
Leflunomide tablets should be stored at 25°C (77°F); excursions are permitted to 15–30°C (59–86°F). Protect from 
light. 
8.1.6 
Preparation 
Leflunomide is commercially available for oral administration as tablets containing 10, 20, or 100 mg of active 
drug. 
8.1.7 
Agent administration 
Leflunomide is administered orally. Participants will be given a study calendar to track all doses taken or missed. 
There will be an initial loading dose of 100 mg/day for the first 3 days of doses. Participants will then receive 
leflunomide at the assigned dose level. See Section 5.3.1 for administration details.  
8.1.8 
 Availability and supply 
Tablets in 10 and 20 mg strengths are packaged in bottles of 30 pills per bottle. Leflunomide will be provided to 
patients by the study as an investigational agent. A commercial supply will be purchased and distributed as an 
investigational agent by the Investigational Drug Pharmacy at City of Hope. 
8.2 Cholestyramine 
Cholestyramine is not the study agent being evaluated for efficacy, but is required for the elimination of the study 
agent leflunomide. Cholestyramine is FDA approved for hypercholesterolemia. Cholestyramine use is indicated 
in the leflunomide package insert to eliminate the leflunomide metabolite.  
8.2.1 
Description  
Cholestyramine is a strong anion exchange resin comprised of a quaternary ammonium group attached to an inert 
styrene-divinylbenzene copolymer. Cholestyramine removes bile acids from the body by forming insoluble 
complexes with bile acids in the intestine, which are then excreted in the feces.  


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8.2.2 
Other names  
Questran®, Questran Light, Cholybar, Olestyr 
8.2.3 
Mode of action 
Cholestyramine resin adsorbs and combines with the bile acids in the intestine to form an insoluble complex which 
is excreted in the feces. This results in a partial removal of bile acids from the enterohepatic circulation by 
preventing their absorption. 
8.2.4 
Toxicology 
See Section 6.2. 
8.2.5 
Storage and stability 
Store between 20º-25ºC (68º-77ºF). [See USP Controlled Room Temperature]. Excursions permitted to 15º-30ºC 
(59º-86ºF). 
8.2.6 
Agent administration 
Cholestyramine should be administered orally after being prepared per package insert (powder diluted in fluid). 
See Section 5.3.2 for study administration details.  
8.2.7 
Availability and supply 
Cholestyramine will be provided to participants by the study. A commercial supply will be purchased and 
distributed by the pharmacy at City of Hope. 
 
9.0 CORRELATIVE/ SPECIAL STUDIES 
9.1 Central Pathology Review 
A slide from a baseline skin biopsy of the participant taken in the preceding 6 months must be sent to City of Hope 
for diagnostic review.  
9.2 Skin Biopsies 
The diagram below diagram provides an overview for the skin biopsy samples. 


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Figure 9.1 Overview of collection and analysis for CD30+LYPD tissue samples 
 
9.2.1 
Collection details 
A single skin lesion will be sampled from participants at baseline and subsequent timepoints. 
Samples will be a ~1x1 cm punch biopsy for all timepoints 
9.2.2 
Timepoints of collection 
Lesion samples will be taken at the following timepoints:  
o Pre-dose Cycle 1 Day 1 (baseline samples may be collected anytime post-informed consent and prior to 
the Cycle 1 Day 1 dose)  
o Cycle 2 Day 1, and Cycle 5 Day 1 if lesions are present 
o At end of protocol therapy (13 or fewer cycles) if lesions are present.  
o At disease progression 
9.2.3 
Processing details 
The collected samples will be processed as follows: 
o ½ of each lesion will be formalin fixed (FFPE). 
o ½ of each lesion will be collected in saline. 
9.2.4 
Labeling of samples 
Samples will labeled with the study number, subject ID, type of biopsy (shave or punch), date and timepoint of 
collection (as stated in Section 9.2.1), and if applicable patient initials.  


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9.2.5 
Sample shipment 
Samples collected at the above indicated timepoints will be taken to Dr. Querfeld’s laboratory (Kaplan Rm#1024) 
for processing as stated in Figure 9.1. 
9.2.6 
Single Cell RNA Sequencing 
The samples at baseline and beginning of cycle 2 for each patient will be analyzed together to identify changes in 
both CD30 tumor cells and other immune cell populations. Cells with mitochondrial read rate > 10% and < 200 
detectable genes are considered as low-quality and filtered out. Unwanted sources of variation will be regressed 
out of the data by constructing linear models to predict gene expression based on the number of UMIs per cell as 
well as the percentage of mitochondrial gene content. Normalized and scaled data will be clustered using the top 
significant principal components of the highly variable genes. The t-distributed stochastic neighbor embedding (t-
SNE) algorithm will be used to visualize the resulting clusters. Cluster specific markers will be identified to generate 
heatmap and identify cell types in each cell cluster. T cell subtype markers, such as T reg, memory T cells, effector 
T cells, exhausted T cells etc. will be used to identify different T cell populations. Chromium’s V(D)J-Loupe will be 
used for analysis of TCR clonotypes and for visualization. Over-represented TCR clone in each patient will be 
identified and considered as indication of malignant cells. Genes will be compared between malignant and non-
malignant cells using Bioconductor package “Limma” on log transformed and normalized scRNA-seq data. Gene 
Set Enrichment analysis (GSEA) v3 will be performed to evaluate the significance activation of the Hallmark and 
KEGG gene sets in MSigDb. This analysis will help us understand what specific pathways are activated in tumor 
cells and how the pathways are changing after treatment. Single cell trajectory analysis will be conducted with 
diffusion pseudotime method using Bioconductor package “destiny”, which will capture the dynamic changes of 
tumor cells before and after treatment.  
9.2.7 
Immunohistochemistry 
In addition, immunohistochemistry will be performed on all specimens to better examine the effect leflunomide 
has on the changing tumor and tumor microenvironment as well as correlate these findings with those from 
scRNA-seq.  Current work in this area has noted that the predominant cells in the tumor microenvironment of 
CD30+LYPDs include CD163+ M2, tumor infiltrating CD8+ lymphocytes, FOXP3+ Tregs and programmed cell death 
(PD-1) lymphocytes.  
The multiplex immunohistochemistry of the tumor microenvironment will distinguish the CD30+ T cells (tumor 
cells) from other cells (M2, Tregs, tumor infiltrating T cells) and whether or not PD1 co-expression is noted. The 
findings will be correlated to clinical response.  
 


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10.0 STUDY CALENDAR 
Table 10 describes required procedures. All procedures may increase in frequency if clinically indicated or oriented following toxicity. Adjustments to the 
treatment cycle due to a hold in study agent are detailed in Section 5.2. 
Table 10.0 Study Activity Calendar 
 
 
Screen 
-ing a 
Cycle 1, 2, 3 
Cycle 
4+ 
End of Treatment e 
Active 
Follow-Up j
Day  
1b 
Day 14c 
Day 
1d 
Day 
0 f 
Days 
1-11g 
Day 
14h 
Day 
30 i 
Informed Consent k 
X s 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria l 
X 
 
 
 
 
 
 
 
 
Registration m 
X n 
 
 
 
 
 
 
 
 
Medical history n 
X 
 
 
 
 
 
 
 
 
Physical exam -. 
X 
X 
 
X 
 
 
 
X 
 
Vital signs o 
X 
X 
 
X 
 
 
 
X 
 
Adverse events assessment p 
 
X 
X 
X 
X 
 
 
X 
 
Concomitant meds review-. 
X 
X 
 
X 
X 
 
 
X 
 
ECOG status (Appendix A)) 
X 
X 
 
X 
 
 
 
X 
 
Pregnancy test q 
X 
 
 
 
 
 
 
 
 
TB antigen test r 
X 
 
 
 
 
 
 
 
 
Hepatitis A, B, C testing-. 
X s 
 
 
 
 
 
 
 
 
Skin photographs t 
X 
X 
 
X 
X 
 
 
X 
X 
mSWAT u 
X 
X 
 
X 
X 
 
 
X 
X 
Skin biopsy v 
 
X w 
 
X w 
 
 
 
X w 
 
CBC with differential x 
X 
X 
X 
X 
 
 
 
X 
X 
Chemistry panel y 
X 
X 
X 
X 
 
 
 
X 
X 
Response assessment z 
 
X 
 
X 
X 
 
 
X 
X 
Teriflunomide clinical testing aa 
 
 
 
 
X 
 
X dd 
X dd 
 
Leflunomide administration bb 
 
Daily 
 
 
 
 
 
Cholestyramine g 
 
 
 
 
 
X g 
 
 
 
 


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a. All screening procedures to be performed within 21 days of start of study agent except informed consent, acute hepatitis panel, skeletal survey 
which may occur within 30 days of start of treatment (footnote u) and except for registration which must occur within 7 days from start of treatment 
(footnote n).  
b. Day 1 assessments to be performed within 5 days (120 hours) prior to Day 1 drug (except footnote u for C1 only). Day 1 safety assessments must be 
resulted and reviewed prior to administration of agent for the cycle that is initiating. Screening assessments, if performed within this aforementioned 
time frame, may serve as C1D1 assessments. Note: items with footnote “aa” are not performed for C1D1; the windows for screening assessments 
still apply. 
c. Day 14 evaluations have +/- 3 day window. 
d. Day 1 assessments to be performed within 5 days (120 hours) prior to Day 1 drug. Day 1 safety assessments must be resulted and reviewed prior to 
administration of agent for the cycle that is initiating. 
e. Reasons to end study treatment include disease progression and unacceptable toxicity. See Section 5.8 for all criteria.  
f. End of Treatment (EOT) Day 0 is defined as the day the determination to end treatment is made. EOT Day 0 assessments to be performed as soon 
as feasible, especially in the event of off treatment due to unacceptable toxicity and no later than 7 days after decision to end treatment; assessments 
performed after last dose of study agent(s) and within 7 days of the decision to end treatment may serve as EOT Day 0 assessments.  
g. EOT Day 1 is defined as the day cholestyramine administration begins; it will usually follow immediately after EOT Day 0, although it will not be 
deviation if this does not occur. If it does not follow immediately after EOT Day 0, the rest of calendar will follow per the actual EOT Day 1 (not EOT 
Day 0). Cholestyramine (8 grams three times daily for 11 days) will be administered according to Section 5.5. 
h. EOT Day 14 assessments must occur after completion of cholestyramine, and may occur on Day 14 +/- 3 day window. If the cholestyramine 
administration period is extended beyond 11 consecutive days, the EOT Day 14 assessments may occur outside of this defined window. 
i. 
EOT Day 30 visit has a +/- 2 day window, however this window may be adjusted without deviation to ensure that it corresponds to the final 
teriflunomide clinical test (see footnote ee). All participants will be followed until resolution or stabilization of any serious adverse events occurring 
during treatment or starting within 30 days of last study drug administration or within the time to complete the EOT Day 30 assessments, which 
every occurs later.  
j. 
Active follow-up will occur for participants who have completed EOT procedures and yet to demonstrate disease progression. Disease response will 
be assessed every 3 months. Active follow-up will continue for 12 months or until disease progression, whichever is earlier.  
k. Informed consent process to be fully documented: e.g. prospective participant had sufficient time for deliberation, all questions were answered, 
treatment options provided by MD, full study reviewed including risks, and a copy of signed consent given to participant.  
l. 
Inclusion/exclusion criteria are detailed in .Section 3.  
m. See Section 4.3 for slot reservation and registration process. Treatment must begin within 7 days of registration. Documentation providing 
Investigator’s confirmation that all eligibility criteria are met must be available prior to registration. 
n. Medical history to include review treatment history for CD30+LYPD medical history pertaining to eligibility, and demographic information. 
o. Vital signs: Weight, heart rate, blood pressure, respiration rate, temp. Height required only at baseline. 


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p. Adverse event (AE) reporting begins for events that occur after start of study agent. AE recording and reporting will continue until the completion 
of the EOT Day 30 visit or until resolution or stabilization of any serious AE occurring before the completion the EOT Day 30 assessments, which 
every occurs later.  
q. Serum or urine pregnancy test for women of child bearing potential only. 
r. T-Spot or other TB antigen test. 
s. Consent, acute hepatitis panel, to be completed within 30 days prior to registration.  
t. Skin photographs: for subjects with skin lesions, up to five designated index lesions, representative of the subject's extent of disease, will be selected 
at baseline and measured and photographed using a digital camera. Photos should be taken against a blue backdrop. The photos will be taken on 
Day 1, prior to the first dose and then Cycle 2 Day 1 (-7 days) then every Cycle. In addition, half-body global photos (waist to feet, waist to top of 
head and sides) will also be obtained. Photos must be labeled with patient's protocol number and initials. 
u. Modified Severity Weighted Assessment Tool (mSWAT)[30] (Appendix C) 
v. skin biopsies for research will not be taken at baseline if patients have a recent biopsy taken containing needed information.  
w. skin biopsies for research at baseline, at C2D1, C5D1, and EOT (if lesions are present), and at disease progression (Section 9.2).  
x. CBC with differential: erythrocytes (RBC), hemoglobin, hematocrit, platelets, total WBC plus absolute differential counts (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils).  
y. Serum chemistry panel: Comprehensive metabolic panel (sodium, potassium, chloride, carbon dioxide, creatinine, urea nitrogen, calcium, glucose, 
albumin, total bilirubin, alkaline phosphatase, total protein, ALT/SGPT, AST/SGOT) LDH, magnesium, phosphorus, and uric acid. 
z. See Section 11.2 for response assessment criteria. 
aa. Teriflunomide clinical blood assay to be ordered as “leflunomide metabolite” miscellaneous clinical test. 
bb. Clinical testing must demonstrate teriflunomide plasma levels less than 0.02 mg/L or 0.02 µg/ml by two separate tests at least 14 days apart. If 
plasma levels are higher than 0.02 mg/L or 0.02 µg/mL, additional cholestyramine treatment will be considered.  
cc. Participants will receive leflunomide orally on a daily basis which will be recorded on the pill diary (Appendix D). The first 3 loading doses will be 
given at a dose of 100 mg, after which treatment will continue at a dose of 20 or 10 mg daily. See administration details in Section 5.3. 
 


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11.0 ENDPOINT DEFINITIONS/MEASUREMENT OF EFFECT 
11.1 Safety Endpoints 
Toxicity will be graded according to the NCI-Common Terminology Criteria for Adverse Events version 5.0.  
11.2 Efficacy Endpoints 
Response on this study will be assessed by mSWAT (see Appendix C). In addition to mSWAT, individual 
lesions will also assessed by the Composite Assessment of Index Lesion Severity (CAILS) tool (see Appendix 
E). 
Overall Response Rate: 
o Defined as the proportion of patients with a documented response (CR or PR) any time during 
study treatment.  
Complete Response Rate: 
o Defined as the proportion of patients with a documented CR any time during study treatment. 
Duration of response: 
o Defined as the time interval from the date of first documented response (CR or PR) to the first 
documented disease progression or death, whichever occurs first. Patients without a 
documented CR or PR will be excluded. Patients who do not achieve CR or PR are excluded from 
this analysis. 
11.3 Exploratory Endpoints 
Endpoints for the exploratory objective on RNA signature are the RNA expression levels. 
  
12.0 STATISTICAL CONSIDERATIONS 
12.1 Study Design 
This study will be conducted as a single center pilot study to obtain some preliminary data on leflunomide 
treatment for patients with cutaneous LYPD. Patients will receive up to 13 cycles of leflunomide until any 
criterion for off-treatment is met. Patients without progressive disease at the time of off-treatment will 
be followed for up to 1 year after off-treatment as active follow-up. Response will be assessed after every 
cycle per mSWAT while on treatment and every 3 months while in active follow-up. The primary endpoint 
is overall response rate. Secondary endpoints include complete response rate, duration of response, and 
toxicities.   
12.2 Sample Size and Accrual Rate  
This study will accrue 12 response evaluable patients, with a maximum accrual of 14 patients. Because 
this is a rare disease that has not been systematically studied in a prospective clinical trial, there is a lack 
of historical data on the response rate (and by mSWAT) in this patient population. The sample size for this 
pilot study was chosen based on feasibility considerations, and not based on any definitive statistical 
criterion.With 12 patients, the 95% exact binomial confidence interval for the overall response rate will 
have a width of 55% (33% response rate, with 4 responders), 57% (42% response rate, with 5 responders), 


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58% (50% response rate, with 6 responders), 57% (58% response rate, with 7 responders), 55% (67% 
response rate, with 8 responders), 52% (75% response rate, with 9 responders), and 46% (83% response 
rate, 10 responders) respectively. For any AE with a true incidence of 15% or higher, with 12 patients there 
is at least an 86% chance of observing 1+ patients with such AE. 
We project to accrue approximately one patient every 3 months. The projected study accrual duration is 
therefore 3 years.  
12.3 Evaluable Participants and Participant Replacement 
All participants who received at least 1 dose of study drug will be evaluable for toxicity. All participants 
who received at least 1 dose of protocol leflunomide and had at least 1 post-baseline response assessment 
will be evaluable for response; patients inevaluable for response (for example patients who did not 
receive any protocol treatment, or patients who had no response assessment on study due to withdrawal 
of consent during cycle 1) will be replaced.  
12.4 Statistical Analysis Plan  
Patient demographic and baseline characteristics, including age, gender, medical history, and prior 
therapy, will be summarized using descriptive statistics. For continuous variables, descriptive statistics 
(number [n], mean, standard deviation, standard error, median, and range will be provided. For 
categorical variables, patient counts and percentages will be provided. 
Observed toxicities will be summarized, in terms of type, grade, time of onset, duration, and attribution 
to the study treatment. The overall response rate and complete response rate will be calculated along 
with the Clopper Pearson binomial 95% exact confidence intervals. Duration of response will be calculated 
using Kaplan-Meier product limit estimator; median duration of response will also be estimated when 
possible. 
The miRNA/mRNA expression profile data will be summarized by descriptive statistics. The data will also 
be used to explore the miRNA/mRNA that show significant differences between responders and non-
responders after leflunomide treatment. For miRNA/RNA profiling, fold changes >3 with an FDR <0.05 will 
be considered significant.  
 
13.0 DATA HANDLING, DATA MANAGEMENT, RECORD KEEPING 
13.1 Source Documents 
Source documents are original documents, data, and records (e.g., medical records, pharmacy dispensing 
records, recorded data from automated instruments, laboratory data) that are relevant to the clinical trial. 
The investigator or their designee will prepare and maintain adequate and accurate source documents. 
These documents are designed to record all observations and other pertinent data for each patient 
enrolled in this clinical trial.  Source documents must be adequate to reconstruct all data transcribed onto 
the case report forms. 
13.2 Data Capture Methods and Management 
Data for this trial will be collected using City of Hope’s electronic capture system that is compliant with 21 
CFR Part 11.  


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Study personnel will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific electronic Case Report Form (eCRF).   
13.3 Case Report Forms/Data Submission Schedule 
Study personnel will enter data from source documents corresponding to a subject’s visit into the 
protocol-specific electronic Case Report Form (eCRF) when the information corresponding to that visit is 
available.  
The investigator is responsible for all information collected on subjects enrolled in this study.  All data 
collected during the course of this study must be reviewed and verified for completeness and accuracy by 
the investigator. All case report forms must be completed by designated study personnel.  The completed 
case report forms must be reviewed, signed and dated by the Investigator or designee in a timely fashion. 
All data will be collected using electronic data collection, stored as indicated in Section 13.2, and will be 
submitted according to the timelines indicated in Table 13.3. 
Table 13.3 Data Submission Schedule 
Form 
Submission Timeline 
Eligibility Checklist 
Complete prior to registration  
On Study Forms 
Within 14 calendar days of registration 
Baseline Assessment Forms 
Within 14 calendar days of registration 
Treatment Forms 
Within 10 calendar days of treatment administration 
Adverse Event Report Forms 
Within 10 calendar days of AE assessment/notification  
Response Assessment Forms 
Within 10 calendar days of the response assessment 
Other Assessment Forms (concomitant 
medications) 
Within 10 calendar days of the assessment 
Off Treatment/Off Study Forms 
Within 10 calendar days of end of treatment/study 
Follow up/Survival Forms 
Within 14 calendar days of the follow up activity 
13.4 Regulatory Records 
The investigator will maintain regulatory records, including updating records in accordance with Good 
Clinical Practice guidelines and FDA regulations. 
14.0 REPORTING OF ADVERSE EVENTS, UNANTICIPATED PROBLEMS & OTHER EVENTS OF INTEREST 
The research team is responsible for classifying adverse events (AEs) and unanticipated problems (UPs) as 
defined in the relevant regulations and reporting to all applicable parties, including but not limited to the 
COH IRB, DSMC, Food and Drug Administration (FDA), National Institutes of Health (NIH) and other 
collaborators, e.g., pharmaceutical companies. The research team is responsible for the continued 
monitoring and tracking of all AEs in order to ensure non-reportable events are reviewed and monitored 
and do not rise to a reporting level. 
14.1 Assessment of Adverse Events  
The site Investigator will be responsible for determining the event name, and assessing the severity (i.e., 
grade), expectedness, and attribution of all adverse events as applicable per the City of Hope Clinical 
Research Adverse Event and Unanticipated Problem policy. Adverse events will be characterized using the 
descriptions and grading scales found in NCI CTCAE v5.0. A copy of the scale can be found at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm. 


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The following definitions will be used to determine the causality (attribution) of the event to the study 
agent or study procedure. 
o Unrelated – The event is clearly NOT related to study treatment, and is clearly related to other 
factors such as the participant’s clinical state, other therapeutic interventions, or concomitant 
medications administered to the participant. 
o Unlikely – The event is unlikely related to the study treatment, and is most likely related to other 
factors such as the participant’s clinical state, other therapeutic interventions, or concomitant 
drugs. 
o Possible – The event may be related to study treatment, as it follows a reasonable temporal 
sequence from the time of drug administration, but could have been produced by other factors 
such as the participant’s clinical state, other therapeutic interventions, or concomitant drugs.  
o Probable – The event is most likely related to the study treatment, as it follows a reasonable 
temporal sequence from the time of drug administration and a known response pattern to the 
study drug, and is unlikely related to the participant’s clinical state, other therapeutic 
interventions, or concomitant drugs.  
o Definite – The event is clearly related to the study treatment, as it follows a reasonable temporal 
sequence from the time of drug administration and a known response pattern to the study drug, 
and is not reasonably explained by other factors such as the participant’s condition, therapeutic 
interventions, or concomitant drugs.  
14.2 Routine AE Collection and Reporting Guidelines 
AEs will be collected from the signing of informed consent until ending study participation.  Routine AE 
reporting will occur via data entry into the study eCRF.  Adverse events will be monitored by the Protocol 
Management Team (PMT). Adverse events that do not meet the criteria of serious OR are not 
unanticipated problems do not require expedited reporting. AEs reported through expedited processes 
(e.g., reported to the IRB, DSMC, FDA, etc.) must also be reported in routine study data submissions. 
Routing AEs recorded in the CRF will include: 
During protocol treatment through EOT, all grade 2 or higher adverse events 
All SAEs 
14.3 Expedited Reporting  
The table below indicates what events to report to expeditiously (Table 14.3). 
Table 14.3 Expedited Reporting Guidelines 
Time point 
What to report  
From signing of the consent to study completion 
 
All UPs and AEs that meet the definition of a UP 
For the time period beginning at treatment 
through 90 days following cessation of treatment, 
or 30 days following cessation of treatment if the 
subject initiates new anticancer therapy, 
whichever is earlier 
 
All SAEs regardless of relationship to protocol 
therapy  
 
All AESIs, overdose 
 
AESIs (Section 14.2)- irAEs, overdose 


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All reportable events will require follow up until 
stabilization or resolution per the agreement of 
the Study PI.  
From Day 1 of protocol therapy up to 90 days 
post-last leflunomide dose 
 
Pregnancies and lactation  
Post Safety follow-up to removal from study  
 
All SAEs that are at least possibly related to 
leflunomide.  
NOTE: All events reported expeditiously require follow-up reporting until the event is resolved, stabilized, or 
determined to be irreversible by the investigator.  
14.3.1 Expedited reporting guidelines  
Serious Adverse Events that require expedited reporting and unanticipated problems will be reported 
according to the approved City of Hope Clinical Research Adverse Event and Unanticipated Problem policy. 
This includes all SAEs and UPs that meet COH DSMC/IRB expedited reporting criteria that occurred at COH 
and non-COH sites. For non-COH sites, the DCC will be responsible for reporting (see section 14.5.2). 
14.4 Adverse Events of Special Interest (AESI) Requiring Expedited Reporting 
14.4.1 Definition of Overdose 
On a per dose basis, an overdose is defined as the following amount over the protocol-specified dose of 
lenalidomide assigned to a given patient, regardless of any associated adverse events or sequelae. 
PO 
any amount over 60 mg leflunomide 
On a schedule or frequency basis, an overdose is defined as anything more frequent than the protocol 
required schedule or frequency.   
Complete data about drug administration, including any overdose, regardless of whether the overdose 
was accidental or intentional, should be reported.  
14.4.2   Second Malignancies 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., treatment with 
investigational agent/intervention, radiation or chemotherapy). A secondary malignancy is not considered 
a metastasis of the initial neoplasm. 
The investigator must immediately notify the Study PI/ DCC via an expedited report. 
15.0 ADHERENCE TO THE PROTOCOL & REPORTING OF PROTOCOL DEVIATIONS 
Deviations from the protocol should be avoided, except when necessary to eliminate immediate hazard(s) 
for the protection, safety, and well-being of a research participant. As a result of deviations, corrective 
actions are to be developed by the study staff and implemented promptly. All protocol deviations and 
planned protocol deviations will be reported in accordance with the Clinical Research Protocol Deviation 
policy. 


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16.0 STUDY OVERSIGHT, QUALITY ASSURANCE, & DATA AND SAFETY MONITORING 
16.1 All Investigator Responsibilities 
An investigator is responsible for ensuring that an investigation is conducted according to the signed 
investigator statement, the investigational plan, and applicable regulations; for protecting the rights, 
safety, and welfare of subjects under the investigator's care; and for the control of drugs under 
investigation.  
16.2 Study PI Responsibilities 
The Study PI is responsible for the conduct of the clinical trial, including overseeing that sponsor 
responsibilities in accordance with federal regulations. 
16.3 Protocol Management Team (PMT) 
The PMT minimally consisting of the Study PI, collaborating investigators, research nurse, clinical research 
associate/coordinator, and the study biostatistician is responsible for ongoing monitoring of the data and 
safety of this study, including implementation of the stopping rules for safety/toxicity. 
The PMT is recommended to meet (in person or via teleconference) to review study status. The meeting 
is a forum to discuss study related issues including accrual, SAE/AE/UPs experienced, study response, 
deviations/violations and study management issues. The appropriateness of further subject enrollment 
and the specific intervention for subsequent subject enrollment are addressed.  
16.4 Auditing & Quality Assurance 
Clinical site auditing is conducted to ensure that the rights of human subjects are protected, that the study 
is implemented in accordance with the protocol and regulatory requirements, and that the quality and 
integrity of study data and data collection methods are maintained. This trial will be audited by the City 
of Hope Office Office for Safety and Data Quality. Details of clinical site auditing are documented in the 
City of Hope Institutional Data and Safety Monitoring Plan (DSMP).  
16.5 Risk Determination 
This is a moderate risk study, as defined in the City of Hope Institutional DSMP.  This determination was 
made because the study is an investigator-initiated Phase 2 study that is IND exempt.  
16.6 City of Hope Data and Safety Monitoring Committee (DSMC) 
The COH DSMC will review and monitor study progress, compliance, toxicity, safety, and accrual data from 
this trial via the PMT Progress Report (submitted by the Study Principal Investigator according to the 
frequency outlined in the City of Hope Institutional DSMP). The DSMC is composed of clinical specialists 
who have no direct relationship with the study. Information that raises any questions about participant 
safety will be addressed with the Protocol Management Team. 
17.0 ETHICAL AND REGULATORY CONSIDERATIONS 
17.1 Ethical Standard 
This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical 
Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for 


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the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the 
Declaration of Helsinki. 
17.2 Regulatory Compliance 
This study is to be conducted in compliance with the IRB approved protocol and according to the following 
considerations: 
o US Code of Federal Regulations (CFR) governing clinical study conduct 
 
Title 21 Part 11 – Electronic Records; Electronic Signatures  
 
Title 21 Part 50 – Protection of Human Subjects  
 
Title 21 Part 54 – Financial Disclosure by Clinical Investigators  
 
Title 21 Part 56 – Institutional Review Boards  
 
Title 21 Part 58 – Good Laboratory Practice for Nonclinical Laboratory Studies  
 
Title 21 Part 312 – Investigational New Drug Application 
 
Title 45 Part 46 – Protection of Human Subjects  
o US Federal legislation, including but not limited to 
 
Health Insurance Portability and Accountability Act of 1996  
 
Section 801 of the Food and Drug Administration Amendments Act   
o Applicable state and local laws. For research occurring in California, this includes but is not 
limited to State of California Health and Safety Code, Title 17 
o Applicable, NIH policies and procedures 
o Applicable institutional research policies and procedures 
17.3 Institutional Review Board 
An Institutional Review Board (IRB) that complies with the federal regulations at 45 CFR 46 and 21 CFR 50, 
56 and State of California Health and Safety code, Title 17, must review and approve this protocol, 
informed consent form and any additional documents that the IRB may need to fulfill its responsibilities 
(Investigator’s Brochure, information concerning patient recruitment, payment or compensation 
procedures, or other pertinent information) prior to initiation of the study.  Revisions to approved 
documents will require review and approval by the IRB before the changes are implemented in the study. 
All institutional, NCI, Federal, and State of California regulations must be fulfilled. 
The IRB’s written unconditional approval of the study protocol and the informed consent document must 
be in the possession of the investigator before the study is initiated. 
The IRB will be informed of serious unexpected, unanticipated adverse experiences, and unanticipated 
problems occurring during the study, and any additional adverse experiences in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect adversely the 
safety of the patients of the conduct of the study; an annual update and/or request for re-approval; and 
when the study has been completed. 
17.4 Informed Consent 
The Principal Investigator or IRB approved named designee will explain the nature, duration, purpose of 
the study, potential risks, alternatives and potential benefits, and all other information contained in the 
informed consent document.  In addition, they will review the experimental subject’s bill of rights and the 
HIPAA research authorization form.  Prospective participants will be informed that they may withdraw 
from the study at any time and for any reason without prejudice, including as applicable, their current or 


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future care or employment at City of Hope or any relationship they have with City of Hope.  Prospective 
participants will be afforded sufficient time to consider whether or not to participate in the research. 
After the study has been fully explained, written informed consent will be obtained from either the 
prospective participant or his/her guardian or legal representative before study participation. The method 
of obtaining and documenting the informed consent and the contents of the consent must comply with 
the ICH-GCP and all applicable regulatory requirements. 
A copy of the signed informed consent will be given to the participant or his/her legally authorized 
representative. The original signed consent must be maintained by the investigator and available for 
inspection by sponsor designated representatives, or regulatory authority at any time. 
Informed consent is a process that is initiated prior to the individual agreeing to participate in the study 
and continues throughout study participation. 
17.5 Participant Withdrawal 
Participants may withdraw from the study at any time and for any reason without prejudice. The 
withdrawal must be documented per institutional policies. The COH DCC should be promptly notified of 
the change in participant status.   
Participant withdrawal may consist of any of the following with regard to study procedures and data 
collection: 
o Withdrawal from study treatment, but agreement to continue with active study procedures 
and chart review and survival follow-up. 
o Withdrawal from study treatment and all active procedures, but agreement for chart review 
and survival follow-up. 
o Withdrawal from study treatment, all active procedures, and any future data collection. 
Participants who agreed to the collection of research blood samples may withdraw consent to use their 
specimens, if they are not yet processed as detailed in the consent form. Once the PI and site PI is notified 
of this withdrawal of informed consent, the research specimens will not be used in any research. At that 
time, any of the existing specimens will be destroyed. 
17.6 Special and Vulnerable Populations 
17.6.1 Women and Minorities 
The study is open to anyone regardless of gender, race or ethnicity.  Efforts will be made to extend the 
accrual to a representative population.  If differences in outcome that correlate to gender, racial, or ethnic 
identity are noted, accrual may be expanded or additional studies may be performed to investigate those 
differences more fully.   
Pregnant women are excluded because the study drugs have been determined to be embryolethal and 
teratogenic in animal testing.  
17.6.2 Pediatric Population 
Pediatric participants (< 18 years of age) are excluded from this study since safety and effectiveness of 
protocol therapy has not yet been defined for the study population. Additional studies may be performed 
in the pediatric population once safety and effectiveness of protocol therapy is defined in the adult study 
population. 
The incidence of CTCL is rare in the pediatric population. 


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17.6.3 HIV Positive Individuals 
Participants with HIV are excluded due to concerns about inadvertent augmentation of infectious and/or 
inflammatory activity. 
17.6.4 Vulnerable Populations 
Per 45 CFR §46.111 (a)(3) and 45 CFR §46, Subparts B-D identifies children, prisoners, pregnant women, 
mentally incapacitated persons, and economically or educationally disadvantaged persons as vulnerable 
populations.  
Adults lacking capacity to consent are not excluded from participation. This study does not pose additional 
risks for adults lacking capacity than for the general population.  In such instances, informed consent will 
be sought and documented from the prospective participant’s legally authorized representative in 
agreement with institutional policies and local IRB approval. 
Economically/educationally disadvantaged persons are not actively targeted for participation, nor are 
they excluded from participation. This study does not pose additional risks for economically/educationally 
disadvantaged persons than for the general population. 
17.7 Participant Confidentiality 
Participant confidentiality is strictly held in trust by the investigators, study staff, and the sponsor(s) and 
their agents. This confidentiality is extended to cover testing of biological samples in addition to any study 
information relating to participants.  
This research will be conducted in compliance with federal and state requirements relating to protected 
health information (PHI), including the requirements of the Health Insurance Portability and 
Accountability Act of 1996 (HIPAA).  HIPAA regulations require a signed subject authorization informing 
the subject of the nature of the PHI to be collected, who will have access to that information and why, 
who will use or disclose that information, and the rights of a research participant to revoke their 
authorization for use of their PHI. In the event that a subject revokes authorization to collect or use PHI, 
the investigator, by regulation, retains the ability to use all information collected prior to the revocation 
of subject authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at the end 
of their scheduled study period. 
Release of research results should preserve the privacy of medical information and must be carried out in 
accordance with Department of Health and Human Services Standards for Privacy of Individually 
Identifiable Health Information, 45 CFR 164.508. When results of this study are reported in medical 
journals or at meetings, identification of those taking part will not be disclosed and no identifiers will be 
used.  
Medical records of subjects will be securely maintained in the strictest confidence, according to current 
legal requirements.  Data will be entered, analyzed and stored in encrypted, password protected, secure 
computers that meet all HIPAA requirements. All data capture records, drug accountability records, study 
reports and communications will identify the patient by initials and the assigned patient number.  
The investigator/institution will permit direct access to source data and documents by sponsor 
representatives, the FDA, and other applicable regulatory authorities.  The access may consist of trial-
related monitoring, including remote monitoring, audits, IRB/IEC reviews, and FDA/regulatory authority 
inspections. The patient’s confidentiality will be maintained and will not be made publicly available to the 
extent permitted by the applicable laws and regulations. 


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Participant specimens with a limited data set will be provided to research laboratories. The specimens will 
be labeled with the study number, subject (accession) ID, date and time point of collection. The key to the 
code will be maintained in the COH clinical trials management system which is a secure environment.  
17.8 Use of Unused (Leftover) Specimens Collected for this Trial  
Unused samples in existence at study completion (i.e. completion of all research activities under this 
study) will either be: (a) placed in a COH IRB approved CTCL biorepository (COH#15185) with some clinical 
information and potentially PHI attached or (b) discarded. 
17.9 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial 
gain greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a 
properly constituted Conflict of Interest Committee with a Committee-sanctioned conflict management 
plan that has been reviewed and approved by the study Sponsor (City of Hope) prior to participation in 
this study.  All City of Hope investigators will follow the City of Hope conflict of interest policy. 
17.10 Financial Obligations, Compensation, and Reimbursement of Participants 
The drugs, leflunomide and cholestyramine, will be provided free of charge by City of Hope. 
Neither the research participant nor the insurance carrier will be responsible for the research procedures 
related to this study. 
Standard of care drugs or procedures provided during the course of study participation will be the 
responsibility of the research participant and/or the insurance carrier. The participant will be responsible 
for all copayments, deductibles, and other costs of treatment and diagnostic procedures as set forth by 
the insurance carrier.  The participant and/or the insurance carrier will be billed for the costs of treatment 
and diagnostic procedures in the same way as if the participant were not in a research study.   
In the event of physical injury to a participant resulting from research procedures, appropriate medical 
treatment will be available at City of Hope to the injured participant. There are no plans for City of Hope 
to provide financial compensation in the event of physical injury to a participant.  
The research participant will not receive reimbursement or payment for taking part in this study. 
17.11 Publication/ Data Sharing 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of 
the information provided by City of Hope for the purposes of performing the study, will be published or 
passed on to any third party without the written approval of the Study PI.  Any investigator involved with 
this study is obligated to provide City of Hope with complete test results and all data derived from the 
study. 
The publication or presentation of any study results shall comply with all applicable privacy laws, including, 
but not limited to, the Health Insurance Portability and Accountability Act of 1996.  
In accordance with the U.S. Public Law 110-85 (Food and Drug Administration Amendments Act of 2007 
or FDAAA), Title VIII, Section 801, this trial will be registered onto ClinicalTrials.gov. Results will be 
reported on ClinicalTrials.gov generally within 12 months after the completion date unless criteria to delay 
submission are met per the final rule. 
 


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18.0 REFERENCES 
1. 
Swerdlow, S.H., et al., The 2016 revision of the World Health Organization classification of lymphoid 
neoplasms. Blood, 2016. 127(20): p. 2375-90. 
2. 
Kim, Y.H., et al., Long-term outcome of 525 patients with mycosis fungoides and Sezary syndrome: clinical 
prognostic factors and risk for disease progression. Arch Dermatol, 2003. 139(7): p. 857-66. 
3. 
Agar, N.S., et al., Survival outcomes and prognostic factors in mycosis fungoides/Sezary syndrome: validation 
of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and 
Treatment of Cancer staging proposal. J Clin Oncol, 2010. 28(31): p. 4730-9. 
4. 
Vergier, B., et al., Transformation of mycosis fungoides: clinicopathological and prognostic features of 45 
cases. French Study Group of Cutaneious Lymphomas. Blood, 2000. 95(7): p. 2212-8. 
5. 
Querfeld, C., et al., Primary cutaneous and systemic anaplastic large cell lymphoma: clinicopathologic 
aspects and therapeutic options. Oncology (Williston Park), 2010. 24(7): p. 574-87. 
6. 
Stefanato, C.M., G. Tallini, and P.L. Crotty, Histologic and immunophenotypic features prior to 
transformation in patients with transformed cutaneous T-cell lymphoma: is CD25 expression in skin biopsy 
samples predictive of large cell transformation in cutaneous T-cell lymphoma? Am J Dermatopathol, 1998. 
20(1): p. 1-6. 
7. 
Laharanne, E., et al., Genome-wide analysis of cutaneous T-cell lymphomas identifies three clinically relevant 
classes. J Invest Dermatol, 2010. 130(6): p. 1707-18. 
8. 
Karenko, L., S. Hahtola, and A. Ranki, Molecular cytogenetics in the study of cutaneous T-cell lymphomas 
(CTCL). Cytogenet Genome Res, 2007. 118(2-4): p. 353-61. 
9. 
McGirt, L.Y., et al., Whole-genome sequencing reveals oncogenic mutations in mycosis fungoides. Blood, 
2015. 126(4): p. 508-19. 
10. 
Breedveld, F.C. and J.M. Dayer, Leflunomide: mode of action in the treatment of rheumatoid arthritis. Ann 
Rheum Dis, 2000. 59(11): p. 841-9. 
11. 
van Roon, E.N., et al., Therapeutic drug monitoring of A77 1726, the active metabolite of leflunomide: serum 
concentrations predict response to treatment in patients with rheumatoid arthritis. Ann Rheum Dis, 2005. 
64(4): p. 569-74. 
12. 
Metzler, C., et al., Elevated relapse rate under oral methotrexate versus leflunomide for maintenance of 
remission in Wegener's granulomatosis. Rheumatology (Oxford), 2007. 46(7): p. 1087-91. 
13. 
Metzler, C., et al., Maintenance of remission with leflunomide in Wegener's granulomatosis. Rheumatology 
(Oxford), 2004. 43(3): p. 315-20. 
14. 
Josephson, M.A., et al., Treatment of renal allograft polyoma BK virus infection with leflunomide. 
Transplantation, 2006. 81(5): p. 704-10. 
15. 
Pawlik, A., et al., The effect of exon (19C>A) dihydroorotate dehydrogenase gene polymorphism on 
rheumatoid arthritis treatment with leflunomide. Pharmacogenomics, 2009. 10(2): p. 303-9. 
16. 
O'Doherty, C., et al., Association of DHODH haplotype variants and response to leflunomide treatment in 
rheumatoid arthritis. Pharmacogenomics, 2012. 13(12): p. 1427-34. 
17. 
Heritage Pharmaceuticals Inc. LEFLUNOMIDE - leflunomide tablet. 2014  November 5, 2014]; Available from: 
http://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=40dd071a-d07f-452f-bf1a-
2a23b9d22ca4&type=pdf&name=40dd071a-d07f-452f-bf1a-2a23b9d22ca4. 
18. 
Xu, X., et al., In vitro and in vivo antitumor activity of a novel immunomodulatory drug, leflunomide: 
mechanisms of action. Biochem Pharmacol, 1999. 58(9): p. 1405-13. 


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19. 
Ringshausen, I., et al., The immunomodulatory drug Leflunomide inhibits cell cycle progression of B-CLL cells. 
Leukemia, 2008. 22(3): p. 635-8. 
20. 
Dietrich, S., et al., Leflunomide induces apoptosis in fludarabine-resistant and clinically refractory CLL cells. 
Clin Cancer Res, 2012. 18(2): p. 417-31. 
21. 
White, R.M., et al., DHODH modulates transcriptional elongation in the neural crest and melanoma. Nature, 
2011. 471(7339): p. 518-22. 
22. 
Hail, N., Jr., P. Chen, and L.R. Bushman, Teriflunomide (leflunomide) promotes cytostatic, antioxidant, and 
apoptotic effects in transformed prostate epithelial cells: evidence supporting a role for teriflunomide in 
prostate cancer chemoprevention. Neoplasia, 2010. 12(6): p. 464-75. 
23. 
Baumann, P., et al., Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and 
diminishes proliferation of multiple myeloma cells. Mol Cancer Ther, 2009. 8(2): p. 366-75. 
24. 
Borcherding, N., et al., Single-Cell Profiling of Cutaneous T-Cell Lymphoma Reveals Underlying Heterogeneity 
Associated with Disease Progression. Clin Cancer Res, 2019. 25(10): p. 2996-3005. 
25. 
Gaydosik, A.M., et al., Single-Cell Lymphocyte Heterogeneity in Advanced Cutaneous T-cell Lymphoma Skin 
Tumors. Clin Cancer Res, 2019. 25(14): p. 4443-4454. 
26. 
Querfeld, C., et al., Primary T Cells from Cutaneous T-cell Lymphoma Skin Explants Display an Exhausted 
Immune Checkpoint Profile. Cancer Immunol Res, 2018. 6(8): p. 900-909. 
27. 
Kartan, S., et al., The spectrum of CD30+ T cell lymphoproliferative disorders in the skin. Chin Clin Oncol, 
2019. 8(1): p. 3. 
28. 
De Souza, A., et al., Characterization of the tumor microenvironment in primary cutaneous CD30-positive 
lymphoproliferative disorders: a predominance of CD163-positive M2 macrophages. J Cutan Pathol, 2016. 
43(7): p. 579-88. 
29. 
Duvic, M., et al., Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of 
refractory or persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol, 2001. 137(5): p. 581-93. 
30. 
Olsen, E.A., et al., Clinical end points and response criteria in mycosis fungoides and Sezary syndrome: a 
consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous 
Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for 
Research and Treatment of Cancer. J Clin Oncol, 2011. 29(18): p. 2598-607. 
31. 
Wu, X., et al., Identification of a 4-microRNA signature for clear cell renal cell carcinoma metastasis and 
prognosis. PLoS One, 2012. 7(5): p. e35661. 
32. 
Oken, M.M., et al., Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol, 1982. 5(6): p. 649-55. 
 
 
 
 


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APPENDIX A: ECOG PERFORMANCE STATUS SCALE 
ECOG Performance Scale [32] 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-
disease performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically 
strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all 
self-care, but unable to carry out any work activities.  Up 
and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-
care, confined to bed or chair more than 50% of waking 
hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on 
any self-care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
 


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APPENDIX B: ISCL/EORTC TNM CLASSIFICATION OF CUTANEOUS LYMPHOMA OTHER THAN MF/SS 
 
T: skin 
T1: solitary skin involvement 
T1a: solitary lesion <5 cm diameter 
T1b: solitary lesion >5 cm diameter 
T2: regional skin involvement : multiple lesions limited to 1 body region or 2 contiguous body 
regions* 
T2a: all-disease-encompassing in a <15 cm diameter circular area 
T2b: all-disease-encompassing in a >15 cm and <30 cm diameter circular area 
T2c: all-disease-encompassing in a >30 cm diameter circular area 
T3: generalized skin involvement 
T3a: multiple lesions involving 2 noncontiguous body regions 
T3b: multiple lesions involving ≥3 body regions 
N: node 
N0: no clinical or pathologic lymph node involvement 
N1: involvement of 1 peripheral lymph node region† that drains an area of current or prior skin 
involvement 
N2: involvement of ≥2 peripheral lymph node regions or involvement of any lymph node region that 
does not drain an area of current or prior skin involvement 
N3: involvement of central lymph nodes 
M: visceral 
M0: no evidence of extracutaneous non-lymph node disease 
M1: extracutaneous non-lymph node disease present 
*Definitions of body regions: Head and neck: inferior border, superior border of clavicles, T1 spinous 
process. Chest: superior border, superior border of clavicles; inferior border, inferior margin of rib cage; 
lateral borders, midaxillary lines, glenohumeral joints (inclusive of axillae). Abdomen/genital: superior 
border, inferior margin of rib cage; inferior border, inguinal folds, anterior perineum; lateral borders, 
midaxillary lines. Upper back: superior border, T1 spinous process; inferior border, inferior margin of rib 


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cage; lateral borders, midaxillary lines. Lower back/buttocks: superior border, inferior margin of rib cage,; 
inferior border, inferior gluteal fold, anterior perineum (inclusive of perineum); lateral borders, midaxillary  
lines. Each upper arm: superior borders, glenohumeral joints (exclusive of axillae); inferior borders, 
ulnar/radial-humeral (elbow) joint. Each lower arm/hand: superior borders, ulnar /radial-humeral (elbow) 
joint. Each upper leg (thigh): superior borders, inguinal folds, inferior gluteal folds; inferior borders, 
midpatellae, midpopliteal fossae. Each lower leg/foot: superior borders, midpatellae, midpopliteal fossae. 
†Definition of lymph node regions is consistent with the Ann Arbor system. Peripheral sites: antecubital, 
cervical, supraclavicular, axillary, inguinal –femoral, and popliteal. Central sites: mediastinal, pulmonary 
hilar, paraortic, iliac. 
 
 


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APPENDIX C: MODIFIED SEVERITY WEIGHTED ASSESSMENT TOOL (MSWAT)  
The mSWAT scoring tool [30] will be used to assess disease severity. Assessments will be performed at 
the time points indicated in Section 10.0. To eliminate inter-observer variability for a given patient, the 
mSWAT should preferably be performed by the same qualified individual at all time points.  
Region 
% TBSA for 
the region 
% TBSA Patch 
(or flat erythema) 
% TBSA Plaque 
(or elevated/indurated 
erythema) 
% TBSA 
Tumor/Ulceration 
(or erythema w/ 
fissuring, ulceration) 
Head 
7 
 
 
 
Neck 
2 
 
 
 
Anterior Trunk 
13 
 
 
 
Posterior Trunk 
13 
 
 
 
Buttocks 
5 
 
 
 
Genitalia 
1 
 
 
 
Upper Arms 
8 
 
 
 
Forearms 
6 
 
 
 
Hands 
5 
 
 
 
Thighs 
19 
 
 
 
Lower Leg 
14 
 
 
 
Feet 
7 
 
 
 
% BSA by 
category 
100 
 
 
 
Severity 
Weighting Factor 
 
×1 
×2 
×4 
Skin Score 
Subtotal 
 
 
 
 
NOTE: mSWAT score equals summation of each column line. 
Abbreviations: TBSA- total body surface area 
 
 


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APPENDIX D-1: LEFLUNOMIDE MEDICATION DIARY INSTRUCTIONS 
Remember to bring this diary, all pill bottles, and any unused pills to each clinic visit. 
Call your study doctor or nurse immediately if you are having any new or worsening side effects. 
Study drug Instructions – When and How: 
Take leflunomide once a day by mouth 
Take the pills with a large glass of water (~250ml) at approximately the same times each day  
Swallow pills; do not chew them or crush them 
Do not skip any doses unless your doctor tells you to. 
When to stop taking leflunomide 
Do not stop taking leflunomide unless your doctor tells you to. 
What if I miss a scheduled dose? 
If less than 3 hours have passed from the scheduled time, then take the missed dose as soon as you 
remember.   
If more than 3 hours have passed from the scheduled time, then skip the missed dose. Wait for your next 
scheduled dose. Do not take extra medicine to make up the missed dose. 
What if I vomit after taking leflunomide? 
If you vomit your pills, write this down in your pill diary.   
Wait until the next scheduled dose; do not take extra medicine to make up the vomited dose.  
 
Additional Instructions: 
Bring this diary, all pill bottles, and any unused pills to each clinic visit.  
Keep your study drug in the original container until you take it. 
Do NOT throw away empty pill bottles or unused pills. 
Your dose may be adjusted based on your side effects 
 
Contact Information 
Study Doctor 
Phone: 
 
Name: 
Study Nurse 
Phone: 
 
Name: 
Backup Study Nurse  
Phone: 
 
Name: 


This document is confidential and for research purposes only. Do not copy, redistribute, disclose or use except as authorized.  
 
APPENDIX D-2: MEDICATION DIARY 
Study Name: Pilot Trial of Leflunomide in Patients with CD30+ Lymphoproliferative Disorders 
 
 
Day 
Week 
Day 
Date 
Time 
Dose (mg)  
# tablets 
taken 
If dose missed, please provide reason: 
1 
 
 
__:__AM/PM 
 
 
 
2 
 
 
__:__AM/PM 
 
 
 
3 
 
 
__:__AM/PM 
 
 
 
4 
 
 
__:__AM/PM 
 
 
 
5 
 
 
__:__AM/PM 
 
 
 
6 
 
 
__:__AM/PM 
 
 
 
7 
 
 
__:__AM/PM 
 
 
 
8 
 
 
__:__AM/PM 
 
 
 
9 
 
 
__:__AM/PM 
 
 
 
10 
 
 
__:__AM/PM 
 
 
 
11 
 
 
__:__AM/PM 
 
 
 
12 
 
 
__:__AM/PM 
 
 
 
13 
 
 
__:__AM/PM 
 
 
 
14 
 
 
__:__AM/PM 
 
 
 
15 
 
 
__:__AM/PM 
 
 
 
 
Participant/Caregiver signature (please sign when submitting your diary): ____________________________________ Date ___/____/____ 
 
 
Subject ID#: 
DPatient Initials (F, M, L): 
Institution:  
Cycle #: 
Cycle start date: 


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Study Name: Pilot Trial of Leflunomide in Patients with CD30+ Lymphoproliferative Disorders 
 
Day 
Week 
Day 
Date 
Time 
Dose 
# tablets 
taken 
If dose missed, please provide reason: 
16 
 
 
__:__AM/PM 
 
 
 
17 
 
 
__:__AM/PM 
 
 
 
18 
 
 
__:__AM/PM 
 
 
 
19 
 
 
__:__AM/PM 
 
 
 
20 
 
 
__:__AM/PM 
 
 
 
21 
 
 
__:__AM/PM 
 
 
 
22 
 
 
__:__AM/PM 
 
 
 
23 
 
 
__:__AM/PM 
 
 
 
24 
 
 
__:__AM/PM 
 
 
 
25 
 
 
__:__AM/PM 
 
 
 
26 
 
 
__:__AM/PM 
 
 
 
27 
 
 
__:__AM/PM 
 
 
 
28 
 
 
__:__AM/PM 
 
 
 
 
Participant/Caregiver signature (please sign when submitting your diary): ____________________________________ Date ___/____/____ 
Subject ID#: 
Patient Initials (F, M, L): 
Institution:  
Cycle #: 
Cycle start date: 


This document is confidential and for research purposes only. Do not copy, redistribute, disclose or use except 
as authorized.  
 
APPENDIX E: COMPOSITE ASSESSMENT OF INDEX LESION SEVERITY (CAILS) 
 
Index Lesion 
Clinical Sign and Degree of Size (scale of 0-8) 
1 
2 
3 
4 
5 
Erythema 
 
 
 
 
 
Scaling 
 
 
 
 
 
Plaque Elevation 
 
 
 
 
 
Hypo- or hyperpigmentation 
 
 
 
 
 
Lesion size* 
 
 
 
 
 
Total (sum of subtotals) 
 
 
 
 
 
NOTE. Cannot be used as skin assessment in global response score. Suggestions for 
improvement include using actual size of lesion versus categorical score for size and 
eliminating pigmentation as a clinical parameter. 
*Lesion size (cm2): 0: no measurable area; 1: > 0 to ≤ 4; 2: > 4 to ≤ 10; 3: > 10 to ≤ 16; 4: 
> 16 to ≤ 25; 5: >25 to ≤ 35; 6: > 35 to ≤ 45; 7: > 45 to ≤ 55; 8: > 55 to ≤ 70; 9: > 70 to ≤ 
90; 10: > 90 to ≤ 110; 11: > 110 to ≤ 130; 12: > 130 to ≤ 155; 13: > 155 to ≤ 180; 14: > 
180 to ≤ 210; 15: > 210 to ≤ 240; 16: > 240 to ≤ 270; 17: > 270 to ≤ 300; 18: > 300.