Conditions: T Cell Leukemia, Adult Leukemia, Adult T-Cell T Cell Leukemia, HTLV I Associated
Keywords: JAK 1/2 Human T-Cell Lymphotropic Virus 1 HTLV-1 Janus Kinase Inhibitor
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 19
Healthy volunteers: no

Brief summary:
Background:

* The human T-cell leukemia virus 1 (HTLV-1) causes adult T-cell leukemia (ATL). Infection does not immediately cause ATL, but it can develop over time. ATL is a rare and aggressive type of cancer that disrupts the body's ability to control the HTLV-1 virus. Infected T lymphocytes that are transformed by HTLV-1 into malignant ATL cell have constitutively activated Interleukin-2 (IL-2), IL-9 and IL-15 production pathways that function as autocrine and paracrine stimulators of these cells by stimulating these cells through the Janus Kinase (JAK) 1 and 3/Signal transducer and activator of transcription 5 (STAT5) pathways.
* Ruxolitinib is a drug that has been approved to treat bone marrow disorders. Ruxolitinib is a tyrosine kinase inhibitor that disrupts signaling through the JAK 1 and 2/STAT3 and 5 pathways and have potential as a treatment for ATL. Researchers want to see if ruxolitinib can be a safe and effective treatment for ATL.
* Initially this trial was designed as a single dose level phase II trial with ruxolitinib given at the dose approved for the treatment of primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis.
* Clinical and correlative laboratory data demonstrated limited inhibition and impact on the subject's disease with the standard 20 mg twice daily dose. Given that the manufacturers of ruxolitinib had safety data for administering ruxolitinib to normal healthy volunteers at doses up to 50 mg twice or 100 mg once daily, the trial was reconfigured as a phase I dose escalation trial giving these higher doses on the twice daily schedule

Objectives:

Initial Phase II design:

* Define clinical or objective response rate for the 20 mg twice daily dose of Ruxolitinib.
* Define safety profile, Time to progression and survival time.

Subsequent Phase I dose escalation with expansion cohort treated at the MTD or MAD:

* Determine the maximum tolerated dose (MTD) and clinical response rate for ruxolitinib administered at the higher dose levels.
* Determine safety profile, time to progression
* To test the safety and effectiveness of ruxolitinib for adult T-cell leukemia.

Eligibility:

\- Individuals at least 18 years of age who have ATL caused by HTLV-1.

Design:

* Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Imaging studies will also be performed.
* Participants will take ruxolitinib twice a day for 28 days. They will have blood tests on days 1, 14, and 28. These tests will look at the levels of HTLV-1 in the blood. Participants will have a final blood test about 2 weeks later. Treatment will also be monitored with imaging studies.
* Participants who have a partial response during treatment may be able to start taking ruxolitinib again after the final blood test. They will continue to take ruxolitinib for as long as it is effective and the side effects are not severe.
* Participants who have a full response during treatment will take ruxolitinib for 56 more days, and then stop treatment. If ATL returns, they may restart treatment and continue it for as long as it is effective.

Detailed description:
Background:

* Adult T-cell leukemia is a lymphoproliferative disorder characterized by the presence of cluster of differentiation 4 (CD4)/cluster of differentiation 25 (CD25) expressing T cells (interleukin-2 receptor (IL-2R) alpha expressing) in the peripheral blood, in lymphoid and other tissues.
* In smoldering and chronic adult T-cell leukemia (ATL) the human T-cell leukemia virus 1 (HTLV-1) encoded protein, Tax constitutively activates interleukin-2 (IL-2), IL-9 and IL-15 autocrine/paracrine systems that in turn activate the Janus kinase (JAK)-1/3/signal transducer and activator of transcription 5 (STAT5) pathways.
* Ruxolitinib a therapeutic agent inhibits cytokine mediated Janus kinase (JAK)-1/2 activation and ex vivo proliferation of malignant T cells from subjects with ATL.
* Ruxolitinib is a potent orally bioavailable JAK1/2 inhibitor not licensed for the treatment of ATL.

Primary Objective:

Objective Initial Phase II:

* To determine clinical or objective response rate for ruxolitinib given at 20 mg twice daily
* Primary Objective Dose Escalation Phase I: To determine the maximum tolerated dose and clinical response rate for ruxolitinib given at doses of 30, 40 or 50 mg orally twice daily in subjects with smoldering, chronic and biologically indolent acute or lymphomatous subtype of ATL

Eligibility

* Subjects greater than or equal to 18 years old with pathologically confirmed adult T-cell leukemia: smoldering or chronic or previously treated lymphomatous or acute subtypes with clinically indolent behavior indicated by lack of significant symptoms and treatment free interval of greater than 6 months.
* Subjects must have measurable or evaluable disease. Subjects with \> 10% of their PBMCs having the characteristic abnormal (i.e., CD3dim, CD4 plus CD25 plus expressing) fluorescence activated cell sorting (FACS) profile for circulating ATL cells will be considered to have measurable disease.
* Subjects with symptomatic leukemic meningitis, bony or gastrointestinal (GI) tract involvement, serum calcium or Lactate dehydrogenase (LDH) \> 1.5 times the upper limit of normal will be excluded. However, subjects that have both ATL and another HTLV-1 associated disease such as tropical spastic paraparesis (human T-cell leukemia virus 1 (HTLV-1) Associated Myelopathy (HAM)/tropical spastic paraparesis (TSP)) will be included.
* No prior treatment with another JAK inhibitor; subjects previously treated in this protocol at the lower dose are eligible to restart treatment at the higher dose levels.

Design

\- This is a pilot open-label, trial with off label-use of oral ruxolitinib that will treat 27 to 33 Subjects with smoldering or chronic or clinically indolent ATL. Groups of 3 to 6 newly enrolled or reenrolled Subjects will begin treatment at an elevated dose of 30 mg orally given twice daily. If this dose is tolerated without exceeding the criteria for dose limiting toxicity (DLT) during the first cycle of treatment, the tolerability of treatment at 40 mg and then 50 mg twice daily will be evaluated.

Arms:
arm 1: Ruxolitinib 20 mg orally twice daily for 28 days. Subjects may continue to receive treatment until progressive disease (PD) or unacceptable toxicity. arm 2: Dose level 1: Ruxolitinib 30 mg orally twice daily for 28 days to determine the maximum tolerated dose (MTD). Subjects may continue to receive treatment until progressive disease (PD) or dose limiting toxicity (DLT) or unacceptable toxicity.

Dose level 2: Ruxolitinib: Ruxolitinib 40 mg orally twice daily for 28 days to determine the maximum tolerated dose (MTD). Subjects may continue to receive treatment until progressive disease (PD) or dose limiting toxicity (DLT) or unacceptable toxicity.

Dose level 3: Ruxolitinib: Ruxolitinib 50 mg orally twice daily for 28 days to determine the maximum tolerated dose (MTD). Subjects may continue to receive treatment until progressive disease (PD) or dose limiting toxicity (DLT) or unacceptable toxicity. arm 3: Ruxolitinib at the maximum tolerated dose (MTD) or the maximum administered dose (MAD) defined in the phase 1 dose escalation cohorts. Subjects may continue to receive treatment until progressive disease (PD) or unacceptable toxicity.

Interventions: intervention 1: Ruxolitinib intervention 2: Ruxolitinib intervention 3: Ruxolitinib intervention 4: Ruxolitinib
Intervention descriptions: intervention 1: Ruxolitinib 20 mg orally twice daily for 28 days. Subjects may continue to receive treatment until progressive disease (PD) or unacceptable toxicity. intervention 2: Ruxolitinib 30 mg orally twice daily for 28 days to determine the maximum tolerated dose (MTD). Subjects may continue to receive treatment until progressive disease (PD) or dose limiting toxicity (DLT) or unacceptable toxicity. intervention 3: Ruxolitinib: Ruxolitinib 40 mg orally twice daily for 28 days to determine the maximum tolerated dose (MTD). Subjects may continue to receive treatment until progressive disease (PD) or dose limiting toxicity (DLT) or unacceptable toxicity. intervention 4: Ruxolitinib 50 mg orally twice daily for 28 days to determine the maximum tolerated dose (MTD). Subjects may continue to receive treatment until progressive disease (PD) or dose limiting toxicity (DLT) or unacceptable toxicity.

Protocol document:
Prot_SAP_000.pdf: 
Abbreviated Title:  Ruxolitinib in ATL 
Version Date:  02/10/2021 
1 
 Abbreviated Title:  Ruxolitinib in ATL  
 
NIH Protocol #:  13-C-0006  
 
Version Date:   02/10/2021 
 
NCT Number: NCT01712659 
 
Phase I/II Trial Evaluating the Safety and Efficacy of Ruxolitinib in Patients with 
Smoldering or Chronic Adult T-Cell Leukemia (ATL) 
 
 
NCI Principal Investigator: Kevin C. Conlon, M.D. 
Lymphoid Malignancies Branch (LYMB) 
Center for Cancer Research (CCR) 
National Cancer Institute (NCI) 
Building 10, Room 4N115 
National Institutes of Health 
Bethesda, MD 20892 
Phone:  240-760-6087 
Email:  conlonkc@mail.nih.gov  
Investigational Agents:  None 
Commercial Agent:  Ruxolitinib 
 
 
 


Abbreviated Title:  Ruxolitinib in ATL 
Version Date:  02/10/2021 
2 
PRÉCIS 
Background: 
• Adult T-cell leukemia is a lymphoproliferative disorder characterized by the presence of 
CD4/CD25 expressing T cells (IL-2R alpha expressing) in the peripheral blood, in 
lymphoid and other tissues. 
• In smoldering and chronic ATL the HTLV-1 encoded protein, Tax constitutively activates 
interleukin-2 (IL-2), IL-9 and IL-15 autocrine/paracrine systems that in turn activate the 
Janus kinase (JAK)-1/3/STAT5 pathways. 
• Ruxolitinib a therapeutic agent inhibits cytokine mediated JAK1/2 activation and ex vivo 
proliferation of malignant T cells from patients with ATL. 
• Ruxolitinib is a potent orally bioavailable JAK1/2 inhibitor not licensed for the treatment 
of ATL. 
Primary Objective: 
• To determine the maximum tolerated dose and clinical response rate for ruxolitinib given 
at doses of 30, 40 or 50 mg orally twice daily in patients with smoldering, chronic and 
biologically indolent acute or lymphomatous subtype of ATL 
Eligibility:  
• Patients  18 years old with pathologically confirmed adult T-cell leukemia: smoldering or 
chronic, or previously treated lymphomatous or acute subtypes with clinically indolent 
behavior indicated by lack of significant symptoms and treatment free interval of greater 
than 6 months.   
• Patients must have measurable or evaluable disease.  Patients with > 10% of their PBMCs 
having the characteristic abnormal (i.e., CD3dim, CD4+ CD25+ expressing) FACS profile 
for circulating ATL cells will be considered to have measurable disease.   
• Patients with symptomatic leukemic meningitis, bony or GI tract involvement, serum 
calcium or LDH > 1.5 X the upper limit of normal will be excluded. However, patients that 
have both ATL and another HTLV-1 associated disease such as tropical spastic paraparesis 
(HAM/TSP) will be included.   
• No prior treatment with another JAK inhibitor; patients previously treated in this protocol 
at the lower dose are eligible to restart treatment at the higher dose levels. 
Design: 
• This is a pilot open-label, trial with off label-use of oral ruxolitinib that will enroll 27 to 33 
patients with smoldering or chronic or clinically indolent ATL. Groups of 3 to 6 newly 
enrolled or reenrolled patients will begin treatment at a dose of 30 mg orally given twice 
daily.  If this dose is tolerated without exceeding the criteria for dose limiting toxicity 
(DLT) during the first cycle of treatment, the tolerability of treatment at 40 mg and then 50 
mg twice daily will be evaluated.   


Abbreviated Title:  Ruxolitinib in ATL 
Version Date:  02/10/2021 
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TABLE OF CONTENTS  
PRÉCIS ............................................................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
STATEMENT OF COMPLIANCE .................................................................................................5 
1 
INTRODUCTION ...................................................................................................................5 
1.1 
Study Objectives ...............................................................................................................5 
1.2 
Background and Rationale ................................................................................................5 
1.3 
Inhibition of Cytokine Stimulation in the Treatment of ATL and Rationale for ruxolitinib
 
8 
1.4 
Preclinical Experiments with JAK inhibitors ....................................................................9 
1.5 
Clinical Experience with Ruxolitinib ..............................................................................14 
1.6 
Rationale for Patient Selection, Change in the Treatment Schedule and Target Response 
Rate in the Initial Phase II Trial .................................................................................................16 
1.7 
Rationale for Multiple Assessments of STAT5 and phosphoSTAT5 .............................19 
2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT ........................................................20 
2.1 
Eligibility Criteria ...........................................................................................................20 
2.2 
Screening Evaluation.......................................................................................................21 
2.3 
Participant Registration and Status Update Procedures ..................................................23 
2.4 
Baseline Evaluation .........................................................................................................24 
3 
STUDY IMPLEMENTATION .............................................................................................25 
3.1 
Study Design ...................................................................................................................25 
3.2 
Drug Administration .......................................................................................................28 
3.3 
Dose Modifications .........................................................................................................28 
3.4 
Clinical Monitoring .........................................................................................................28 
3.5 
Study Calendar ................................................................................................................31 
3.6 
Concurrent Therapy.........................................................................................................34 
3.7 
Cost and Compensation ...................................................................................................34 
3.8 
Criteria for Removal from the Protocol Treatment and Off-Study Criteria ....................34 
4 
CONCOMITANT MEDICATIONS/MEASURES ...............................................................35 
5 
BIOSPECIMEN COLLECTION ...........................................................................................35 
5.1 
Correlative Studies for Research .....................................................................................35 
5.2 
Sample Storage, Tracking and Disposition .....................................................................36 
6 
DATA COLLECTION AND EVALUATION ......................................................................38 


Abbreviated Title:  Ruxolitinib in ATL 
Version Date:  02/10/2021 
4 
6.1 
Data Collection ................................................................................................................38 
6.2 
Response Criteria ............................................................................................................39 
6.3 
Toxicity Criteria ..............................................................................................................41 
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING ..............41 
7.1 
Definitions .......................................................................................................................41 
7.2 
OHSRP Office of Compliance and Training / IRB Reporting ........................................41 
7.3 
NCI Clinical Director Reporting .....................................................................................42 
7.4 
NIH Required Data and Safety Monitoring Plan ............................................................42 
8 
STATISTICAL CONSIDERATIONS ...................................................................................42 
9 
COLLABORATIVE AGREEMENTS ..................................................................................43 
10 HUMAN SUBJECTS PROTECTIONS ................................................................................43 
10.1 Rationale for Subject Selection .......................................................................................43 
10.2 Participation of Children .................................................................................................43 
10.3 Participation of Subjects Unable to Give Consent ..........................................................44 
10.4 Evaluation of Benefits and Risks/Discomforts ...............................................................44 
10.5 Consent and Assent Process and Documentation ...........................................................45 
11 REGULATORY AND OPERATIONAL CONSIDERATIONS ..........................................46 
11.1 Study Discontinuation and Closure .................................................................................46 
11.2 Quality Assurance and Quality Control ..........................................................................46 
11.3 Conflict of Interest Policy ...............................................................................................46 
11.4 Confidentiality and Privacy .............................................................................................47 
12 PHARMACEUTICAL INFORMATION ..............................................................................47 
12.1 Ruxolitinib (Jakafi, ICNB018424) ..................................................................................48 
13 REFERENCES ......................................................................................................................50 
14 APPENDICES .......................................................................................................................53 
APPENDIX A:  PERFORMANCE STATUS CRITERIA ........................................................54 
APPENDIX B:  DEFINITIONS OF ATL SUBSETS ...............................................................55 
APPENDIX C:  STRONG INHIBITORS of P450 ISOFORM CYP 3A4 ................................56 
 
 
 


Abbreviated Title:  Ruxolitinib in ATL 
Version Date:  02/10/2021 
5 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP) and the following:  
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study.  In addition, all changes to the consent form will be IRB-approved; an 
IRB determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Primary Objective 
• To determine the maximum tolerated dose and clinical response rate for ruxolitinib given 
at doses of 30, 40 or 50 mg orally twice daily in patients with smoldering, chronic and 
biologically indolent acute or lymphomatous subtype of ATL 
1.1.2 Secondary Objective 
• To define the safety profile, time to progression when ruxolitinib is administered at doses 
of 30, 40 or 50 mg orally twice daily in patients with smoldering, chronic and biologically 
indolent acute or lymphomatous subtype of ATL 
1.2 
BACKGROUND AND RATIONALE 
1.2.1 Epidemiology of ATL 
ATL is an aggressive T-cell lymphoproliferative disorder characterized by the presence of 
malignant CD4/CD25-expressing T cells in the peripheral blood and in lymphoid and other tissues 
1-6.  The disease exhibits a striking clustering of cases in certain geographic regions, notably 
southwestern Japan, the Caribbean basin, northeastern South America, central Africa, and the 
southeastern United States.  Epidemiologic studies demonstrate a clear association of the disease 
with the presence of a retrovirus, human T-cell lymphotropic virus type 1 (HTLV-1)7, 8. The vast 
majority of HTLV-1-infected individuals are asymptomatic carriers, but infected individuals are 
nevertheless capable of transmitting the virus.  An infected individual appears to have an 
approximately 0.1 percent per year risk of developing frank ATL; this is equivalent to a cumulative 
lifetime risk of 2 to 5 percent 2, 3. 
1.2.2 Biology of HTLV-1 Associated ATL 
ATL cells exhibit characteristic morphological features (flower-like cells with deeply indented 
nuclei, derived from mature helper T-cells with the surface phenotype CD3+dim, CD4+, CD7-, 
CD8-, CD25+) 9.  ATL cells usually contain chromosomal abnormalities. Although no individual 


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6 
cytogenetic change is characteristic of the disease; the degree of aneuploidy correlates with clinical 
aggressiveness. The molecular mechanism by which HTLV-1 transforms T cells is not fully 
defined, but the HTLV-1 genome is not reported to contain an oncogene. The site of integration 
for the provirus for an individual patient is identical for all the transformed cells for the particular 
individual, but the integration site differs from person to person and the mechanism of 
transformation is not insertional mutagenesis. HTLV-1 is a complex retrovirus that encodes 
regulatory (Tax and Rex) genes and accessory p12, p13, p30 and HBZ genes to control viral 
replication and proliferation of infected cells 10-13.  The HTLV-1 bZIP factor (HBZ) gene is 
transcribed from the minus strand of provirus using 3’ the long terminal repeat 14.  The contribution 
of HBZ to the pathophysiology of ATL is being seen as increasingly important as its role in the 
immune suppression and transformation into leukemia or lymphoma is described 15, 16.  Another 
relatively novel feature of the HTLV-1 genome is the presence of a region called pX, which 
encodes nonvirion proteins including 42-kDa Tax and 27-kDa Rex 10, 11.  Tax is a trans-activating 
transcription factor that interacts with members of the HTLV-1 long terminal repeat (LTR) 
activating transcription factor/cAMP responsive element (CRE) and stimulates the expression of 
a number of viral genes 12, 13.  Deletion of the sequences within these two genes renders an 
infectious viral clone noninfectious. Tax induces the transcription of various cellular genes 
including those encoding IL-2 receptor alpha chain (IL-2Rα), IL-2, IL-3, IL-9, IL-15, IL-15 
receptor alpha chain (IL-15Rα), TNF, GM-CSF, TGF-, PTHrP, vimentin, and c-fos 17-21.  HTLV-
1 infection of T cells in vivo and in vitro is also associated with constitutive IL-2R alpha gene 
expression and facilitates IL-2 expression inducing an autocrine IL-2/IL-2R loop in infected T-
cells in the early stages of ATL 18.  It has been proposed that in the early phases of ATL the HTLV-
1 induced leukemogenesis result from Tax driven stimulation of these genes involved in cellular 
proliferation 16, 17 eventually resulting in T-lymphocyte immortalization 10, 16.    Investigators in the  
Lymphoid Malignancies Branch have also described another Tax driven autocrine stimulatory loop 
involving IL-15 and its private receptor, IL-15R alpha and analogous paracrine stimulatory loop 
with IL-9 production by ATL cells and IL-9R alpha expression on monocytes 19-21.  The presence 
of these non-IL-2 driven autocrine or paracrine loops point toward potential escape mechanisms 
developing in Lymphoid Malignancies Branch patients treated with the anti-IL-2Rα monoclonal 
antibody (daclizumab, anti-Tac) that has been a core component of many of our clinical trials.  Still 
the efficacy of Daclizumab suggests that targeting the common IL-2, IL-9, and IL-15 c cytokine 
receptor subunit and its associated signal transduction elements JAK1, (Janus kinase) JAK3 and 
STAT5 might be a more viable treatment strategy 22.  More direct inhibition of this signal 
transduction pathway with clinically effective JAK1 or JAK3 inhibitors that are now available 
could have greater efficacy than could be achieved by antibody-mediated inhibition of the single 
IL-2/IL-2R cytokine system22-25.   
1.2.3 Clinical Features of ATL 
Frank ATL often has its onset 20-30 years following a blood transfusion from an infected 
individual or perinatal infection from the mother infected with HTLV-1 3, 4, 8.  The principal clinical 
features of full-blown acute ATL include frequent skin involvement, moderate lymphadenopathy 
with relative sparing of the mediastinum, CNS and lung involvement, and hepatosplenomegaly.  
The peripheral blood may show a high leukemic cell count without much anemia and with only 
modest involvement of the bone marrow. The occurrence of hypercalcemia, unusual in other types 
of leukemia and lymphoma, is characteristic of ATL.  Patients with ATL manifest a profound 
degree of immunosuppression and often develop opportunistic infections including Pneumocystis 
carinii and Cryptococcus meningitis.   The clinical aggressiveness of ATL varies from patient to 


Abbreviated Title:  Ruxolitinib in ATL 
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7 
patient over a very broad spectrum.  Attempts to define the different subtypes of ATL eventually 
led to the now widely accepted Shimoyama classification system that subdivides the disease into 
four categories (Table 1) 5.  
 
Table 1:   Shimoyama classification ATL  
Subtype of 
ATL 
Clinical features 
Lymphocyte count 
Associated 
Biochemical 
abnormalities 
Smoldering 
Skin and pulmonary lesions 
No lymphadenopathy (LNs) 
or organ involvement 
≥ 5% abnormal T cells 
but normal absolute 
lymphocyte count (ALC) 
< 4 x 109/L 
Calcium, lactic 
dehydrogenase (LDH) 
< 1.5 x upper limit of 
normal (ULN) 
Chronic 
Skin and lung involvement, 
no CNS, bone, GI tract 
involvement, no ascites or 
pleural effusions 
ALC > 4 x 109/L 
T cells > 3 x 109/L 
Elevated LDH but 
< 2 x ULN 
Normal Calcium 
Lymphoma 
Biopsy proven LN 
Normal ALC, ≤ 1% 
abnormal circulating T-
cells 
 
Acute 
Tumor lesions 
leukemia 
Not required for 
diagnosis 
1.2.4 Treatment of ATL 
1.2.4.1 Cytotoxic Chemotherapy for ATL 
The standard combination chemotherapy regimens known to be active against the more 
common aggressive non-Hodgkin’s lymphomas or acute lymphoblastic leukemia have shown 
increasingly disappointing activity in the treatment of ATL patients 5, 26, 27.  Over the past few 
years the majority of patients with the more aggressive categories of ATL, acute and 
lymphoma type; have been treated with combination chemotherapy including CHOP 
(cyclophosphamide, adriamycin, vincristine, and prednisone) and VEPA (vincristine, 
cyclophosphamide, prednisolone, and adriamycin). The Japanese Lymphoma Study Group 
protocol also assessed a combination treatment regimen with nine drugs (doxorubicin, 
cyclophosphamide, vincristine, prednisone, vindesine, methotrexate, etoposide, procarbazine, 
and bleomycin), or a comparable protocol with these drugs plus cisplatin 26, 27.  A total of 854 
patients with HTLV-1-antibody-positive ATL newly diagnosed from 1983-1987 were 
analyzed for prognostic factors and survival following combined chemotherapy by the 
Japanese Lymphoma Study Group 4.  The median survival time (MST) was 10 months and 
projected 2- and 4-year survival rates of all patients were 28 percent, and 12 percent, 
respectively.  Impaired performance status, high lactic dehydrogenase values, age > 40 years, 
greater number of lesions, and hypercalcemia were associated with shortened survival.  
Survival data for treated patients in the different clinical subtypes, most often receiving 
combination chemotherapy, showed MST of 6.2 months for acute type, 10.2 months for 
lymphoma type, and 24.3 months for chronic type.  This correlated with projected 4-year 
survival rates of 5% for acute subtype, 5.7% for lymphomatous subtype, 26.9% for chronic 
subtype and 58% for smoldering subtype.  The members of the Lymphoma Study Group 
concluded after reviewing 854 cases of treated ATL patients that “The various combination 
chemotherapies so far developed have not increased significantly the survival of patients with 


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ATL.”  As a consequence of this generally held opinion, investigational therapies with 
monoclonal antibodies, biological response modifiers, anti-retroviral drugs and recently 
molecular therapeutics have become the most common treatments administered to ATL 
patients. 
1.2.4.2 Azidothymidine and interferon alpha (AZT/IFNα) for ATL 
In part due to the generally poor results for conventional combination chemotherapy in the 
treatment of ATL patients, attempts to target the underlying HTLV-1 driven pathophysiology 
with less toxic agents led to combination therapy with the antiviral agent AZT and cytokine 
IFNα, a synthetic version the anti-viral protein. In a study reported by Gill 28, 6 partial and 5 
complete remissions (PRs and CRs) were observed in 11 of 19 ATL patients treated with this 
combination. Despite the response rate, the median survival duration of the whole group was 
only 3 months and 13 months in the 11 responding patients 28.  The recent meta-analysis by 
Bazarbachi reported that first line therapy with AZT plus IFNα produced a 5-year overall 
survival rate of 46% in 75 patients 29 . While this is an encouraging result unlike most patients 
referred the NCI, the Bazarbachi group does not treat patients who have received previous 
cytotoxic treatment such as CHOP.   It must be emphasized that patients treated with 
chemotherapy followed by AZT and IFN had a much poorer response rate29.  Furthermore, 
in contrast, only 2 of 11 (18%) heavily pretreated ATL patients receiving AZT/IFNα from our 
group showed a response; in both cases a partial response (PR).  There is some information 
regarding cellular or molecular changes that occurs in previously treated ATL patients that 
could account for this diminished responsiveness. Pancewicz 30 reported that previously 
treated patients with mutated p53 did not respond to AZT/IFNα treatment and that relapse in 
individual metastases was associated with a tumor clone carrying the mutated inactive p53.  
Patients with elevated IRF4 and cRel are also described as being resistant to antiviral treatment 
31. These results are all consistent with the notion that ATL patients with biologically 
aggressive disease (needing multiple rounds of treatment) are not appropriate patients for the 
AZT/IFNα combination. 
1.3 
INHIBITION OF CYTOKINE STIMULATION IN THE TREATMENT OF ATL AND RATIONALE 
FOR RUXOLITINIB  
1.3.1 Anti-IL-2R alpha-Directed Monoclonal Antibodies for ATL 
The  Lymphoid Malignancies Branch has evaluated treatment with antibodies targeting the IL-2R 
alpha 32  in a number of lymphoid malignancies including ATL. Targeting the IL-2Rα interrupts 
the binding of IL-2 to the receptor inhibiting the cellular activation which we now understand 
transmitted through the JAK1, JAK3/STAT5 pathways.  Initially, the efficacy of the murine 
monoclonal anti-Tac antibody was assessed in 19 patients with acute, chronic and lymphomatous 
ATL (NCI Protocol 83-C-0023) resulting in 2 CRs, 4 PRs and one mixed response 33.  The 
emergence of human anti-mouse antibodies (HAMA) limited the ability to administer the 
treatment repeatedly.  Following the conclusion of that trial, the efficacy of unlabeled Hu-anti-Tac 
(NCI Protocol 00-C-0030) administered at high doses (4, 6 and 8 mg/kg given every 2nd and 3rd 
week) to ATL patients was examined.  While 2 of 14 phase I patients responded to treatment, there 
were no additional responses among nine patients in the phase II portion of the trial. Of note, none 
of the patients enrolled in the trial had the less aggressive chronic or smoldering disease 
(unpublished observations); all of the patients had lymphomatous or acute ATL. Previous 
protocols 90-C-0043, 93-C-0066 and 96-C-0147 assessed the efficacy and toxicity of the anti-Tac 
mAb conjugated with Yttrium 90 (90Y) and later with the addition of the chelater Ca-DTPA to 


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Version Date:  02/10/2021 
9 
reduce toxicity by accelerating the urinary excretion of 90Y.  Seven of the 16 evaluable patients so 
treated achieved a PR and two a CR 33. Although 45% of patients in 96-C-0147 responded to 
treatment during the phase I portion of this trial only one response was seen among nine patients 
treated with the phase II dose of 25mCi of 90Y.   
1.3.2 Role of JAK in Cytokine Driven Transactivation and the Pathogenesis of ATL 
The HTLV-1 encoded Tax protein that constitutively activates the IL-2, IL-9 and IL-15 signaling 
pathways, transmitting an activation signal through intermediaries JAK1 and JAK3 to STAT5 
proteins that ultimately bind to gamma activation sites in the promoters of inducible cytokines in 
the cell nucleus. The JAK tyrosine kinases function as common relay elements in the Tax initiated 
proliferative signal (Figure 1) and point out the potential therapeutic impact for JAK1 and JAK3 
inhibition in the treatment of ATL 17, 22-25.   
 
 
 
We previously utilized the antibody to the IL-2 receptor alpha developed in our laboratory 
(daclizumab) in the treatment of patients with ATL with meaningful efficacy 32.  However, the 
presence of two autocrine and one paracrine cytokine stimulatory loop presented limitations for 
this therapeutic strategy that involved a single monoclonal antibody directed toward IL-2 receptor 
alpha. 
1.4 
PRECLINICAL EXPERIMENTS WITH JAK INHIBITORS 
1.4.1 In vitro treatment of PBMCs and Cell lines with JAK inhibitors 
To begin the examination of JAK inhibition in the treatment of ATL, our laboratories performed 
experiments to evaluate the activity of the JAK3 and  JAK2 inhibitor, CP-690,550 (Tofacitinib) in 
Figure 1:  Rationale for use of JAK1 inhibitor ruxolitinib.  The interaction of IL-
2 or IL-15 with its heterotrimeric alpha-beta gamma receptor initiates signaling 
that involves JAK1 associated with IL-2/IL-15R beta and JAK3 associated with 
the common gamma chain.  Activated (phosphorylated) JAK1 and JAK3 then 
lead to the phosphorylation and transfer of STAT5 to the nucleus.  Inhibitors of 
either JAK1 or JAK3 inhibit this cytokine mediated-signaling pathway. 


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the cytokine dependent ex vivo proliferation that is characteristic of the peripheral blood 
mononuclear cells (PBMCs) from patients with smoldering or chronic subtypes of ATL 34.  CP-
690,550 at 50 nM concentration inhibited the 6-day ex vivo spontaneous proliferation of PBMCs 
from ATL patients by a mean of 66% (Figure 2).   
 
 
 
Increasing the concentration of CP-690,550 to 100nM an achievable in vivo level showed only 
marginally increased inhibition (73%) of these ATL cells.  The suppression of proliferation by 
690,550 even at 50 nM was significantly greater than anti-IL-9 or anti-IL-15 monoclonal antibody 
treatment.  The JAK3 inhibitor was slightly more effective in suppression of proliferation the 
patient’s cells than anti-IL-2 antibody and less effective than the combination of all three 
antibodies.  The ability of CP-690,550 to inhibit the JAK-STAT activation cascade was tested in 
splenocytes obtained from the IL-15 transgenic CD8 T-cell leukemic mice that have an autocrine 
IL-15/IL-15R loop analogous to the Tax driven process seen in HTLV-1 associated ATL.  As 
Figure 2:   Ex vivo peripheral blood mononuclear cells from patients with ATL were 
cultured in RPMI 1640 median supplemented with 10% fetal bovine serum for 6 days 
in the presence or absence of monoclonal antibodies or the JAK inhibitor CP-690,550 
(Tofacitinib).  To assay proliferation the cells were pulsed for 6 hours with Ci of 3H-
thymidine harvested and counted with a -plate counter.  The upper left side image 
demonstrates that the ex vivo PBMCs of this single patient with ATL manifested 
spontaneous proliferation (CPM 13,000) when cultured in FBS alone.  This 
proliferation was inhibited by the addition of an antibody to IL-2 or the combination 
of anti-IL-2/IL-9 and IL-15 antibodies.  Comparable inhibition was achieved with 50 
and 100 nM of CP-690,550.  The results of studies of 8 patients with chronic or 
smoldering ATL are shown in the lower right side with a mean percent inhibition of 
65.9% at 50 nM CP-690,550. 


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can be seen in Figure 3, treatment with CP-690,550 substantially inhibited the phosphorylation of 
JAK3 and prevented the phosphorylation of STAT-5. 
 
 
Similarly, Ruxolitinib, AZD1480 (JAK1, 2 inhibitors) and Tofacitinib (JAK 2, 3 inhibitor) have 
also been shown to effectively inhibit the IL-2 and IL-15 stimulation of the cytokine dependent 
NK92 cell line (Craig Thomas unpublished observations). (Figure 4)  
 
 
As seen in Figure 5, ruxolitinib could profoundly inhibit proliferation in cell line of an ATL patient 
at doses that have no effect on control cell lines (e.g. CEM). 
Figure 3:  CP-690,550 (Tofacitinib) inhibited the phosphorylation status of 
JAK3/STAT5 in splenocytes from IL-15 transgenic CD8 T-cell leukemia bearing mice 
that manifest an autocrine IL-15/IL-15R alpha CD8 leukemic T-cell proliferation. 
Figure 4:  The proliferation of the cytokine-dependent NK-92 cell line mediated by IL-2, 
assessed by 3H-thymidine addition during the last 6 hours of a 48-hour culture were inhibited 
by serially-increasing concentrations of the JAK3/JAK2 inhibitor CP-690,550 (Tofacitinib), 
the JAK1/2 inhibitors AZD1480, and ruxolitinib (INCB018424).  


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Figure 6 shows preliminary results with Ruxolitinib inhibiting the spontaneous proliferation of 
PBMCs ex vivo from patients with smoldering or chronic ATL. This particular patient seems to 
have a largely IL-2 driven clone with some IL-9 stimulation based on the results with the individual 
anti-cytokine antibodies. Of interest are the results in the last 2 columns to the right showing that 
ruxolitinib at concentrations of 1 and 10 µM inhibited these cells better than the combination of 
anti-IL-2, anti-IL-15 and anti-IL-9 antibodies.   
 
 
Figure 5:  The proliferation of the peripheral blood mononuclear cells containing 
leukemic cells from an ATL patient cell line were inhibited by serially-increasing 
concentrations of the JAK3/2 inhibitor CP-690,550 (Tofacitinib) or the JAK1/2 
inhibitors AZD1480 and INCB018424 (ruxolitinib).3H-thymmidine was added 
during the last 6 hours of the cultures. 
Figure 6:  Ex vivo peripheral blood mononuclear cells from patients with ATL were 
cultured in RPMI 1640 median supplemented with 10% fetal bovine serum for 6 days 
in the presence or absence of monoclonal antibodies or the JAK1/2 inhibitor ruxolitinib 
(yellow).  To assay proliferation the cells were pulsed for 6 hours with Ci of 3H-
thymidine harvested and counted with a -plate counter. 


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Additionally, we have seen that ruxolitinib inhibited the proliferation of CD8 T-cell lines derived 
from patients with refractory celiac disease which has been shown to have an IL-15 autocrine loop 
as well as the survival of CD8 T-cells (studied immediately ex vivo) from intestinal biopsies of 
such patients.  
1.4.2 Molecular Interference Screening with JAK loss of function cell lines 
To perform a molecular interference screening analysis of target tumor cell lines including ATL, 
Lymphoid Malignancies Branch laboratory investigators led by Dr. Louis Staudt have created a 
library of retroviral vectors for inducible expression of small hairpin RNAs (shRNAs) 35.  A critical 
feature of this system is the inclusion of a 60-base pair molecular barcode in each vector which 
allows the abundance of each vector to be monitored in a population of transduced cells.  This 
extensive shRNA library contains 11,274 vectors that targets 3,033 human genes and can be used 
to assess therapeutic potential of molecular therapeutics.  Using this inducible shRNA library, a 
loss-of-function genetic screen, half of the cultures were induced to express shRNA and half served 
as the control to assess the consequence of depleting essential genes in the intended treatment 
population.  Relative abundance of shRNAs is monitored by their unique barcodes using 
microarray and the relative amount of shRNA indicates how much “interference” was required to 
suppress the target gene.  When this screen was applied to three distinct ATL cell lines, JAK1 was 
shown to be critical in the proliferation and survival of the six of the seven cell lines studied 
(Figure 7) adding support to the notion that JAK signaling is critical in ATL and an appropriate 
therapeutic target. 
 
 
Figure 7:  Using an inducible shRNA for JAK1 a loss of function screen applied to seven distinct ATL cell 
lines JAK1 was shown to be critical in the proliferation and survival of six of seven lines studied. 


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1.4.3 In Vitro Matrix screening assessment 
Preliminary results from matrix high-throughput screening for cellular signaling analyses directed 
at known targets and pathways showed that a JAK1/2 inhibitor inhibited the proliferation and 
survival of the 5 ATL cell lines tested with LD50s of 1.6 uM, 5.1 uM, 8.1 uM, 18.7 uM and 25.6 
uM.  Taken as a whole, these preclinical studies have demonstrated the importance of the JAK1 
and 3 signaling elements in ATL lymphocytes, the ability of current clinical agents to inhibit 
pathophysiologic IL-2, IL-9 and IL-15 driven stimulation in ATL and strongly support a clinical 
trial evaluating the JAK1 inhibitor ruxolitinib for the treatment of patients with smoldering or 
chronic ATL. 
1.5 
CLINICAL EXPERIENCE WITH RUXOLITINIB  
1.5.1 Pharmacokinetics (PK) and Pharmacodynamics (PD) of Ruxolitinib  
The Janus-associated kinases 1 and 2 mediate the signaling of a number of cytokines and growth 
factors that are important for hematopoiesis and immune function.  Absorption, distribution, 
metabolism and excretion (ADME) and pharmacokinetic studies performed to support the 
licensing application for ruxolitinib showed rapid and near complete absorption (95%) after 
administration with maximum plasma concentration (Cmax) of 1.47 M achieved within 1 to 2 
hours post dose. The mean Cmax and total exposure (AUC) of ruxolitinib increased proportionately 
over the (single) dose range of 50 to 200 mg.  The apparent volume of distribution of ruxolitinib 
at steady state is 53 to 65 L with high protein binding (97%) that is mostly to albumin.  Ruxolitinib 
administration resulted in maximum inhibition of STATs phosphorylation 2 hours after dosing 
with return to near baseline by 10 hours in both healthy subjects and myelofibrosis patients.  
CYP3A4 is the major enzyme responsible for the metabolism of ruxolitinib.  Following a single 
dose of [14C]-labeled ruxolitinib in healthy adult subjects, elimination was predominantly through 
metabolism with 74% of radioactivity excreted in urine and 22% via feces 36. 
1.5.2 Ruxolitinib Clinical Trial Results 
Several Phase 1, 2 studies and two randomized Phase 3 studies (studies 1 and 2) were conducted 
in patients with myelofibrosis (MF) (either primary myelofibrosis, post-polycythemia Vera 
myelofibrosis [PV] or post-essential thrombocytopenia-myelofibrosis [ET]) (36, 37).  Patients with a 
platelet count > 200 x 109/L were started on ruxolitinib orally 20 mg twice daily.  In the 155 MF 
patients receiving ruxolitinib there was a 35% reduction in spleen volume in 65 (41.9%), as 
compared to one (0.7%) in the 154 patients in the placebo group.  148 patients receiving ruxolitinib 
achieved  50% improvement from baseline in the total symptoms score, in contrast to 8 of 152 
patients 5.3% in the placebo-control group 36, 37. The safety data base in solid tumors and 
hematologic malignancies consisted of 787 patients treated with ruxolitinib in 6 studies evaluating 
patients with MF (N=679), prostate cancer (N=22), multiple myeloma (N=13), ET and PV (N=73), 
of whom 617 patients received ruxolitinib.  Hematologic events were the most frequently reported 
adverse events (AEs) primarily thrombocytopenia and anemia.  The majority of these AEs are 
grade 1-2 and seldom led to drug discontinuation (<1% of patients).  Of the 155 patients who 
received ruxolitinib in study one 10 (6.5%) had grade 3 thrombocytopenia and one (0.6%) had 
grade 4 thrombocytopenia as contrasted with one and 0 patients in the placebo group.  Ten patients 
had grade 3 and 6 patients had grade 4 anemia compared to 5 and 0 in the placebo group.  
Biochemistry abnormalities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) 
and cholesterol were also reported and again the majority of these increases were grade 1 or 2 with 
no grade 4 observed.   In this study there were 9 deaths in the ruxolitinib group and 11 in the 
placebo group.  The safety data base which is primarily from patients with an underlying 


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15 
hematopoietic production defect indicates a well-tolerated drug that did cause additional decreases 
in blood elements. 
1.5.3 Summary of Adverse Events 
 
 
Table 2:  Adverse Reactions Occurring in Patients on the Phase III MF Trial     
                        
Adverse 
Reaction* 
Ruxolitinib 
(N=155) 
Placebo 
(N=151) 
All Grades 
(%) 
Grade 3 
(%) 
Grade 4 
(%) 
All Grades 
(%) 
Grade 3 
(%) 
Grade 4 
(%) 
Bruising 
23.2 
0.6 
0 
14.6 
0 
0 
Dizziness 
18.1 
0.6 
0 
7.3 
0 
0 
Headache 
14.8 
0 
0 
5.3 
0 
0 
Urinary Tract Infections 
9.0 
0 
0 
5.3 
0.7 
0.7 
Weight Gain 
7.1 
0.6 
0 
1.3 
0.7 
0 
Flatulence 
5.2 
0 
0 
0.7 
0 
0 
Herpes Zoster 
1.9 
0 
0 
0.7 
0 
0 
*CTCAE version 3 
 
 
Table 3:  Worst Hematology Laboratory Abnormalities in Patients on the Phase III MF Trial  
 
Laboratory 
Parameter 
Ruxolitinib 
(N=155) 
Placebo 
(N=151) 
All Grades 
(%) 
Grade 3 
(%) 
Grade 4 
(%) 
All Grades 
(%) 
Grade 3 
(%) 
Grade 4 
(%) 
Thrombocytopenia 
69.7 
9.0 
3.9 
30.5 
1.3 
0 
Anemia 
96.1 
34.2 
11.0 
86.8 
15.9 
3.3 
Neutropenia 
18.7 
5.2 
1.9 
4.0 
0.7 
1.3 
 
1.6 
RATIONALE FOR PATIENT SELECTION, CHANGE IN THE TREATMENT SCHEDULE AND 
TARGET RESPONSE RATE IN THE INITIAL PHASE II TRIAL 
1.6.1 Preclinical Experiments 
Eligibility for entry into the present trial is limited to patients with smoldering or chronic ATL 
since the ex vivo PBMCs containing ATL cells from such patients proliferated spontaneously and 
this proliferation was inhibited by the addition of ruxolitinib. Furthermore, the survival and 
proliferation of cytokine-dependent ATL cell lines were inhibited by the addition of ruxolitinib or 
shRNA for JAK1—a target of ruxolitinib. In contrast the ex vivo PBMCs from patients with acute 
and lymphomatous ATL did not proliferate spontaneously. Furthermore, the survival of cytokine-
independent ATL cell lines was not inhibited by the addition of ruxolitinib or by the addition of a 
shRNA for JAK1. Although the Shimoyama Classification5 System is valuable and generally 
accurate, there are patients who are not easily assigned to a subtype. This problem is most apparent 
in patients considered the chronic type, since chronic subtype patients can have lymphadenopathy, 
hepatomegaly and splenomegaly that are key criteria for the lymphomatous subtype patients. A 
key distinction that separates chronic from lymphomatous subtype is that chronic patients have an 
elevated absolute lymphocyte count with circulating ATL cells whereas lymphomatous patients 
have no evidence of leukemic involvement. 


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1.6.2 Results of Standard Treatment for ATL 
Many of the Lymphoid Malignancies Branch chronic subtype patients will have received prior 
chemotherapy.  Their classification will be determined on their status when they are being 
considered for ruxolitinib therapy rather than that at their initial presentation. While the 
Shimoyama classification system generally separates patients into the biologically indolent 
subtypes (smoldering and chronic) and the more aggressive subtypes (lymphomatous and acute), 
ATL is a highly variable disease and unusually poorer prognosis lymphomatous or acute subtype 
patients can have durable symptom free intervals following standard treatment where their disease 
behaves more like the indolent subtype. We believe it is appropriate to consider these patients for 
treatment on this protocol when there is clear evidence their ATL is quiescent and does not require 
urgent treatment for symptomatic progressive disease. 
As noted above, there is data to suggest that the response rates to IFN and AZT in previously 
treated ATL patients was much lower (18% and 26%) in two reports than the response rates for 
treatment of naïve patients 42, 43. Recently this resistance to AZT/IFN therapy has been 
demonstrated to be associated with P53 mutation and elevated IRF4 and cRel levels in the ATL 
cells of previously treated patients 44,45. In the initial report by Shimoyama and coworkers, patients 
with chronic ATL had a median survival duration of 24.3 months. Patients with chronic ATL and 
adverse disease characteristics such as poorer performance status, lower neutrophil count and 
receive chemotherapy have poorer median survival compared to other chronic subtype patients 
and is reflected in the 47% 5-year survival rate noted in this long term follow up of “indolent” 
ATL patients 46. Since duration of benefit is important in the treatment of chronic diseases such as 
chronic and smoldering ATL, survival is the clinical endpoint most often captured in these 
treatment reports. Response rates are frequently not sited and survival data can be difficult to 
compare in reports of different clinical trials based on the type of “chronic” ATL patients enrolled. 
One Japanese study reported a 4-year OS rate of 26.9% in patients managed with watchful waiting 
and then chemotherapy 47 that is very different than the survival data sited in the Journal of Clinical 
Oncology “Meta- analysis.” The Takahasi review46 indicates heavily pretreated patients further 
along in the natural history of their ATL respond less well to any form of treatment and initial 
target response rate of 30% in our referral patient population is an appropriate target value for 
response in a phase II trial41  
1.6.3 Early Experience in this Trial 
The initial 12 patients enrolled in the trial were treated with the standard 20 mg dose twice daily 
of off label ruxolitinib and tolerated the drug with little if any side effects, but responses were seen 
in only 4 of these patients. Three of these patients had more than a 50% decrease in the volume of 
their skin involvement and the other patient had 50% improvement in the number of circulating 
ATL cells, but the duration of these responses were 2 to 6 months.  Serial analysis of 
phosphoSTAT 3 and phosphoSTAT5 on patients’ samples after treatment showed only transient 
inhibition of the phosphorylation of STAT 5 in the immediate post-treatment period. These results 
are consistent with the ex vivo inhibition experiments performed with ruxolitinib at the 1 and 10 
μM concentrations and ruxolitinib’ s known pharmacokinetics (Cmax of 1.47μM ≈ 2 hours post 
dose and terminal elimination t ½ of ≈ 3 hours) resulting in a transient inhibition of the JAK-STAT 
signaling pathway that is marginally clinically active.  
 


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1.6.4 Clinical Experience with Ruxolitinib Dose Escalation in Normal Healthy Volunteers 
As part of the initial clinical safety studies performed by commercial drug sponsor, patients and 
normal healthy volunteers (NHV) were treated with 50 mg twice daily, 100 mg once daily and in 
some cases individual doses of 200 mg (Figure 9).  
A. Percent Inhibiton of STAT3 Phophorylation versus Serum concentration of Ruxolitinib 
 
 
B. Serum Ruxolitinib Concentration with Augmented Dosing Regimens 
Figure 8:  Effect of ruxolitinib on the endogenous phosphorylation of STAT3 and STAT 5 in ATL cells (ex 
vivo PBMCs isolated after oral ruxolitinib 20mg) 


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Figure 9 A and B: Percent inhibition of phosphoSTAT3 versus log concentration of (INCB018424) 
Ruxolitinib and serum Ruxolitinib concentrations with augmented dosing regimens48 
 
Results from these NHV showed the more dose intense regimens achieved serum concentrations 
of ruxolitinib with greater potential to inhibit STAT3 phosphorylation without producing clinically 
significant AEs. In addition to monitoring for clinical toxicities, the sponsor also performed studies 
on cardiac conductance the was negative for QT prolongation for any of these doses. The subjects’ 
heart rates increased maximally by 3.7 beats per minutes. Dose limiting toxicity was neutropenia 
at the 50 mg twice daily dose; with one of the 3 subjects having grade 4 neutropenia. A reversible 
increase in neutrophil counts was frequently seen at the higher doses tested and generally wore off 
within 24 hours of stopping treatment. The overall safety profile of ruxolitinib is good and the 
hematopoietic toxicities (i.e., thrombocytopenia, anemia and neutropenia) that were of greater 
concern in the Myelodysplastic Syndrome (MDS) patients with chronic treatment have not been 
observed in our ATL patients who received prolonged treatment previously as part of this protocol. 
This should not be that surprising with the genetic defect in MDS patients extending all the way 
down to their hematopoietic stem cells in contrast to the aberrant clone in ATL patients.49 
All patients who fulfill the Shimoyama Classification for smoldering or chronic or quiescent 
lymphomatous, or acute ATL, at the time of evaluation for entry into this study whether they have 
had prior treatment or not will be deemed eligible for this study. Patients will have their burden of 
circulating ATL cells assessed by serial FACS analysis of their PBMCs and when appropriate have 
their soft tissue disease formally assessed by the (cutaneous lesions) Dermatology Service or by 
CT scans of their known sites of disease. New patients will begin treatment at 30 mg orally twice 
daily.  Despite the modest clinical experience with augmented dosing in NHVs, the long-term 
tolerability in ATL patients will have to be established with standard phase I dose escalation plan. 
If the first 3 patients treated at this dose level, do not have dose limiting toxicities dosing will 
proceed sequentially to 40 and, then, 50 mg twice daily in a standard 3+3 fashion.  A total of 9 
patients will be treated at the MTD or maximum administered dose (MAD) to better evaluate the 
clinical activity of the augmented dosing regimen.  
Patients with a transient response to previous treatment at the standard 20 mg twice daily dose and 


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later progressed but otherwise meet the eligibility criteria on treatment  will also be eligible to 
restart treatment.   
1.7 
RATIONALE FOR MULTIPLE ASSESSMENTS OF STAT5 AND PHOSPHOSTAT5 
1.7.1 Cycle 1 day 1 
Additional analysis in vitro of inhibition of proliferation in ATL cells obtained from patients with 
JAK inhibitors and results of the first patients treated in this trial suggest transient inhibition of 
JAK signaling in the patients’ malignant cells may be occurring, but is not sustained due to our 
inability to maintain ruxolitinib serum levels above the 1 micromolar concentration required to 
inhibit signaling through JAK1. To investigate this hypothesis, we will be performing serial 
intracellular FACS analysis of STAT5 and phosphoSTAT5 and coordinate measurement of serum 
ruxolitinib levels on Cycle 1 Day 1 to more accurately characterize changes in STAT5 occurring 
after ruxolitinib treatment. Results from these analyses may provide preliminary in vivo 
information that will allow the next iteration of this treatment strategy to be analyzed in a more 
advanced manner. 
1.7.2 Cycle 2 and later time points 
Rather than have a fixed schedule of STAT5 and phosphoSTAT5 of assessments based on 
hypotheses, we have chosen to make the correlative immunologic and molecular correlative 
laboratory assessments at these later time points optional and determined by clinically important 
events.  The plan will be to assess several patients treated with prolonged administration of 
Ruxolitinib at the time of their clinical safety evaluations to detect changes in the JAK-STAT 
signaling pathway. If a provocative signal is detected at a particular time point, continued testing 
of all patients being treated on a regular basis will be instituted.  
 
 


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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
NOTE:  After approval and activation of Amendment D, patients who have failed this protocol 
treatment previously at the initial dose level may be eligible for re-enrollment and retreatment if 
they otherwise meet eligibility criteria. 
2.1.1.1 Patients  18 years old with pathologically confirmed adult T- cell leukemia: 
smoldering or chronic, or previously treated lymphomatous or acute subtypes with 
clinically indolent behavior indicated by lack of significant symptoms and treatment 
free interval of greater than 6 months are eligible for treatment in the dose escalation 
and expansion cohorts (see also APPENDIX B).   
2.1.1.2 Patients must have serum antibodies directed to HTLV-1.   
2.1.1.3 Patients must have measurable or evaluable disease.  Patients with > 10% of   the 
PBMCs having the characteristic abnormal (i.e., CD3dim, CD4+ CD25+ expressing) 
FACS profile for circulating ATL cells will be considered to have evaluable disease.   
2.1.1.4 Patients must have adequate physiologic parameters: 
• Absolute granulocyte count  500 K/uL, platelet count  75,000 K/uL and 
hemoglobin  10 g/dL.  
• Bilirubin and creatinine   1.5 x institutional ULN.  
• AST, ALT   3.0 x institutional ULN. 
2.1.1.5 Karnofsky Performance Score ≥ 70% or ECOG ≤ 1 (APPENDIX A). 
2.1.1.6 Patients must be able to understand and sign Informed Consent Form. 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients with symptomatic leukemic meningitis, bony or GI tract involvement, serum 
calcium or LDH > 1.5 X the upper limit of normal will be excluded. However, 
patients that have both ATL and another HTLV-1 associated disease such as tropical 
spastic paraparesis (HAM/TSP) will be included. 
2.1.2.2 Patients with symptomatic leukemic meningitis, bony or GI tract involvement, serum 
calcium or LDH > 1.5 X the upper limit of normal will be excluded.  However, 
patients that have both ATL and another HTLV-1 associated disease such as tropical 
spastic   paraparesis (HAM/TSP) will be included.   
2.1.2.3 Patients who have received high doses of systemic corticosteroids for the treatment 
of their ATL within 4 weeks prior to the start of therapy.  
2.1.2.4 Patients who have received any cytotoxic therapy, immunotherapy, antitumor 
vaccines or monoclonal antibodies in the 4 weeks prior to the start of the study. 
2.1.2.5 Life expectancy of less than 3 months. 
2.1.2.6 Documented active bacterial infections, HTLV-II infection, or hepatitis B or C as 


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follows:   
• A positive hepatitis B serology indicative of previous immunization (i.e., HBsAb 
positive and HBc Ab negative), or a fully resolved acute hepatitis B infection is not 
an exclusion criterion. 
• Patients with an indolent chronic hepatitis B infection (normal ALT, AST, albumin 
and no radiographic or biopsy evidence of cirrhosis) may be eligible. 
• Patients with active hepatitis C are excluded.  Patients positive for hepatitis C virus 
(HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative 
for HCV RNA.  
2.1.2.7 Patients who have untreated human immunodeficiency virus (HIV) are not eligible 
for this study because by definition they have a defective immune response and are 
at much higher risk for opportunistic infections due to immune dysregulation by both 
HTLV-1 and HTLV-III (HIV) viruses. Patients on HIV therapy with undetectable 
viral loads as measured by HIV RNA quantitative real time PCR may be eligible. 
2.1.2.8 Inability or refusal to practice effective contraception during therapy. Men and 
women of childbearing potential must use an effective method of birth control or 
abstinence during treatment and for 1 week after completion of the treatment. 
2.1.2.9 Patient has significant and/or uncontrolled cardiac, renal, hepatic or other systemic 
disorders or significant psychological conditions at baseline visit that in the 
investigator’s judgment would jeopardize subject enrollment or compliance with the 
study procedures. 
2.1.2.10 Patients with an absolute requirement for a medication that is a strong inhibitor of 
P450 CYP3A4 (per APPENDIX C) are not eligible.  
2.1.3 Recruitment Strategies  
Patient accrual will be facilitated by the large number of clinical investigators who refer patients 
to the NCI and CCR. Contact letters or emails will be sent to the regional University referral 
center’s Medical Oncologists informing them of this trial. In addition, this protocol may be 
abstracted into a plain language announcement posted on NIH websites and on NIH social media 
platforms. 
2.2 
SCREENING EVALUATION 
2.2.1 Screening activities performed prior to obtaining informed consent 
Minimal risk activities that may be performed before the subject has signed a consent include the 
following:  
• Email, written, in person or telephone communications with prospective subjects  
• Review of existing medical records to include H&P, laboratory studies, etc.   
• Review of existing MRI, x-ray, or CT images 
• Review of existing photographs or videos 
• Review of existing pathology specimens/reports from a specimen obtained for diagnostic 
purposes 
A waiver of consent for these activities has been requested in section 10.5.2 


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2.2.2 Screening activities performed after a consent for screening has been signed 
The following activities will be performed only after the subject has signed the study consent OR 
the consent for study 01-C-0129 (Eligibility Screening and Tissue Procurement for the NIH 
Intramural Research Program Clinical Protocols) (provided the procedure is permitted on that 
study) on which screening activities may also be performed.  Assessments performed at outside 
facilities or on another NIH protocol within the timeframes below may also be used to determine 
eligibility once a patient has signed the consent. 
Screening evaluation must be documented or performed within 28 days prior to initiating 
treatment: 
2.2.3 Baseline history with documentation of sites of disease, physical examination, eligibility 
laboratory assessments. NOTE: For patients with skin lesions or other visually-apparent 
signs of disease, photographs may be taken to document and follow disease with 
permission.    
2.2.4 Baseline imaging and circulating ATL cell count   
• CT scan of the neck, chest, abdomen and pelvis  
• Other imaging studies may be done to document disease as appropriate and at the 
direction of the PI. 
• Determination of marker lesion measurements as per ATL International Consensus 
meeting3.  
2.2.5 FACS analysis for circulating CD3dim CD4+ cells (see Section 3.4.1.6)  
2.2.6 Documentation of Karnofsky or ECOG Performance Score (APPENDIX A). 
2.2.7 Pathology confirmed by the Laboratory of Pathology, NCI prior to registration.  
• Pathological confirmation of diagnosis can be carried out on available slides from 
either the primary diagnostic biopsy or subsequent biopsies performed at the Clinical 
Center or outside institutions.   
• For the subset of patients who do not have circulating abnormal cells a lymph node or 
skin biopsy will be obtained for diagnostic purposes and to evaluate the expression of 
the CD25 (Tac) on the malignant cells.  
• Patients with suspected skin involvement from ATL should have skin biopsies. All skin 
or lymph node biopsies should be submitted fresh in saline to the Hematopathology 
Section of the Laboratory of Pathology.  
• Biopsy specimens will be processed for routine histopathology as well as 
immunohistochemistry in frozen sections and/or flow cytometry for expression of 
CD25 (Tac) and other lymphocyte surface antigens.  
• Lymph node aspirates will be handled as per the standard procedures of the cytology 
section.  
• If the original pathological material or other diagnostic biopsies are not available, or if 
there is uncertainty concerning the diagnosis, a repeat biopsy may be undertaken to 
confirm the diagnosis of ATL. 


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23 
2.2.8 Complete blood count (CBC) with differential, platelet count and reticulocyte count. 
2.2.9 Acute Care panel (sodium, potassium, chloride, CO2, glucose, BUN, creatinine).  
2.2.10 Hepatic panel (alkaline phosphatase, ALT, AST, total and direct bilirubin), LDH, and 
mineral panel (serum calcium, phosphate, magnesium and albumin). 
2.2.11 Serum pregnancy test in women of childbearing potential. 
2.2.12 Hepatitis B Surface Antigen, Hepatitis B Surface Antibody, Hepatitis B core Antibody, 
Hepatitis B DNA Quantitative, and Hepatitis C: HIV 1/2 and HTLV-I/II serology. 
2.3 
PARTICIPANT REGISTRATION AND STATUS UPDATE PROCEDURES 
Registration and status updates (e.g., when a participant is taken off protocol therapy and when a 
participant is taken off-study) will take place per CCR SOP ADCR-2, CCR Participant 
Registration & Status Updates found here. 
NOTE:  Patients previously treated with the standard 20-mg twice daily dose who came off 
protocol for disease progression are eligible to re-enroll and be treated at the higher doses. These 
re-enrolled patients will be given new patient numbers to clarify their treatment outcomes for each 
of the 2 treatment regimens (standard vs. dose escalated).  
2.3.1 Treatment Assignment and Randomization/Stratification Procedures  
2.3.1.1 Cohorts 
Number 
Name 
Description 
1 
 T-Cell Leukemia patients  
(CLOSED) 
HTLV-associated smoldering, chronic, or clinically indolent T-
cell leukemia (ATL) (12 subjects) 
2 
T-Cell Leukemia patients – 
Dose Escalation 
HTLV-associated smoldering, chronic, or clinically indolent T-
cell leukemia (ATL) (up to 20 subjects) 
3 
T-Cell Leukemia patients – 
Dose Expansion 
HTLV-associated smoldering, chronic, or clinically indolent T-
cell leukemia (ATL) (up to 6 subjects) 
2.3.1.2 Arms 
Number 
Name 
Description 
1 
Experimental Treatment  
(CLOSED) 
Ruxolitinib 20mg orally twice daily for 28 days. Patient may 
continue to receive treatment until PD.  
2 
Experimental Treatment – 
Dose Escalation 
Ruxolitinib 30-50 mg orally twice daily for 28 days to determine 
the maximum tolerated dose (MTD). Patients may continue to 
receive treatment until PD or unacceptable toxicity. 
3 
Experimental Treatment –  
Dose Expansion 
Ruxolitinib at the MTD orally twice daily for 28 days. Patients 
may continue to receive treatment until PD or unacceptable 
toxicity. 
2.3.1.3 Randomization and Arm Assignment  
Single arm/group: open-label and non-randomized. New patients in Cohort 2 or 3 directly 
assigned to treatment arm 2 or 3 based on the arm open at the time of enrollment.  NOTE:  
Previously enrolled subjects are allowed to re-enroll on this study.   


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2.3.2 Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently assigned to the study intervention or entered in the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants, to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of an 
eligibility criterion (e.g., laboratory parameter) may be rescreened at the discretion of the 
investigator.  
2.4 
BASELINE EVALUATION 
The following tests will be done after the patient is enrolled or re-enrolled in the study and within 
28 days (except as indicated below) of initiating treatment with ruxolitinib. Tests do not need to 
be repeated if completed during screening and meet the timeframe for baseline evaluation. 
2.4.1 Complete blood count (CBC) with differential, platelet count and reticulocyte count 
(within 2 weeks). 
2.4.2 Acute Care Panel (sodium, potassium, chloride, CO2, glucose, BUN, creatinine) and C-
Reactive Protein (within 2 weeks). 
2.4.3 Hepatic panel (alkaline phosphatase, ALT, AST, total and direct bilirubin), LDH, and 
mineral panel (serum calcium, phosphate, magnesium and albumin) (within 2 weeks). 
2.4.4 Pretreatment assessment of circulating ATL cells present in the PBMC by CellaVision 
differential (see Sections 3.4.1.4 and 3.4.1.6, and Table 4) for T-cell receptor gamma 
(TCRγ) gene rearrangement to detect clonality (see Section 5.1).  
2.4.5 CMV serology and CMV antigens 
2.4.6 FACS, Inflammatory marker and cytokine analysis  
• Baseline flow cytometry to assess lymphocyte sets and subsets (one 10-mL purple-top 
tubes; see  Section 3.4.1.6 and Table 4) to be sent to Flow Cytometry/ Immunology 


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Laboratory Department of Laboratory Medicine for the Clinical Center. NOTE:  In 
case of scheduling conflicts, TBNK may be substituted. 
2.4.7 In vitro analysis of sensitivity to JAK inhibitors and other molecular therapeutics in 6-day 
proliferation assay (see Section 5.1.2) 
2.4.8 Serum pregnancy test in women of childbearing potential within 3 days prior to starting 
the study drug. 
2.4.9 Optional Tumor Biopsy: Patients with easily accessible tumor deposits who consent to 
this procedure will have a fine-needle aspiration or punch biopsy of one of their tumors for 
research (see Section 5.1.6). These biopsies may be done by CT guidance. 
2.4.10 Electrocardiogram  
2.4.11 Bone marrow aspirate and biopsy will be obtained before treatment (biopsies performed at 
the Clinical Center within a year prior to treatment may be accepted at the discretion of the 
Principal Investigator).  
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN  
This is a phase I/II pilot open-label, trial of off label oral ruxolitinib that will enroll up to 35 patients 
with smoldering or chronic or biologically indolent lymphomatous or acute subtype ATL.  
Each treatment cycle will be 28 days in length and new patients will begin treatment at 30 mg 
orally twice daily.  If this dose is tolerated without exceeding the criteria for maximum tolerated 
dose (MTD) during the first cycle of treatment, the tolerability of treatment at 40 mg and then 50 
mg twice daily will be evaluated.  A total of 9 patients will be treated at the MTD or maximum 
administered dose (MAD) to better evaluate the clinical activity of the augmented dosing regimen. 
The start of subsequent treatment cycles may be delayed up to 7 days for social reasons or patients’ 
convenience without impacting on a patient’s ability to continue protocol treatment. 
Patients who begin treatment with the higher dose level will stay local to the NCI Clinical Center 
for their initial 2 weeks of treatment. These patients will be monitored closely for the first month 
of treatment for the emergence of AEs. The patients will be seen in the outpatient clinic twice 
during the first week (day 1 and day 4 or 5) after starting treatment and on day 8 during week 2 
for clinical and AE assessment, to have standard chemistry and hematology tests. If a patient 
appears to be tolerating their first 2 weeks of treatment well (grade 1 and 2 AEs) are considered 
reliable and have a referring physician willing to perform standard laboratories weekly (days 15 
and 22 ± 2 days), they may be eligible to be monitored at home for the 3rd and 4th weeks of their 
cycle 1 treatment. Patients who have new complaints suggestive of toxicities will be seen as soon 
as possible for outpatient assessment of their condition. Patients who cannot meet these conditions 
or where there is concern that DLT will occur will remain near the NCI Clinical Center until 
completion of their cycle 1 treatment.  
3.1.1 Dose Limiting Toxicity 
Patients must complete their first cycle of treatment (28 days) without interruption or dose 
adjustment or DLTs to continue protocol specified treatment. 
DLT will be defined as follows:  
Any grade 3 or 4 toxicity, if deemed possibly, probably or definitely related to the study drug by 


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26 
the PI during the first cycle of treatment, with the following exceptions: 
• Grade 3 anemia without hemolysis 
• Grade 3 or 4 granulocytopenia or leukopenia without infection 
• Grade 3 thrombocytopenia without bleeding 
• Grade 3 or 4 lymphopenia 
Patients who tolerate treatment at these higher dose levels without DLTs will continue treatment 
at their initial dose level for the remainder of their protocol treatment and will not be eligible for 
further dose escalation.  Patients who subsequently develop ≥ grade 3 toxicities after the DLT 
evaluation period will hold their treatment until this toxicity resolves.  
The following toxicities will not require discontinuation of study drug, but treatment will be 
interrupted for a maximum of 10 days until the toxicity has resolved: 
• Reversible grade 3 or 4 anemia without hemolysis 
• Reversible grade 3 or 4 granulocytopenia or leukopenia without infection 
• Reversible grade 3 or 4 thrombocytopenia without bleeding 
• Reversible grade 3 or 4 non-hematologic toxicities 
• Reversible grade 3 or 4 lymphopenia 
These patients will be eligible to resume treatment at their starting dose one time if their AEs 
resolve within the 10-day treatment break; however, treatment will discontinue for recurrence of 
AE(s).  Patients whose neutropenia does not resolve promptly may receive standard dose G-CSF 
to speed the recovery, but patients may not receive simultaneous G-CSF and Ruxolitinib.  
Patients who have evidence of an ongoing response will continue their treatment in the absence of 
unacceptable toxicity or disease progression.  All treatment cycles will be 28 days in length and 
patient’s response to treatment will be assessed by FACS analysis and/or radiographic assessment 
of their disease performed after cycles 1, 2 and subsequent even numbered cycles.  Patients will 
continue ruxolitinib until they experience unacceptable side effects, there is worsening of the ATL 
or a complete response is achieved. Response is defined in the report 4 of the 2009 International 
Consensus Meeting on ATL.  
Patients who achieve a complete response will receive an additional 56 days (2 cycles) of treatment 
beyond the assessment that documented their CR and then stop treatment. These patients will 
continue to have disease reassessments every 3 months for evidence of relapse after completion of 
treatment. 
3.1.2 Dose Escalation 
Dose escalation will proceed in cohorts of 3-6 patients. The MTD is the dose level at which no 
more than 1 of up to 6 patients experience DLT during the first cycle (28 days) treatment, and the 
dose below that at which at least 2 (of ≤6) patients have DLT as a result of the drug. If a patient 
did not experience DLT and did not finish treatment, he or she will not be evaluable for toxicity 
and will be replaced in the dose level. 


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Dose Escalation Schedule 
Dose Level 
Dose of Ruxolitinib 
Level 1 
30 mg PO BID 
Level 2 
40 mg PO BID 
Level 3 
50 mg PO BID 
Dose escalation will follow the rules outlined in the table below; this study plans to treat 9 patients at 
the MTD/MAD: 
Number of Patients with 
DLT at a Given Dose Level 
Escalation Decision Rule 
0 out of 3 
Enter up to 3 patients at the next dose level 
> 2 
Dose escalation will be stopped.  This dose level will be 
declared the maximally administered dose (highest dose 
administered).  Up to three (3) additional patients will be 
entered at the next lowest dose level if only 3 patients 
were treated previously at that dose. 
1 out of 3 
Enter up to 3 more patients at this dose level. 
• If 0 of these 3 patients experience DLT, proceed to the 
next dose level. 
• If 1 or more of this group suffer DLT, then dose 
escalation is stopped, and this dose is declared the 
maximally administered dose.  UP to three (3) 
additional patients will be entered at the next lowest 
dose level if only 3 patients were treated previously at 
that dose. 
<1 out of 6  
This is the MTD and is generally the recommended phase 
2 dose.  NOTE:  If <1 out of 6 patients with DLT occurs 
at DL3, the MTD will not have been identified and DL3 
will be declared the MAD for further study.    
 
3.1.3 Safety Assessment and Study Stopping Rules 
AEs will be assessed and graded according to CTEP Common Toxicity Criteria (CTC) version 4 
and the decisions regarding MTD or tolerability of the augmented dosing will be changed to follow 
standard phase I criteria.  
Overall drug safety will be further characterized by examining adverse events, laboratory 
abnormalities, physical examination and ECOG performance status change from baseline. All AEs 
occurring within 30 days from the last study treatment will be summarized for all patients and 
reviewed after the 9th and 20th patients to determine if later toxicities occurring outside of the DLT 
evaluation period are placing the patients at greater risk for SAEs. If the protocol meets the 
stopping criteria, all patients will discontinue study treatment, including patients who have been 
treated at different, and presumably tolerable, doses.  
Stopping rules for the study to address delayed clinically significant AEs are defined as ≥ 2 of the 


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28 
first 9 patients experiencing grade 4 or greater toxicity attributed as possibly, probably or definitely 
related to ruxolitinib, or ≥ 4 of the first 20 patients experiencing similar toxicity.  
Treatment will be discontinued for unacceptable toxicity defined as any grade 4 infection, febrile 
neutropenia treated with IV antibiotics, bleeding associated with thrombocytopenia, any evidence 
of sustained organ dysfunction or clinically significant biochemical laboratory abnormalities 
lasting more than 10 days which occurs during the treatment and is deemed by the PI to be possibly, 
probably or definitely related to the study drug.  
3.2 
DRUG ADMINISTRATION 
Ruxolitinib will be given orally (PO) twice daily to newly enrolled patients at sequentially 
increasing dose levels of 30, 40 and 50 mg. In the absence of DLT, dose escalation will proceed 
until an MTD dose is defined or the 50 mg twice daily dose is shown to be tolerable.  
3.3 
DOSE MODIFICATIONS 
There will be no modifications of the ruxolitinib dose for individual patients. Patients will be 
treated throughout the study with the same dose as initially administered and if this dose is not 
tolerable (e.g., DLT or late clinically significant toxicity) their treatment will be discontinued.  
Ruxolitinib will be held for up to 10 days for the toxicities listed above in Section 3.1.3 that occur 
after the cycle 1 determination of the MTD until the toxicity has resolved to ≤ grade 1 or baseline 
and then resumed at the patient’s starting dose one time.  
Treatment will be discontinued for any patient has recurrence of the AEs that prompted 
interruption of treatment. 
3.4 
CLINICAL MONITORING 
3.4.1 Clinical Monitoring and Assessments During Treatment 
The following assessments will be performed on the patient evaluation days listed below and in 
the study calendar. Please refer to Section 2.4 for tests to be performed at baseline.  The window 
for assessments is ±2 days during cycle 1 and ±5 days during cycle 2 and beyond, unless otherwise 
noted below or on the Study Calendar (Section 3.5).   
Patients who tolerate cycles 1 and 2 without any ≥ grade 2 toxicities or unanticipated adverse 
events, clinical monitoring visit may be extended to every 2 cycles for the first year of treatment. 
For patients continuing treatment beyond 1 year, clinical monitoring and response assessments 
may be extended to every 3rd or 4th cycle at the discretion of the investigator during year 2 and 
beyond.  
Patients who have symptoms or findings suggestive of disease progression or delayed toxicity at 
later dates will have the appropriate laboratory and radiographic assessment to when they present 
to the clinic. Monitoring tests listed below will be performed once the tolerability of the treatment 
is established when the patient is seen in clinic. 
3.4.1.1 Vital signs: Including weight, heart rate, blood pressure, respiration, temperature and 
arterial oxygen saturation (SO2) by transcutaneous pulse oximeter on whenever the 
patients are seen for follow-up clinical evaluations. 
3.4.1.2 Interval history, physical examination and performance status: Days 1, 4 or 5 
and 8 of cycle 1. Patients may also be seen on day 15 and 22 of cycle 1 and as needed 
to assess potential toxicities. Patients will be seen on day 1 of cycle 2, and at every 
subsequent outpatient follow-up in the clinic. NOTE: For patients with skin lesions 


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or other visually-apparent signs of disease, photographs may be taken to document 
response to treatment with permission. 
3.4.1.3 Routine chemistry and hematology tests, including acute care panel, mineral and 
hepatic panels, LDH, C Reactive Protein (CRP) and CBC with differential:  These 
labs will be obtained at any NCI outpatient visit during cycle 1; cycle 1 days 15 and 
22 at home if the patient is being monitored remotely.  The laboratories will be 
obtained on cycle 2 day 1 and at all subsequent NCI outpatient visits during the 
period of protocol treatment.  These routine tests may also be performed at home by 
the patient’s referring physician when the patient is not seen in the outpatient clinic 
or if there is suspicion of clinical progression, if feasible. 
3.4.1.4 CellaVision differential to quantitate circulating ATL: At pre-treatment and the 
same schedule as routine chemistry and hematology laboratories.  The CellaVision 
differential will be performed on a slide produced from the routine hematology 
sample of the day to identify atypical appearing T-cells with characteristics. Dr. 
Katherine Calvo or designee Hematology service/Hematopathology Bldg. 10 RM 
2C418A will determine that the smear is adequate for analysis and send the processed 
slides to the Lymphoid Malignancies Branch for storage prior to analysis by a single 
hematopathologist at a later date. 
3.4.1.5 Radiographic restaging for response: CT scan neck, chest, abdomen and pelvis (or 
other imaging studies as appropriate and at the direction of the PI) for patients with 
radiographically measurable or evaluable disease pre-treatment, at the end of cycles 
1 and 2, every 2 cycles while the patient is on treatment (*see note), and at the end 
of treatment (if feasible) for all patients who have radiographically assessible disease. 
*NOTE:  For patients continuing treatment beyond 1 year, assessments may be 
extended to every 3rd or 4th cycle at the discretion of the investigator. The clinical 
and other research assessments may also be updated accordingly without being 
considered a protocol deviation.   
Patients who do not have radiographically evident disease at their initial evaluations 
are not required to have these restaging films unless there is clinical concern for 
disease progression. Patients with radiographically evident disease who have 
subjective or objective evidence (physical exam or laboratory results) that suggests 
disease progression may also undergo radiographic restaging to assess for new 
radiographic lesions. 
Patients who come off treatment for a reason other than disease progression, will 
continue to be followed until progression (or another off-study reason per Section 
3.8.2).  Assessments may be done at NIH or outside, with optional imaging at the 
timing discretion of the investigator. 
3.4.1.6 FACS panel restaging for response: These samples will be collected at:  pre-
treatment; on day 15 and pre-cycle 2 and 3 (if feasible); at the same time as disease 
restaging occurs; and, at the end of treatment and off study evaluations (if 
appropriate). The multicolor FACS panel listed below in Table 4 will be performed 
to determine percentage and absolute number of CD3dim CD4+ ATL. Changes in 
CD4+ CD8+, NK cells and T-cell central and effector memory subsets will also be 
assessed in these analyses (see Section 5.1.3). Additional tubes or cell surface 


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markers maybe inserted or substituted into this panel later during the conduct of the 
trial without increasing the amount of blood sampled.  NOTE:  In case of scheduling 
conflicts, TBNK may be substituted. 
Table 4:  FACS panel surface markers and fluorokine  
Tube 
FITC 
PE 
PerCP 
PE-Cy7 
APC 
APC-efluor 780 
1 
CD14 
 
 
 
 
CD45 Ungated 
2 
IgG 
IgG 
IgG 
IgG 
IgG 
CD45 
3 
CD45RA 
CD62L 
CD4 
CD3 
CD8 
CD45 
4 
CD7 
CD25 
CD4 
CD3 
CD8 
CD45 
5 
CD3/CD16+CD56 
CD20 
 
 
CD45 
6 
CD2 
IL15Rα 
CD4 
CD3 
 
CD45 
7 
CD57 
MIKβ3 
CD127 
CD3 
CD4 
CD45 
Initial Study Only 
8 
CD3 
CD25 
CD194(CCR4) 
 
CD4 
CD45 
3.4.1.7 Hepatitis B serologies and quantitative DNA:  These will be repeated for patients 
with indolent hepatitis B infections every 3-4 months during treatment as indicated 
in Section 3.5 Study Calendar; and, at least yearly after treatment. 
3.4.1.8 Optional Bone marrow aspirate and biopsy to confirm a complete response  
3.4.1.9 Optional Tumor Biopsy: Patients with easily accessible tumor deposits who 
consent to this procedure will have a fine-needle aspiration (FNA) of one of their 
tumors during the first 28 days of treatment (between days 14 through 28) to assess 
for changes in their ATL infiltration and changes in gene expression associated with 
ruxolitinib treatment. These biopsies may be done by CT guidance.  Patients who 
consent to additional optional FNA’s may be asked to undergo an FNA during the 
study treatment and/or if they have progressive disease while on-study. These 
biopsies will help us gain additional insight into the in vivo effects of ruxolitinib. 
These samples will be used for research. 
3.4.1.10 Other Studies 
Patients may have additional laboratory or radiological studies performed as 
clinically indicated, in particular if there were a suspicion of disease progression that 
would warrant an urgent therapeutic intervention. 


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3.5 
STUDY CALENDAR 
 
Procedure/  
Assessment 
Screening Baseline 
Treatment1 
End of 
Treatment 
and 
Off Study2,17 
Cycle 1 
Cycle 2 Cycles 3 and 4, 
and beyond 
D1 D4-5, 
D8 
D15 
D22 D29 D1 D29 D1 
Every 2 
cycles year 
1, every 3rd 
or 4th cycle 
year 2+  
Windows: D -28 to -1 
D -14 to -1 
±2 days 
±5 days 
±10 days 
 Ruxolitinib treatment 3 
 
 
X (daily) 
 Informed consent 
 
X 
 
 
 
 
 
 
 
 
 
 
NCI pathology review/confirmation 4 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical exam/interval history, Vital signs, Performance status 5 
X 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Serum pregnancy test 7 
X 
X 
X 
 
 
 
 
X 
 
X 
 
 
CBC w/differential  
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Chemistries panels, LDH and CRP 6 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
Reticulocyte count 
X 
X 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
Radiographic disease assessment 8 
X 
 
 
 
 
 
X 
 
X 
 
X 
(X) 
Photography for skin lesions (if applicable) 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
CellaVision differential & FACS assessment: TBNK or 
lymphocyte subset analysis 9 
X 
 
X 
 
 
 
X 
 
X 
 
X 
X 
HIV, HTLV, Hepatitis C serology 10 
X 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B serology, Hepatitis B Quantitative DNA 10 
X 
 
 
 
 
 
 
 
 
X (see footnote) 
 
Bone marrow biopsy and aspirate 11 
 
X 
 
 
 
 
 
 
 
 
 
 
CMV serology and CMV antigens 
 
X 
 
 
 
 
 
 
 
 
 
 
Soluble IL-2 receptor alpha, IL-15/IL-15 receptor alpha, IL-18, 
TNFα 12 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
In vitro/PBMC proliferation assays13 
 
(X) 
(X) 
 
(X) 
 
(X) 
 
 
(X) 
(X) 
(X) 
STAT5, phosphoSTAT5 and ruxolitinib levels14 
 
(X) 
(X) 
(X) 
(X) 
 
(X) 
 
 
(X) 
(X) 
(X) 
Molecular analysis of TCRγ chain15 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
Optional tumor biopsy16 
 
(X) 
 
 
(X) 
(X) 
(X) = Optional 
NOTE:  Perform additional assessments as clinically indicated.  Baseline studies do not need to be repeated if completed during screening and meet 
the timeframe for baseline evaluation requirements. 
1. 
Each cycle will be 28 days in length.  The start of subsequent cycles may be delayed up to 7 days for social occasions or patient’s 
convenience. The patients will be seen in the outpatient clinic twice during the first week (day 1 and day 4 or 5) after starting treatment and 


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on day 8.  Patient who are tolerating their first 2 weeks of treatment well may be eligible to be monitored at home for the 3rd and 4th weeks 
of their cycle 1 treatment as stated in Section 3.1. Patients who have new complaints suggestive of toxicities will be seen as soon as possible 
for outpatient assessment of their condition Patients who tolerate cycles 1 and 2 without any ≥ grade 2 toxicities or unanticipated adverse 
events, clinical monitoring visit maybe extended to every 2 cycles (i.e., 56 days) after cycle 4 once the tolerability of their treatment is 
established. For patients continuing treatment beyond 1 year, assessments may be extended to every 3rd or 4th cycle at the discretion of the 
investigator. The clinical and other research assessments may also be updated accordingly without being considered a protocol deviation 
2. 
Denotes testing to be performed at the “end of study visit” (just prior to the patient being taken off study), if feasible. 
3. 
Doses are 30, 40 and 50 mg twice daily. 
4. 
Including biopsies of clinically suspicious skin lesions. 
5. 
Vital signs include: weight, heart rate, blood pressure, respiration, temperature and arterial oxygen saturation (SO2) by transcutaneous pulse 
oximeter, for follow up clinical evaluations. 
6. 
Chemistry tests include acute care (sodium, potassium, chloride, CO2, glucose, BUN, creatinine), mineral (serum calcium, phosphate, 
magnesium and albumin) and hepatic (alkaline phosphatase, ALT, AST, total and direct bilirubin) panels, LDH and CBC will be obtained 
twice weekly (e.g., M, Th) during the first week and then weekly during the first month of treatment with the higher doses.  C-reactive 
protein (CRP) will at minimum be assessed day 1 of cycle 1, day 29 of cycles 2 and 4, and every 3-4 months in follow-up for all subsequent 
treatment cycles. These labs may also be performed at home by the patient’s referring physician when the patient is not seen in the outpatient 
clinic or if there is suspicion of clinical progression, if feasible. 
7. 
Pretreatment day 1 or within 3 days prior to starting each cycle of treatment (ideally) when the patients are seen in follow-up at the Clinical 
Center in women of childbearing potential. 
8. 
Radiographic restaging for response for patients with radiographically measurable or evaluable disease: CT scan neck, chest, abdomen and 
pelvis (or other imaging studies as appropriate) on pretreatment for all patients and then day 29 of cycles 1 and 2, and then every 2 cycles 
for patients who have radiographically measurable or evaluable disease.  
9. 
CellaVision differential and FACS panel shown in Table 4, and Sections 3.4.1.6 and 3.4.1.4 for additional details. One 10 mL lavender top 
tube will be drawn for the FACS panel and sent to the Immunology Lab of the NIH Clinical Center 10/2C410. TBNK can be substituted for 
scheduling conflicts. 
10. HIV and Hepatitis C testing only during screening. Hepatitis B testing as indicated also at screening; patients who have an indolent chronic 
Hepatitis B infection will have repeat serial Hepatitis B Quantitative DNA and serology every 2 cycles during treatment; this testing may be 
extended to every 3rd or 4th cycle at the discretion of the investigator after year 1 if the timing for other assessments is adjusted. 
11. Patients who are complete responders by FACS evaluation of circulating ATL cells and/or radiographic assessment may have a second BM 
biopsy (optional) to confirm their response. 
12. Samples to assess for IL-2Rα IL-18 and TNFα will be drawn in 5mL SST tubes at pre-treatment, on day 15 (if feasible), pre-cycle 2 and 3, 
at the same time as disease restaging occurs, and at the end of treatment off study visits for all patients. Samples will be held at room 
temperature until picked up by a Lymphoid Malignancies Branch clinical researcher who will ship the samples to a Contractor for 
performance of the assays. Serum samples will also be routed by the Department of Laboratory Medicine to Mayo Laboratories for CLIA-
certified analysis of soluble IL-2Rα levels. See Section 5.1.3 for additional details. 
13. In vitro (PBMC) proliferation assays will be an optional test for all patients to potentially be performed pre- and post-treatment on cycle 1 
day 1, 15 and 29 and at the time of any subsequent follow-up visit at the PI’s discretion. Up to 50 mL of whole blood will be drawn in a 
heparinized (green top) tubes.  NOTE:  These assays will not be performed if the absolute lymphocyte count indicates an insufficient number 
of cells to form these assays at these time points. 


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14. Assessment of the STAT 5 and phosphoSTAT 5 or other JAK-STAT pathway associated proteins in intracellular FACS analyses will be an 
optional test to potentially be performed on cycle 1 day 1 (pre-treatment, and 1, 3, 6 and 24 hours after treatment), days 15 and 29, and at 
the time of any subsequent follow-up visit at the PI’s discretion. If drawn independently of the samples for in vitro proliferation assays, 
approximately 30 mL of blood may be drawn in heparinized (green top) tubes along with a 5 mL serum (SST tube) sample to allow for 
comparison of ruxolitinib level to STAT5 and phosphoSTAT5 measurements.  See Section 5.1.4 for additional details.   
15. Blood (4 mL) will be collected in light blue (citrate) tube at baseline, pre-cycle 2 (i.e., day 29 of cycle 1), at the same time as disease 
restaging occurs, and at the off-study evaluation, if feasible. The blood will be transported to room 3S247 attention to Dr. Mark Raffeld (see 
Section 5.1.5). 
16. Patients with easily accessible tumor deposits who consent to this procedure will have a fine-needle aspiration of one of their tumors at 
baseline and during the first 28 days of treatment (between days 14 through 28) to assess for changes in their ATL infiltration and changes 
in gene expression associated with ruxolitinib treatment. Consideration for additional tumor biopsies will be given in patients with evidence 
of an ongoing response, at the time of relapse and/or other clinically notable time points to gain additional insight into the in vivo effects of 
ruxolitinib. These biopsies are optional. 
17. End of treatment visit will occur approximately 30 days after the last dose of study drug. If the patient cannot return to the Clinical Center 
for this visit, a request will be made to collect required clinical labs (specify as needed) from a local physician or laboratory. If this is not 
possible, patients may be assessed by telephone for symptoms. If a patient comes off treatment for a reason other than disease progression, 
we will continue to follow the patient until progression (or another off-study reason); in these cases, optional imaging will be at the discretion 
of the investigator.   
 
 
 


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3.6 
CONCURRENT THERAPY 
Concurrent anti-cancer therapy to include immunotherapy, immunosuppressive therapy, radiation 
therapy or chemotherapy, and administration of systemic corticosteroids except for physiologic 
replacement doses of cortisone acetate is not permitted while on the study.  Initiation of medically 
indicated, non-oncologic medications such as anti-hypertensive agents or antibiotics for urinary 
tract infections that do not have significant potential for interaction with the ruxolitinib treatment 
are allowable with prior approval of the PI.   
Concurrent use of strong CYP3A4 inhibitors is to be avoided, if possible. Per the eligibility, 
patients with an absolute requirement for medications that are CYP3A4 inhibitors are not eligible 
for enrollment.  Consideration of initiation on treatment must be considered and only with the 
approval of the Principal Investigator.  Alternative medications should be used whenever possible.  
3.7 
COST AND COMPENSATION  
3.7.1 Costs 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that participants receive at the NIH Clinical Center.  If some tests and procedures performed 
outside the NIH Clinical Center, participants may have to pay for these costs if they are not covered 
by insurance company.  Medicines that are not part of the study treatment will not be provided or 
paid for by the NIH Clinical Center.     
3.7.2 Compensation 
Participants will not be compensated on this study. 
3.7.3 Reimbursement  
The NCI will cover the costs of some expenses associated with protocol participation.  Some of 
these costs may be paid directly by the NIH and some may be reimbursed to the 
participant/guardian as appropriate.  The amount and form of these payments are determined by 
the NCI Travel and Lodging Reimbursement Policy.   
3.8 
CRITERIA FOR REMOVAL FROM THE PROTOCOL TREATMENT AND OFF-STUDY CRITERIA 
Prior to removal from study, effort must be made to have all subjects complete a safety visit 
approximately 30 days after the last dose of study therapy.  
3.8.1 Off-Treatment Criteria 
• Unacceptable toxicity as defined in Section 3.1.3 or 3.3 
• Disease progression not responsive to highest dose level that can be safely administered 
• Persistent (> 14 days) treatment-related adverse events ≥ grade 2 
• Investigator discretion 
• Positive pregnancy test 
3.8.2 Off-Study Criteria 
• Completion of protocol therapy, with evidence of progression, including a 30-day safety 
visit 
• Voluntary withdrawal of consent by the patient 


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35 
• Patient non-compliance with treatment and research plans 
• The institution of another anticancer treatment 
• Any new medical or psychiatric condition that, in the opinion of the PI, precludes the safe 
continuation of the study 
• Death 
4 
CONCOMITANT MEDICATIONS/MEASURES 
Patients will be followed and managed as clinically appropriate with IV fluids, anti-emetics, anti-
pyretics or other standard interventions based on the clinical experience with Ruxolitinib.   
5 
BIOSPECIMEN COLLECTION 
5.1 
CORRELATIVE STUDIES FOR RESEARCH 
All samples will be collected at the time points identified in the Study Calendar (Section 3.5).  The 
volumes for blood samples noted below may be adjusted at the time of collection based upon tube 
availability; in no case will the maximum amount of blood allowed to be collected from patients 
be exceeded.   
5.1.1 Soluble IL-2 Receptor alpha chain, IL-15/IL-15 Receptor alpha (IL-15 Rα), IL-18 and 
TNFα assessments 
Samples for IL-2Rα, IL-15/IL-15Rα, IL-18 and TNFα will be drawn in SST tubes (5 mL).  
Labels listing the date and time of the blood draw as well as the patient’s name will be affixed to 
all the tubes by the staff person who obtained the samples. Lymphoid Malignancies Branch 
Clinical Research personnel will arrange for these samples to be sent via courier to Clinical 
Support Laboratory at NCI/ Leidos Biomedical Research, Inc., for analysis. Patient identifiers will 
be removed from all specimens, and they will have assigned a unique number and will be labeled 
with this number. Serum samples will also be routed by the Department of Laboratory Medicine 
to Mayo Laboratories for CLIA-certified analysis of soluble IL-2Rα levels. 
5.1.2 In Vitro Proliferative Assays  
NOTE:  These samples are optional and will be collected at the discretion of the PI. When 
collected, the following applies:   
Samples for in vitro proliferative assays (PBMCs) will be drawn in a heparinized (green top) tubes 
(50 mL). The assays will not be performed if the absolute lymphocyte count indicates an 
insufficient number of cells to perform these assays at these time points. If there is an insufficient 
number of circulating cells at these time points, the medical record will indicate this 
assessment was not performed due to insufficient material and will not be considered a 
protocol deviation. Lymphoid Malignancies Branch Clinical Research personnel will pick up 
these tubes from phlebotomy.  
These concentrations of the JAK inhibitors is based on the human pharmacokinetic data to 
represent a low but achievable in vivo drug level and a higher inhibitory level that cannot safely 
be achieved in patients to assess the drugs’ potential inhibitory properties. The effect on 
proliferation will be assessed by addition of 3H-thymidine 6 hours before the end of the 6-day 
cultures. Culture supernatants will be assessed by specific ELISAs for IL-2, IL-9, IL- 15 and IL-
21. 


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These specimens may also be used to perform additional exploratory molecular analyses limited 
to immune response genes or genes known to be critical to the pathophysiology of HTLV-1 related 
ATL including but not limited to JAK1, JAK2, JAK3, IRF4, CCR4, NOTCH1 and p53. 
5.1.3 FACS Analyses 
FACS analyses of CD4+, CD8+, NK cells and T-cell central and effector memory subsets will also 
be assessed at the same time the patient’s ATL count is assessed to explore the effects of ruxolitinib 
on the immune effector cells.  NOTE:  Flow cytometry samples to assess lymphocyte sets and 
subsets will also be sent to Flow Cytometry/Immunology Laboratory Department of Laboratory 
Medicine for the Clinical Center (Section 3.4.1.6). 
5.1.4 Analysis of STAT5; phosphoSTAT5 and serum ruxolitinib level 
NOTE:  These samples are optional and will be collected at the discretion of the PI. When 
collected, the following applies:   
If sufficient numbers of ATL cells are obtained from the PBMC samples drawn for the 
proliferation assays, the cellular lysates will also be used to perform the intracellular FACS 
analyses for expression of STAT 5 and phosphoSTAT5 or other proteins of interest associated 
with the JAK-STAT pathway. When samples are collected independently of time points for PBMC 
samples for in vitro proliferation assays (e.g., Cycle 1 Day 1 post-treatment), blood will be drawn 
in a heparinized (green top) tubes.  For these analyses, about 30 mL of blood is anticipated to be 
needed; however, may be adjusted based upon the number of cells collected and ongoing assay 
development with observation of the maximum amount of blood allowed to be collected within 
any 8-week period.    
A serum sample will also be collected at each of the same time points (5 mL SST tubes) and 
retained to allow for comparison of ruxolitinib level to STAT5 and phosphoSTAT5 measurements.  
5.1.5 Molecular Analysis for T-cell Receptor Gamma (TCRγ) Gene Rearrangement 
To detect clonality and analysis of HTLV-1 viral titer, blood will be collected in light blue (citrate 
buffer) tubes (4 mL). The blood will be transported to room 2N116A attention to Dr. Mark Raffeld 
or designee. These samples will be stored at -70º C until batch analysis is performed.   
5.1.6 Optional Tumor Biopsies 
Patients with easily accessible tumor deposits who consent to this procedure will have a fine-
needle aspiration or punch biopsy of one of their tumors at baseline and during the first 28 days of 
treatment (between days 14 through 28) to assess for changes in their ATL infiltration and changes 
in gene expression associated with ruxolitinib treatment. Patients who consent to additional 
optional FNA’s may be asked to undergo an FNA during the study treatment and/or if they have 
progressive disease while on-study. These biopsies will help us gain additional insight into the in 
vivo effects of ruxolitinib. These samples will be used for research. A 23-gauge hypodermic needle 
will be used to obtain biopsies from the tumor mass. After insertion, multiple passes at changing 
angles of insertion will be made through all quadrants of the tumor.  Alternatively, standard punch 
biopsy technique will be followed.  
5.2 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system. 
Should a CRIS screen not be available, the CRIS downtime procedures will be followed. Samples 
will not be sent outside NIH without appropriate approvals and/or agreements, if required.  
All specimens obtained in the protocol are used as defined in the protocol. Any specimens that are 
remaining at the completion of the protocol will be stored in the conditions described below.  The 


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37 
study will remain open so long as sample or data analysis continues.  Samples from consenting 
patients will be stored until they are no longer of scientific value or if a subject withdraws consent 
for their continued use, at which time they will be destroyed.   
If the patient withdraws consent his/her data will be excluded from future distributions, but data 
that have already been distributed for approved research use will not be able to be retrieved.  The 
PI will record any loss or unanticipated destruction of samples as a deviation. Reporting will be 
per the requirements of section 7.2.1. 
5.2.1 Research Sample Control  
• For research samples obtained for investigation, the Clinical Support Laboratory, Leidos 
Biomedical Research, Inc.-Frederick processes and cryopreserves samples in support of 
IRB-approved, NCI clinical trials.  The laboratory is located in a controlled-access building 
and laboratory doors are kept locked at all times.  Upon specimen receipt, each sample is 
assigned a unique, sequential laboratory accession ID number.  All products generated by 
the laboratory that will be stored either in the laboratory freezers or at a central repository 
facility are identified by this accession ID.  An electronic database is used to store 
information related to patient samples processed by the laboratory.  Vial labels do not 
contain any personal identifier information.  Samples are stored inventoried in locked 
laboratory freezers and are routinely transferred to the NCI-Frederick repository facilities 
for long-term storage.  These facilities are operated under subcontract to Leidos Biomedical 
Research, Inc.-Frederick.  Access to stored clinical samples is restricted.  Investigators 
establish sample collections under “Source Codes” and the investigator responsible for the 
collections, typically the protocol Principal Investigator, specifies who has access to the 
collection. 
• When requests are submitted by the NCI investigator for shipment of samples outside of 
the NIH, it is the policy of the laboratory to request documentation that appropriate 
approvals and/or agreements, if required. are in place that covers the specimen transfer.  
The laboratory does not provide patient identifier information as part of the transfer process 
but may, at the discretion of the NCI investigator, group samples from individual patients 
when that is critical to the testing process.  The NCI investigator responsible for the sample 
collection is responsible for ensuring appropriate approvals and/ or agreements are in place 
prior to requesting the laboratory to ship samples outside of the NIH. 
• Blood and tissue specimens collected in the course of this research project may be banked 
and used in the future to investigate new scientific questions related to this study.  However, 
this research may only be done if the risks of the new questions were covered in the consent 
document and the proposed research has undergone prospective IRB review and approval.  
If new risks are associated with the research (e.g., analysis of germline genetic mutations), 
the Principal Investigator must amend the protocol and obtain informed consent from all 
research subjects. 
• Once primary research objectives for the protocol are achieved, intramural researchers can 
request access to remaining samples provided they have an IRB-approved protocol and 
patient consent.  Access to these samples will only be granted following IRB approval of 
an additional protocol, granting the rights to use the material. 


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5.2.2 Tracking 
• All samples will be barcoded, with data entered and stored in the Labmatrix Data 
Management System utilized by the Lymphoid Malignancies Branch. This is a secure 
program, with access to this system limited to defined MB personnel, who are issued 
individual user accounts. The program creates a unique barcode ID for every sample and 
sample box, which cannot be traced back to patients without Labmatrix access. The data 
recorded for each sample includes the patient ID, name, trial name/protocol number; time 
drawn, cycle time point, dose, material type, as well as box and freezer location. Patient 
demographics associated with the Clinical Center patient number are provided in the 
system. For each sample, there are notes associated with the processing method (delay in 
sample processing, storage conditions on the ward, etc.). 
• Barcoded samples are stored in barcoded boxes in a locked freezer at either -20C or -80C 
according to stability requirements.  These freezers are located onsite in the Clinical 
Support Laboratory and offsite at NCI-Frederick Central Repository Services in Frederick, 
MD. Samples will be stored until requested by a researcher named on the protocol. All 
requests are monitored and tracked in the Labmatrix System. All researchers are required 
to sign a form stating that the samples are only to be used for research purposes associated 
with this trial (as per the IRB-approved protocol) and that any unused samples must be 
returned to the Clinical Support Laboratory. 
• Sample barcodes are linked to patient demographics and limited clinical information. This 
information will only be provided to investigators listed on this protocol, via registered use 
of the Labmatrix System.  
6 
DATA COLLECTION AND EVALUATION  
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 
with the data management efforts.  All data obtained during the conduct of the protocol will be 
kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. AEs will 
be documented from the first study intervention, through 30 days following the last dose of study 
agent. Beyond 30 days after the last intervention, only adverse events which are serious and related 
to the study intervention need to be recorded 
End of study procedures: Data will be stored according to HHS, FDA regulations, and NIH 
Intramural Records Retention Schedule as applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, this will be reported expeditiously per 
requirements in section 7.2.1.  


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6.1.1 Data Collection/Recording Exceptions 
6.1.1.1 Abnormal Laboratory Values 
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator 
will provide details about the action taken with respect to the test drug and about the 
patient’s outcome. 
6.1.1.2 Hospitalizations 
Hospitalizations or prolonged hospitalization for the following reasons do not require 
reporting: 
• Technical, practical, or social reasons, in absence of an AE 
• Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition, including scheduled therapy or standard procedure for the 
target disease of the study, and those required to allow efficacy measurement for the 
study 
• Diagnostic or elective surgical procedures for preexisting conditions or a procedure 
that is planned (e.g., planned prior to starting of treatment on study) 
• Emergency outpatient treatment or observation that does not result in admission, unless 
fulfilling other seriousness criteria  
6.2 
RESPONSE CRITERIA 
Response assessment will be based on three sets of response criteria: Revised Response Criteria 
for lymphoma by Cheson et al38, also by Cheson et al39, and International Consensus Meeting 
Criteria for ATL4.  
6.2.1 Criteria of response for Malignant Lymphoma 57 
6.2.1.1 Complete response 
The designation of a complete response (CR) requires all of the following: (1) Complete 
disappearance of all detectable clinical evidence of disease and disease-related symptoms if 
present before therapy; (2) a post-treatment residual mass is permitted as long as it is PET 
negative.  If a pretreatment PET scan was negative, all lymph nodes and nodal masses must 
have regressed on CT to normal size (<1.5 cm in their greatest transverse diameter for nodes 
> 1.5 cm before therapy); (3) Previously involved nodes that were 1.1 to 1.5 cm in their long 
axis and more than 1.0 cm in their short axis before treatment must have decreased to < 1.0 
cm in their short axis after treatment; (4) The spleen and/or liver if considered enlarged before 
therapy based on a physical examination or CT scan, should not be palpable on physical 
examination and should be considered normal size by imaging studies, and (5) If the bone 


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40 
marrow was involved by lymphoma before treatment the infiltrate must have cleared on repeat 
bone marrow biopsy. 
6.2.1.2 Partial response 
The designation of a partial response (PR) requires all of the following: (1) At least a 50% 
reduction in the sum of the product of the diameters of up to six of the largest dominant nodes 
or nodal masses. These nodes or masses should be selected according to all of the following: 
they should be clearly measurable in at least two perpendicular dimensions; if possible they 
should be from disparate regions of the body; and they should include mediastinal and 
retroperitoneal areas of disease whenever these sites are involved; (2) No increase in the size 
of other nodes, liver, or spleen; (3) Splenic and hepatic nodules must regress by >50% in their 
SPD or for single nodules in the greatest transverse diameter; (4) With the exception of splenic 
and hepatic nodules, involvement of other organs is usually assessable and no measurable 
disease should be present.  Bone marrow assessment is irrelevant for determination of a PR if 
the sample was positive before treatment. Patients who achieve a CR by the above criteria but 
who have persistent morphologic bone marrow involvement will be considered partial 
responders; (5) No new sites of disease; (6) If the pretreatment PET scan was positive, the 
post-treatment PET should be positive in at least one previously involved site; and (7) If a 
pretreatment PET was negative, CT criteria should be used. 
6.2.1.3 Stable disease 
A patient is considered to have stable disease (SD) when he or she fails to attain the criteria 
needed for a CR or PR, but does not fulfill those for progressive disease.  The PET should be 
positive at prior sites of disease with no new areas of involvement on the post treatment CT 
or PET.  If the pretreatment PET was negative, there must be no change in the size of the 
previous lesions on the post treatment CT scan. 
6.2.1.4 Progressive disease 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm regardless 
of the short axis.  If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered 
abnormal if its short axis is more than 1.0 cm.  Lymph nodes < 1.0 X < 1.0 cm will not be 
considered as abnormal for relapse or progressive disease. Other criteria for progressive 
disease include the following: (1) Appearance of any new lesion more than 1.5 cm in any axis 
during or at the end of therapy, even if other lesions are decreasing in size. Increased FDG 
uptake in a previously unaffected site should only be considered relapsed or progressive 
disease after confirmation with other modalities. (2) At least a 50% increase from nadir in the 
sum of the products of the diameters of any previously involved nodes, or in a single involved 
node, or the size of other lesions A lymph node with a diameter of the short axis of less than 
1.0 cm must increase by >50% and to a size of 1.5 X 1.5 cm or more than 1.5 cm in the long 
axis. (3) At least a 50% increase in the longest diameter of any single previously identified 
node more than 1 cm in its short axis; (4) Lesions should be PET positive if the lesion was 
PET positive before therapy unless the lesion is too small to be detected by PET; (5) 
Measurable extranodal disease should be assessed in a manner similar to that for nodal disease.  
For these recommendations, the spleen is considered nodal disease. Disease that is only 
assessable will be recorded as present or absent only, unless, while an abnormality is still 
noted by imaging studies or physical exam, it is found to be histologically negative. 


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6.2.2 Criteria of Response for ATL  
6.2.2.1 Complete response 
Complete response (CR) is defined as disappearance of all clinical, microscopic, and 
radiographic evidence of disease. All nodes must have regressed to normal size (1.5 cm in 
their greatest transverse diameter) and previously involved nodes that were 1.1 to 1.5cm must 
have decreased to 1.0 cm.   Because HTLV-1 carriers frequently have a small percentage of 
abnormal lymphocytes with polylobated nuclei, so called flower cells in peripheral blood, 
provided that less than 5% of such cells remained and the absolute lymphocyte count, 
including flower cells, was less than 4 x 109/L, CR is attained. 
6.2.2.2 Complete response unconfirmed 
A designation of unconfirmed complete response (CRu) requires a 75% reduction in tumor 
size with a residual mass after treatment. 
6.2.2.3 Partial response 
Partial response (PR) is defined as a ≥50% reduction in the sum of the products of the greatest 
diameters of measurable disease without the appearance of new lesions. In addition, a 50% or 
greater reduction in absolute abnormal lymphocyte counts in peripheral blood is required to 
attain PR. 
6.2.2.4 Progressive disease 
Progressive disease (PD) in peripheral blood is defined by a 50% increase from nadir in the 
count of flower cells and an absolute lymphocyte count, including flower cells, of 4 x 109/L. 
PD or relapsed disease in the other lesions is defined as a 50% increase from nadir in the sum 
of the products of measurable disease or the appearance of new lesions excluding skin. 
6.2.2.5 Stable disease 
Stable disease is defined as failure to attain CR/PR or PD.  
6.3 
TOXICITY CRITERIA 
The following adverse event management guidelines are intended to ensure the safety of each 
patient while on the study.  The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE 
reporting.  All appropriate treatment areas should have access to a copy of the CTCAE version 
4.0.  A copy of the CTCAE version 4.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40).  
7 
NIH REPORTING REQUIREMENTS / DATA AND SAFETY MONITORING  
7.1 
DEFINITIONS 
Please refer to definitions provided in Policy 801: Reporting Research Events found here. 
7.2 
OHSRP OFFICE OF COMPLIANCE AND TRAINING / IRB REPORTING 
7.2.1 Expedited Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and Policy 
802 Non-Compliance Human Subjects Research found here.  
7.2.2 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events found here.  


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42 
7.3 
NCI CLINICAL DIRECTOR REPORTING  
Problems expeditiously reported to the OHSRP in iRIS will also be reported to the NCI Clinical 
Director.  A separate submission is not necessary as reports in iRIS will be available to the Clinical 
Director. 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email to the Clinical Director unless they are due to progressive 
disease.   
To report these deaths, please send an email describing the circumstances of the death to Dr. Dahut 
at NCICCRQA@mail.nih.gov within one business day of learning of the death. 
7.4 
NIH REQUIRED DATA AND SAFETY MONITORING PLAN 
7.4.1 Principal Investigator/Research Team  
The clinical research team will meet on approximately a weekly basis when patients are being 
actively treated on the trial to discuss each patient. Decisions about dose level, enrollment and 
dose escalation if applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator. Events 
meeting requirements for expedited reporting as described in section 7.2.1 will be submitted within 
the appropriate timelines.  
The principal investigator will review adverse event and response data on each patient to ensure 
safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
8 
STATISTICAL CONSIDERATIONS 
The primary goal of this study is to evaluate the safety and efficacy of ruxolitinib in patients with 
smoldering or chronic adult T-cell leukemia (ATL). Despite the Shimoyama Classification 
system4, smoldering and chronic phase ATL patients appear to be a biologically heterogeneous 
group. Chronic ATL with adverse disease characteristics such as poorer performance status, lower 
neutrophil count receiving chemotherapy have been reported to have a poorer median survival than 
is generally expected for this subtype of ATL and this should be reflected in lower response rate 
to treatments. Picking an acceptable phase II target response rate can be difficult, due to the lack 
of clarity in the historical database for treated chronic or smoldering ATL. Survival is the clinical 
endpoint most often captured in these treatment reports and response rates are frequently not sited 
and, as previously discussed (Section 1.6), survival data can be inconsistent.47 Given the available 
data that indicates previously treated chronic or smoldering subtype ATL patients who are further 
along in the natural history of their ATL and respond less well to any form of treatment, we believe 
that an initial target response rate of 30% in our referral patient population is an appropriate target 
value for response in a phase II trial41. We will adhere strictly to the definition of chronic and 
smoldering subtypes as defined by Shimoyama for the enrolled patients. 
Original Study Design:  In this study for chronic or smoldering ATL will use an optimal two-stage 
Simon design to test for early evidence for efficacy based on complete and partial response. The 
design is based on the following: (a) the response proportion (partial and complete response) will 
be less than 5% if the treatment is totally ineffective (Po=0.05), (b) the treatment will be considered 
effective and worthy of future investigation if the true response proportion >30% (P1=0.30) (see 
Section 1.6), (c) a type I error rate of 5% (i.e., the probability of concluding that the treatment is 


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43 
effective if the true response rate is 5% is 0.05), (d) a power of 90% (i.e., the probability of 
concluding that the treatment is effective if the true response proportion is 30% is 0.95). 
Updated Study Design (Amendment D):  Although there were 4 responding patients in the first 12 
patient who were treated, the activity was not sustained even in these patients; therefore, we are 
now changing the treatment regimen to evaluate the activity of augmented dosing (effective with 
Amendment D).  We plan to treat a total of 9 patients at the MTD or MAD and will not proceed 
with the same original two-stage phase 2 dosing. Patients who discontinue treatment within the 
first 28 days for reasons other than toxicity will be considered inevaluable.  In order to allow for 
this assessment of patients attempting higher treatment doses, the protocol will require an 
additional 15-21 patients.  Accounting for the previously enrolled 12 subjects, the new design, and 
to assess up to 9 patients for response at the MTD/MAD level with the new increased dose levels 
as well as allowing for up to two (2) inevaluable patients:  the new accrual ceiling will be set at 35 
patients. 
The major objective of this study continues to be to determine the antitumor activity of ruxolitinib 
with regard to response rate and time to progression. Response rate will be based on the number 
of patients who achieve either a complete or partial response to therapy. Time to progression will 
be measured from the date of registration until documentation of disease progression.. 
An exploratory analysis will be performed in the two subgroups of patients defined by the 
inhibition of their pretreatment in vitro ATL cells proliferation by ruxolitinib treatment. The 
patients will be distinguished on the basis of the results of a 6-day ex vivo culture analyses 
performed on patient peripheral blood mononuclear cells prior to drug administration. One 
subgroup of patients will be defined as those who fulfill the following criteria: peripheral blood 
mononuclear cells proliferate ex vivo ( 5,000 CPM/1C) in 6-day culture and their thymidine 
uptake must be reduced by 40% by the addition of 10 M ruxolitinib. The other group of patients 
would be all the remaining treated patients that do not fulfill these criteria. Since a limited number 
of patient samples have been assessed to date, it is not clear what percentage of smoldering or 
chronic stage ATL patients will fulfill the criteria for group 1. 
9 
COLLABORATIVE AGREEMENTS 
Not applicable.   
10 HUMAN SUBJECTS PROTECTIONS 
10.1 RATIONALE FOR SUBJECT SELECTION 
Men and women age 18 years or older of all races and ethnic groups are eligible for this trial if 
they meet the eligibility criteria.  If differences in outcome that correlate to gender, racial, or ethnic 
identity were noted, accrual may be expanded or additional studies may be performed to 
investigate those differences more fully. Because there is no significant preclinical information 
regarding the risk to a fetus or newborn infant, pregnant or breastfeeding women will be excluded 
from participation in this trial. Since ATL patients have an underlying defect in their immunity 
due to the chronic infection, T-cell dysfunction and are already at risk for opportunistic infections, 
patients with hepatitis B with evidence of end organ damage or dysfunction or active hepatitis C 
are not eligible for this trial. 
10.2 PARTICIPATION OF CHILDREN 
Individuals under the age of 18 years of age are not eligible to participate in this trial.  The immune 
physiology of children and the potential toxicity in this population are felt to be sufficiently 


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different from those of adult patients that a separate protocol, dedicated to pediatric patients, 
appears warranted.  Therefore, children may be the object of a separate protocol once toxicity and 
a dose range with biological activity are defined in adults. 
10.3 PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason and because there is a prospect of direct benefit from 
research participation (Section 10.5), all subjects will be offered the opportunity to fill in their 
wishes for research and care, and assign a substitute decision maker on the “NIH Advance 
Directive for Health Care and Medical Research Participation” form so that another person can 
make decisions about their medical care in the event that they become incapacitated or cognitively 
impaired during the course of the study. Note: The PI or AI will contact the NIH Ability to Consent 
Assessment Team (ACAT) for evaluation to assess ongoing capacity of the subjects and to identify 
an LAR, as needed.  Please see section 10.5.1 for consent procedure. 
10.4 EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The discomforts of a 28-day or longer treatment with oral ruxolitinib are expected to be minimal. 
The primary risk to patients participating in this research study is from unexpected or unforeseen 
toxicity from ruxolitinib as an investigational agent for this indication. Patients will be carefully 
monitored for any adverse events and appropriate care provided.  
10.4.1 Risks from Study Procedures 
10.4.1.1 CT Scans 
CT scans often use a contrast agent.  There is a small risk of having a reaction to the contrast 
and most often include nausea, pain in the vein where the contrast is given, headache, metallic 
and/ or bitter taste in the mouth and a warm, flushing feeling.  Rarely, some people have more 
severe allergic reactions to the contrast which may include skins rashes, shortness of breath, 
wheezing or low blood pressure. 
10.4.1.2 Radiation Exposure 
On this study, patients will receive up to eight (8) CT Scans (CT Scan of neck, chest, abdomen 
and pelvis) maximum in annual period. Participants will undergo up to three (3) optional CT 
guided biopsy. The procedures for performing the CT will follow clinical policies, no special 
procedures will apply to these assessments for research purposes. 
The total radiation dose for research purposes will be approximately 12.8 rem. This amount 
is more than would be expected from everyday background radiation. Being exposed to excess 
radiation can increase the risk of cancer. 
10.4.1.3 Optional Tumor Biopsy  
The biopsy may cause pain, bruising, bleeding and infection. The risks associated with 
biopsies are pain and bleeding at the biopsy site. In order to minimize pain, local anesthesia 
will be used. Rarely, there is a risk of infection at the sampling site. CT guidance may be used 
in obtaining biopsies (see 10.4.1.2 for radiation risk). 
10.4.1.4 Bone Marrow Aspiration 
These procedures usually cause only brief discomfort at the site from which the biopsy is 
taken.  Rarely, infection or bleeding may occur at the needle site.  A numbing agent that can 
cause a stinging or burning sensation may be injected at the site of your bone marrow biopsy.  


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The biopsy needle will go through the skin into the bone and may produce a brief, sharp pain.  
As the bone marrow liquid is taken from the bone, there may be a brief, sharp pain.  Since the 
inside of the bone cannot be numbed, this procedure may cause some discomfort, however 
not all patients experience discomfort.  The possible side effects associated with a bone 
marrow biopsy include pain, bleeding, bruising, and infection, as well as a reaction to the 
numbing agent.  
10.4.1.5 Blood Sampling 
Side effects of blood draws include pain and bruising, lightheadedness, and rarely, fainting. 
10.4.1.6 Electrocardiogram 
Some skin irritation can occur where the ECG/EKG electrodes are placed. The test is 
completely painless, and generally takes less than a minute to perform. 
10.5 CONSENT AND ASSENT PROCESS AND DOCUMENTATION 
The informed consent document will be provided to the participant or consent designee(s) as 
applicable for review prior to consenting.  A designated study investigator will carefully explain 
the procedures and tests involved in this study, and the associated risks, discomforts and benefits. 
In order to minimize potential coercion, as much time as is needed to review the document will be 
given, including an opportunity to discuss it with friends, family members and/or other advisors, 
and to ask questions of any designated study investigator. A signed informed consent document 
will be obtained prior to entry onto the study. 
The initial consent process as well as re-consent, when required, may take place in person or 
remotely (e.g., via telephone or other NIH approved remote platforms) per discretion of the 
designated study investigator and with the agreement of the participant.  Whether in person or 
remote, the privacy of the subject will be maintained. Consenting investigators (and participant, 
when in person) will be located in a private area (e.g., clinic consult room). When consent is 
conducted remotely, the participant will be informed of the private nature of the discussion and 
will be encouraged to relocate to a more private setting if needed. 
10.5.1 Consent Process for Adults Who Lack Capacity to Consent to Research Participation 
For participants addressed in section 10.3, an LAR will be identified consistent with Policy 403 
and informed consent obtained from the LAR, as described in Section 10.5.  
10.5.2 Request for Waiver of Consent for Screening Activities 
Prior to the subject signing the consent for this study pre-screening activities listed in section 2.2.1 
may be performed.  
We request a waiver of consent for these activities as they involve only minimal risk to the subjects.  
A waiver will not adversely affect the rights and welfare of the subjects given that the activities 
are only intended to determine suitability for screening for participation in research protocols.  
These activities could not practicably be carried out without the wavier as central recruiting 
services, utilized in the NIH Clinical Center, perform pre-screening activities for multiple studies 
and obtaining consent for each one is beyond their resources.  The subjects will be provided with 
additional pertinent information after participation as they will be informed whether or not they 
are eligible to sign a consent for additional screening. 


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11 REGULATORY AND OPERATIONAL CONSIDERATIONS  
11.1 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to study participants, 
investigator, funding agency, and regulatory authorities.  If the study is prematurely terminated or 
suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional 
Review Board (IRB), and sponsor and will provide the reason(s) for the termination or suspension.  
Study participants will be contacted, as applicable, and be informed of changes to study visit 
schedule. 
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the IRB. 
11.2 QUALITY ASSURANCE AND QUALITY CONTROL 
The clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion.  An individualized quality management plan 
will be developed to describe a site’s quality management. 
Quality control (QC) procedures will be implemented beginning with the data entry system and 
data QC checks that will be run on the database will be generated. Any missing data or data 
anomalies will be communicated to the site(s) for clarification/resolution. 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical 
trial is conducted and data are generated and biological specimens are collected, documented 
(recorded), and reported in compliance with the protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
The investigational site will provide direct access to all trial related sites, source data/documents, 
and reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 
11.3 CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be disclosed and 
managed. Furthermore, persons who have a perceived conflict of interest will be required to have 


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such conflicts managed in a way that is appropriate to their participation in the design and conduct 
of this trial.  The study leadership in conjunction with the National Cancer Institute has established 
policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest. 
11.4 CONFIDENTIALITY AND PRIVACY 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s). This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, 
the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the 
Institutional Review Board (IRB), and/or regulatory agencies may inspect all documents and 
records required to be maintained by the investigator, including but not limited to, medical records 
(office, clinic, or hospital) and pharmacy records for the participants in this study. The clinical 
study site will permit access to such records. 
The study participant’s contact information will be securely stored at the/each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by the reviewing IRB, Institutional policies, or sponsor 
requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be transmitted to and stored at the NCI CCR. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified 
by a unique study identification number. The study data entry and study management systems used 
by the clinical site(s) and by NCI CCR research staff will be secured and password protected. At 
the end of the study, all study databases will be archived at the NIH. 
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued 
by the National Institutes of Health (NIH).  This certificate protects identifiable research 
information from forced disclosure. It allows the investigator and others who have access to 
research records to refuse to disclose identifying information on research participation in any civil, 
criminal, administrative, legislative, or other proceeding, whether at the federal, state, or local 
level. By protecting researchers and institutions from being compelled to disclose information that 
would identify research participants, Certificates of Confidentiality help achieve the research 
objectives and promote participation in studies by helping assure confidentiality and privacy to 
participants. 
12 PHARMACEUTICAL INFORMATION 
There will be no IND obtained for the use of any of the commercial agents used in this study.  
 
This study meets the criteria for exemption for an IND as this investigation is not intended to 
support a new indication for use or any other significant change to the labeling; 
the drugs are already approved and marketed and the investigation is not intended to support a 
significant change in advertising; and the investigation does not involve a route of administration 


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or dosage level in use in a patient population or other factor that significantly increases the risks 
(or decreases the acceptability of the risks) associated with the use of the drug product. The 
discussion of safety rationale is presented in section 1.6.4 
 
12.1 RUXOLITINIB (JAKAFI, ICNB018424)  
Chemical Name: ruxolitinib phosphate 
Other names: none 
Classification: a Janus kinase (JAK) 1 and 2 Inhibitor 
Description: 20 (elongated curved) and 15 (ovaloid curved) mg tablets embossed with NVR 
Ruxolitinib (Jakafi, ICNB018424) is an orally administered, potent selective inhibitor of JAK1 
and JAK2 that was recently approved by the FDA for the treatment of patients with 
myelofibrosis (MF) (36).  Ruxolitinib, chemical name is (CAS) 1H-Pyrazole-1-propanenitrile, 
-cyclopentyl-4-(7H-pyrrolo [2, 3-d] pyrimidin-4-yl)-, (R)-, phosphate (1:1) is shown below: 
 
 
The Janus-associated kinases 1 and 2 mediate the signaling of a number of cytokines and growth 
factors that are important for hematopoiesis and immune function.  Absorption, distribution, 
metabolism and excretion (ADME) and pharmacokinetic studies performed to support the 
licensing application for ruxolitinib showed rapid and near complete absorption (95%) after 
administration with maximum plasma concentration (Cmax) of 1.47 M achieved within 1 to 2 
hours post dose. The mean Cmax and total exposure (AUC) of ruxolitinib increased proportionately 
over the (single) dose range of 50 to 200 mg.  The apparent volume of distribution of ruxolitinib 
at steady state is 53 to 65 L with high protein binding (97%) that is mostly to albumin.  Ruxolitinib 
administration resulted in maximum inhibition of STATs phosphorylation 2 hours after dosing 
with return to near baseline by 10 hours in both healthy subjects and myelofibrosis patients.  
CYP3A4 is the major enzyme responsible for the metabolism of ruxolitinib.  Following a single 
dose of [14C]-labeled ruxolitinib in healthy adult subjects, elimination was predominantly through 
metabolism with 74% of radioactivity excreted in urine and 22% via feces (35). 
12.1.1 Source 
Ruxolitinib is manufactured by DSM Pharmaceuticals (Greenville NC 27834) for Incyte 
Corporation (Wilmington DE 19880) and has been licensed by the US FDA for the treatment of 
primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia 
myelofibrosis. The drug will be purchased by the National Institutes of Health (NIH) Clinical 
Center (CC) Pharmacy. The study drug for the patients enrolled in this study will be distributed to 
by the NIH CC Pharmacy.  


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12.1.2 Toxicity 
Several phase 1, 2 studies and two randomized Phase 3 studies (studies 1 and 2) were conducted 
in patients with MF (either primary myelofibrosis, post-polycythemia Vera myelofibrosis [PV] or 
post-essential thrombocytopenia-myelofibrosis [ET]) 36, 37.  Patients with a platelet count > 200 x 
109/L were started on ruxolitinib orally 20 mg twice daily.  In the 155 MF patients receiving 
ruxolitinib there was a 35% reduction in spleen volume in 65 (41.9%), as compared to one (0.7%) 
in the 154 patients in the placebo group.  148 patients receiving ruxolitinib achieved  50% 
improvement from baseline in the total symptoms score, in contrast to 8 of 152 patients 5.3% in 
the placebo-control group (36, 37). The safety data base in solid tumors and hematologic 
malignancies consisted of 787 patients treated with ruxolitinib in 6 studies evaluating patients with 
MF (N=679), prostate cancer (N=22), multiple myeloma (N=13), ET and PV (N=73), of whom 
617 patients received ruxolitinib.  Hematologic events were the most frequent reported adverse 
events (AEs) primarily thrombocytopenia and anemia.  The majority of these AEs are grade 1-2 
and seldom led to drug discontinuation (<1% of patients).  Of the 155 patients who received 
ruxolitinib in study one 10 (6.5%) had grade 3 thrombocytopenia and one (0.6%) had grade 4 
thrombocytopenia as contrasted with one and 0 patients in the placebo group.  Ten patients had 
grade 3 and 6 patients had grade 4 anemia compared to 5 and 0 in the placebo group.  Biochemistry 
abnormalities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and 
cholesterol were also reported and again the majority of these increases were grade 1 or 2 with no 
grade 4 observed.   In this study there were 9 deaths in the ruxolitinib group and 11 in the placebo 
group.  The safety data base which is primarily from patients with an underlying hematopoietic 
production defect indicates a well-tolerated drug that did cause additional decreases in blood 
elements. 
12.1.3 Summary of Adverse Events 
See Section 1.5.3 and the informed consent document for full listing.   
12.1.4 Caution 
Women of child-bearing age and fertile men should be advised to use adequate and effective 
contraception during treatment with ruxolitinib and for at least six months after therapy. The 
effects of ruxolitinib on embryogenesis, reproduction, and spermatogenesis are unknown. 
12.1.5 Formulation and Preparation 
Refer to the Jakafi package insert. 
12.1.6 Stability and Storage  
Refer to the Jakafi package insert. 
12.1.7 Administration Procedures 
Refer to the Jakafi package insert. 
12.1.8 Drug Incompatibilities 
None known 


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38. Cheson BD, Horning SJ,  Coiffier B,  Shipp MA,  Fisher RI,  Connors JM,  Lister TA, 
Vose J, Grillo-López A,  Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, 
Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP. Report of an 
International Workshop to Standardize Response Criteria for Non-Hodgkin's Lymphomas. 
J Clin Oncol 1999; 17: 1244-1253 
39. Cheson, B.D., et al., Revised response criteria for malignant lymphoma. J Clin Oncol, 
2007. 25:  579-586.  
40. Bazarbachi A, Suarez F, Fields P, Hermine O.  How I treat adult T-cell 
leukemia/lymphoma.  Blood 2011; 118: 1736-1745 
 
41. Shimoyama M: Treatment of patients with adult T-cell leukemia-lymphoma: An overview, 
in Takatsuki K, Hinuma Y, Yoshida M (eds): Advances in Adult T-Cell Leukemia and 
HTLV-I Research. Tokyo, Japan, Japan Scientific Societies, 1992, pp 43-56. 
42. Hermine O, Allard I, Lévy V, Arnulf B, Gessain A, Bazarbachi A; French ATL therapy 
group. A prospective phase II clinical trial with the use of zidovudine and interferon-alpha 
in the acute and lymphoma forms of adult T-cell leukemia/lymphoma. Hematology J 2002; 
3: 276-282. 


Abbreviated Title:  Ruxolitinib in ATL 
Version Date:  02/10/2021 
53 
43. Matutes E, Taylor GP, Cavenagh J, Pagliuca A, Bareford D, Domingo A, Hamblin M, 
Kelsey S, Mir N, Reilly JT. Interferon alpha and zidovudine therapy in adult T-cell 
leukaemia lymphoma: response and outcome in 15 patients. Brit J Haematol 2001; 113: 
779-784. 
44. Ramos JC, Ruiz P Jr, Ratner L, Reis IM, Brites C, Pedroso C, Byrne GE Jr, Toomey NL, 
Andela V, Harhaj EW, Lossos IS, Harrington WJ Jr. IRF-4 and c-Rel expression in 
antiviral-resistant adult T-cell leukemia/lymphoma. Blood. 2007;109: 3060-3068. 
45. Datta A, Bellon M, Sinha-Datta U, Bazarbachi A, Lepelletier Y, Canioni D, Waldmann 
TA, Hermine O, Nicot C. Persistent inhibition of telomerase reprograms adult T-cell 
leukemia to p53-dependent senescence. Blood. 2006;108: 1021-1029 
46. Takasaki Y, Iwanaga M, Imaizumi Y, Tawara M, Joh T, Kohno T, Yamada Y, Kamihira 
S, Ikeda S, Miyazaki Y, Tomonaga M, Tsukasaki K. Long-term study of indolent adult T-
cell leukemia-lymphoma. Blood 2010: 115: 4337-4343.  
47. Takasaki Y, Tsukasaki K, Iwanaga M, et al: A long-term study of prognosis in indolent 
types of adult T-cell leukemia/lymphoma (ATLL): 13th International Conference on 
Human Retrovirology, Hakone, Japan, 2007. AIDS Res Hum Retroviruses  23:597-598, 
2007 (abstr 208). 
48. Shi JG, Chen X, McGee RF, Landman RR, Emm T, Lo Y, Scherle PA, Punwani NG, 
Williams WV, Yeleswaram S. The pharmacokinetics, pharmacodynamics, and safety of 
orally dosed INCB018424 phosphate in healthy volunteers. J Clin Pharmacol. 
2011;51(12):1644-1654. 
49. Zhou T, Hasty P, Walter CA, Bishop AJR, Scott LM, Rebel VI. Myelodysplastic 
Syndrome: an inability to appropriately respond to damaged DNA? Exp Hematol 2013; 
41: 665-674. 
 
 
14 APPENDICES 
 


Abbreviated Title:  Ruxolitinib in ATL 
Version Date:  02/10/2021 
54 
APPENDIX A:  PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able to 
carry on all pre-disease performance 
without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities.  Up and about more than 
50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance 
and frequent medical care. 
3 
In bed >50% of the time.  Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% 
bedridden. 
 
Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 


Abbreviated Title:  Ruxolitinib in ATL 
Version Date:  02/10/2021 
55 
APPENDIX B:  DEFINITIONS OF ATL SUBSETS 
 
 
Smoldering Chronic Lymphoma Acute  
HTLV-1 AB 
+ 
+ 
+ 
+ 
Lymphocyte (x10e9) <4 
4a 
<4 
* 
Abnormal T cells 
5 
+b 
1% 
+b 
LDH 
1.5N 
2N 
NA 
NA 
Ca (mmol/L) 
<2.74 
<2.74 
NA 
NA 
Histology 
No 
NA 
+ 
NA 
Tumor lesion 
 
 
 
 
Skin 
** 
* 
* 
* 
Lung 
** 
* 
* 
* 
Lymph node 
No 
* 
Yes 
* 
Liver 
No 
* 
* 
* 
Spleen 
No 
* 
* 
* 
CNS 
No 
No 
* 
* 
Bone 
No 
No 
* 
* 
Ascites 
No 
No 
* 
* 
Pleural effusion 
No 
No 
* 
* 
GI tract 
No 
No 
* 
* 
 
* No essential qualification except terms required for other subtypes 
** No Essential qualifications if other terms are fulfilled, but histology-proven malignant lesion is required 
in case abnormal T-lymphocytes are less than 5% in peripheral blood 
a:  Accompanied by T-lymphocytosis (3.5 x 109/1 or more) 
b:  In case abnormal T-lymphocytes are less than 5% in peripheral blood, histology-proven tumor lesion is 
required 
 
 


Abbreviated Title:  Ruxolitinib in ATL 
Version Date:  02/10/2021 
56 
APPENDIX C:  STRONG INHIBITORS OF P450 ISOFORM CYP 3A4 
 
acitretin 
amiodarone 
amprenavir 
aprepitant 
cimetidine 
ciprofloxacin 
clarithromycin 
cyclosporine 
danazol 
delavirdine 
diltiazem 
diethyldithiocarbamate 
efavirenz 
erythromycin 
ethinyl estradiol 
fluconazole 
fluoxetine 
fluvoxamine 
gestodene 
grapefruit 
indinavir 
imatinib 
isoniazid 
itraconazole 
ketoconazole 
metronidazole 
methylprednisolone 
miconazole 
mifepristone 
nefazodone 
nelfinavir 
nicardipine 
nifedipine 
norethindrone 
norfloxacin 
norfluoxetine 
oxiconazole 
prednisone 
quinine 
ritonavir 
roxithromycin 
saquinavir 
sertraline 
Synercid 
troleandomycin 
verapamil 
voriconazole 
zafirlukast 
zileuton 
 
 
 
Reference:  http://medicine.iupui.edu/CLINPHARM/DDIS  
 

ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 12/30/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  Kevin Conlon, M.D.
STUDY TITLE:
Phase I/II Trial Evaluating the Safety and Efficacy of Ruxolitinib in Patients 
with Smoldering and Chronic Adult T-Cell Leukemia (ATL)
STUDY SITE:
NIH Clinical Center
Cohort: Affected patient
Consent Version:  12/30/2020
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Principal Investigator:
Kevin Conlon, M.D. 
Phone: 240-760-6087
Email: conlonkc@mail.nih.gov
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions). Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers. Taking part in research at the NIH is your choice.
If the individual being asked to participate in this research study is not able to give consent for 
themselves, you, as the Legally Authorized Representative, will be their decision-maker and you 
are being asked to give permission for this person to be in this study. For the remainder of this 
document, the term “you” refers to you as the decision-maker and/or the individual being asked to 
participate in this research
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason. If you join this study, you may change 
your mind and stop participating in the study at any time and for any reason. In either case, you 
will not lose any benefits to which you are otherwise entitled. However, to be seen at the NIH, you 
must be taking part in a study or are being considered for a study. If you do choose to leave the 
study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
Human T-cell leukemia virus 1 (HTLV-1) is a virus that causes Adult T-cell Leukemia (ATL). 
ATL is a complex disease that causes disruptions in your body’s ability to control the HTLV-1 
virus and the growth and reproduction of cells infected with the virus. Ruxolitinib was recently 
approved by the FDA for the treatment of patients with myelofibrosis (MF). Ruxolitinib is an oral 
IRB NUMBER: 13C0006
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drug that has the ability to interfere with the regulatory proteins that are important to the 
development and growth of ATL cells. Experiments suggest that drugs like ruxolitinib can 
interrupt important activity in ATL cells. In addition, we have tested the ability of ruxolitinib to 
limit the growth and reproduction of ATL cells and we have shown that ruxolitinib is able to slow 
the growth of leukemic cells, indicating that this treatment could potentially be effective in treating 
ATL.
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You are being asked to take part in this study because you have HTLV-1 associated ATL which 
has or has not been treated.  You may have been a patient who took part in this study before or 
who is being asked to take part again with a higher dose of study drug.  
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
There will be up to 35 patients on this trial.
DESCRIPTION OF RESEARCH STUDY
WHAT WILL HAPPEN IF YOU TAKE PART IN THIS RESEARCH STUDY?
If the screening tests show that you are eligible to take part, you will receive ruxolitinib orally at a 
dose of 30, 40, or 50 milligrams (mg) twice daily.  This will be given in cycles of 28 days, generally 
planned to be on an outpatient basis.  This dose is higher than the currently FDA approved dose, 
but some other patients have been able to tolerate increased dosage and we believe that this 
increased dose will be more effective in treating ATL without causing patients to have too many 
bad side effect (also called unacceptable toxicity or side effects).  
In order to confirm that the doses are safe, patients will be enrolled and start treatment on study in 
groups as follows:

Dose escalation part:  First, 3-6 study participants will receive ruxolitinib at the lowest 
dose.  If the study drug does not cause serious side effects, the next group of 3-6 patients 
will receive ruxolitinib at the next highest dose, and so on.  Each group of patients will be 
3-6 each, with the study staff closely monitoring side effects for at least 4 weeks before 
enrolling the next group and/or moving on to the next dose.  

Dose expansion part:  Once the highest safe dose of ruxolitinib is found, then at least a 
total of 9 patients will receive that dose to learn more about the drug and its effect on 
HTLV-1 associated ATL.
BEFORE YOU BEGIN THE STUDY
Before you begin the study, you will have several tests performed to check whether the study is 
suitable for you. This is called screening. Some of these will be done before signing the informed 
consent document for this study or as part of another screening study. Your doctor will review 
your medical history and the drugs that you are currently taking as well as the previous treatments 
of your disease to determine whether you can participate in this study.

Your medical history, including previous cancer treatments, any current or previous 
medications (prescription, supplement, and over-the-counter medicines), will be reviewed. 
IRB NUMBER: 13C0006
IRB APPROVAL DATE: 01/11/2021


PATIENT IDENTIFICATION
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If you have medical records from another clinic or hospital, you will be asked to get copies 
of these records, or your study doctor may be able to request them on your behalf.

A complete physical examination will be performed that will include your vital signs 
(blood pressure, pulse, body temperature, and respiratory rate) and recording your height 
and weight, and evaluation of your ability to carry out daily activities.

Blood tests will be collected to:
o
measure your liver, kidney, and other organ function, red and white blood cells, 
platelets, electrolytes and others;
o
test for certain viruses and infections (such as hepatitis)
o
test for human immunodeficiency virus (HIV) infection. This is the virus that 
causes AIDS. If you are infected with HIV you will not be able to participate in this 
study. We will tell you what the results mean, how to find care, how to avoid 
infecting others, how we report HIV infection, and the importance of informing 
your partners at possible risk because of your HIV infection.
o
run routine tests done in people with your type of cancer to confirm your diagnosis 
and the status of your disease.

For females of child-bearing potential, a pregnancy test will be done (blood sample). You 
will not be able to participate if you are pregnant or you are breast feeding because we 
don’t know how this medicine would affect your baby or your unborn child.

Bone marrow testing will be done to check your disease (any time prior to treatment; one 
may not be needed if done in the past year).  These are done by numbing your hipbone 
using a small needle containing local anesthesia, and then a needle will be put into the 
hipbone, and a small amount of bone marrow will be taken out through the needle

Imaging will include a CT scan of neck, chest, abdomen and pelvis. Other body areas may 
be imaged if clinically indicated.
DURING THE STUDY
You should plan to stay at/near the Clinical Center during the first 2 weeks of treatment.  You will 
be seen in the outpatient clinic on days 1, day 4 or 5, and day 8 to be examined by a doctor and get 
blood tests to monitor how you are doing and to evaluate your response to the treatment. If are 
doing well, you may be able to receive ongoing blood testing for the rest of cycle 1 closer to home, 
returning to the Clinical Center for cycle 2; otherwise, we may ask you to remain nearby for closer 
monitoring.  After cycle 1 you will be seen at least once per cycle.  
While ruxolitinib has been very well tolerated, if you have any significant side effects during 
treatment, you may have extra outpatient clinic visits. You will receive appropriate medications 
for relief of your particular symptoms and your ruxolitinib may be held.  There are also 
medications that you should avoid while receiving ruxolitinib as these may interact with the study 
drug.  The medications to avoid include some antibiotics, steroids, and hormones.  Please talk with 
your study doctor before you take any new medication while you are on study.  You should also 
avoid eating grapefruit or drinking grapefruit juice while taking ruxolitinib.  
IRB NUMBER: 13C0006
IRB APPROVAL DATE: 01/11/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
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If there is evidence that your ATL is responding and there is a dose that does not cause 
unacceptable side effects for you, you may be given the option to continue ruxolitinib until there 
is evidence that the treatment has stopped working.  If your ATL completely responds (no evidence 
of the disease), you will stop treatment and continue close monitoring only.  
Standard procedures being done because you are in this study; these may be done more often 
because you are in the study:

Medical history and physical exam

Photographs of skin lesions or other visually-apparent signs of your disease (if present) at 
your initial and follow-up visits

CT scans of the neck chest, abdomen and pelvis to identify your tumor locations and size 

Measurements of tumor markers in your blood

Standard blood tests
Tests and procedures that are being done to see how the ruxolitinib is affecting your ATL:

Blood tests to measure changes in the number and percentages of specific sets of ATL cells 
circulating in your blood 

Blood tests to measure the changes in the metabolic rate of ATL cells and markers of 
immune stimulation produced in your blood. 

Some patients with ATL skin lesions that are easily accessed may be asked to have 
additional biopsies to measure changes in the cell processes or genes induced by ruxolitinib 
treatment. 

CT scans may also be done, as needed, to identify your tumor locations and size
Optional Biopsy
We may request biopsies after you sign consent, with the first 28 days after the start of treatment 
and at disease progression.  Some of the biopsies to be performed may be done using CT guidance 
and are to be used for research purposes and will not benefit you.  It might help other people in the 
future.  The decision to participate in this part of the research is optional, and no matter what you 
decide to do, it will not affect your care.
If you agree to have the optional biopsy, you will be asked to sign a separate procedure consent 
before you have the procedure.
WHEN YOU ARE FINISHED TAKING THE STUDY DRUG
When you are finished taking the study therapy you will have a repeat physical exam, CT scans 
and blood tests within about 30 days after the last dose.  We will continue to collect information 
from CT scans or other tests to monitor your disease if you come off treatment for a reason other 
than a worsening or progression of your disease.  If you are having side effects related to the 
ruxolitinib, we may continue to follow you until these side effects improve or until you start 
another treatment.  After this time, you will be taken off study.   
IRB NUMBER: 13C0006
IRB APPROVAL DATE: 01/11/2021


PATIENT IDENTIFICATION
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BIRTH CONTROL
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how ruxolitinib would affect your baby or your unborn child. If you are a woman 
who can become pregnant, you will need to practice an effective form of birth control before 
starting study treatment, during study treatment, and for 1 week after you finish study treatment.  
If you think that you are pregnant, you should tell your study doctor or nurse at once.  
Effective forms of birth control include:
•
abstinence 

intrauterine device (IUD)
•
hormonal [birth control pills, injections, or implants]
•
tubal ligation
•
vasectomy
RISKS OR DISCOMFORTS OF PARTICIPATION
What side effects or risks can I expect from being in this study? 
Ruxolitinib is generally well tolerated in patients with primary myelofibrosis. Below is a list of 
the side effects people have experienced who have taken this drug:
Likely:

Anemia (lowered numbers of red blood cells) that may require blood transfusion

Decreased platelets (aid in blood clotting) 

Lowered numbers of a type of infection-fighting white blood cells (leukocytes, 
granulocytes and lymphocytes)

Dizziness
Unlikely:
•
Headaches
•
Infections (bacterial, viral, fungal)
•
Weight gain
•
Flatulence (increased bowel gas)
•
Abnormal liver blood tests
•
Elevation of blood cholesterol level
•
Increased bruising
Rare:
•
Drug infusion reactions
Risks of blood sampling:  
The blood samples collected as part of this study are not expected to produce any important 
decrease in the total amount of blood in your body. Side effects may include pain and discomfort, 
IRB NUMBER: 13C0006
IRB APPROVAL DATE: 01/11/2021


PATIENT IDENTIFICATION
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bruising, and rarely inflammation of the vein, bleeding or infection. Additionally, some patients 
can experience light-headedness or fainting.
Risks associated with biopsy of tumor, bone marrow and skin samples:  

Bone marrow: These procedures usually cause only brief discomfort at the site from which 
the biopsy is taken.  Rarely, infection or bleeding may occur at the needle site.  A numbing 
agent that can cause a stinging or burning sensation may be injected at the site of your bone 
marrow biopsy.  The biopsy needle will go through the skin into the bone and may produce 
a brief, sharp pain.  As the bone marrow liquid is taken from the bone, there may be a brief, 
sharp pain.  Since the inside of the bone cannot be numbed, this procedure may cause some 
discomfort, however not all patients experience discomfort.  The possible side effects 
associated with a bone marrow biopsy include pain, bleeding, bruising, and infection, as 
well as a reaction to the numbing agent.  

Optional Tumor biopsy: Once treatment is complete as part of follow-up assessments, you 
may agree to the biopsy now and change your mind later. If at any time you do not want to 
have a biopsy done, please tell us, it will not affect your care. If you agree to have the 
biopsy, you will be asked to sign a separate procedure consent before you have the 
procedure(s). The likely side effects include discomfort or pain, redness, swelling, and/or 
bruising at the site of the needle insertion.  Bleeding from the site of the needle insertion is 
a less likely risk.  Rarely, significant infection or bleeding from this procedure, allergic 
reaction to the anesthetic, or formation of a scar at the site of needle entry occurs.  If you 
will have sedation with the procedure, these risks will be discussed with you prior to the 
procedure.  You will be asked to sign a separate consent form prior to any biopsy procedure. 

Imaging/scans:  CT scans are used to monitor your disease while you are in this study.  CT 
scans expose you to radiation; the amount depends on the number of body areas scanned.  
In addition, scans involve use of contrast (oral and/or IV) that the cancer may be seen better 
on the images.  You will have scans done (based on your disease at the discretion of your 
doctor) prior to treatment (if these need to be repeated from screening), at Day 29 Cycle 1, 
Day 29 Cycle 2 and every 2 Cycles thereafter during treatment.
The below describes more information about the risks of the contrast and imaging:
o
Contrast Agents:  There is a chance of developing an allergic reaction from the 
contrast material, which may cause symptoms ranging from mild itching or a rash 
to severe difficulty breathing, shock or rarely, death.  The contrast material may 
also cause kidney problems.  The study doctors will do a blood test prior to the test 
to confirm that it is safe you to receive the contrast.
For IV contrast: You may feel discomfort when the contrast material is injected. 
You may feel warm, flushed, get a metallic taste in your mouth or, rarely, may 
make you vomit or feel sick to your stomach.  
For oral contrast:  You may experience vomiting, nausea, cramping, bloating, 
constipation or diarrhea after drinking the contrast.
o
CT Scans:  The CT scanner is a doughnut-shaped machine that uses x-rays to create 
computer pictures showing the inside of your body.  During the procedure, you will 
need to lie still on a table inside the CT machine.  The table will move you in and 
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PATIENT IDENTIFICATION
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out of the machine during the scan and you will be instructed to hold your breath.  
The scan itself will only take a few minutes to complete, the entire visit will take 
about 30 minutes.  For the risks, see “Radiation” below & “Contrast Agent” above.
o
Radiation – CT Scans:  During your participation in this research study, you may 
be exposed to radiation from 8 CT Scans each year and up to 3 CT guided Biopsies. 
The amount of radiation exposure from these procedures is equal to approximately 
12.8 rem. A rem is a unit of absorbed radiation.
Every day, people are exposed to low levels of radiation that come from the sun 
and the environment around them.  The average person in the United States 
receives a radiation exposure of 0.3 rem per year from these sources. This type of 
radiation is called “background radiation.”  This study will expose you to more 
radiation than you get from everyday background radiation. No one knows for 
sure whether exposure to these low amounts of radiation is harmful to your body. 
The CT scans that you get in this study will expose you to the roughly the same 
amount of radiation as 42.7 years’ worth of background radiation. Being exposed 
to too much radiation can cause harmful side effects such as an increase in the 
risk of cancer. The risk depends on how much radiation you are exposed to. Please 
be aware that about 40 out of 100 people (40%) will get cancer during their 
lifetime, and 20 out of 100 (20%) will die from cancer. The risk of getting cancer 
from the radiation exposure in this study is 1.3 out of 100 (1.3%) and of getting 
a fatal cancer is 0.6 out of 100 (0.6%).

Blood draws: The possible side effects of drawing blood include pain, bleeding, bruising, 
dizziness, light-headedness, fainting and, on rare occasions, local blood clot formation or 
infection with redness and irritation of the vein.

Electrocardiogram (ECG/EKG): Some skin irritation can occur where the ECG/EKG 
electrodes are placed. Once the electrodes are placed, the test will begin, is completely 
painless, and generally takes less than a minute to perform. After the test, the electrodes 
are removed. 
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
Taking part in this study may or may not have any effect on your disease or benefit for your general 
condition. We hope that you will get personal medical benefit from taking part in this study, but 
we cannot be certain.  These potential benefits could include shrinking of your tumor or lessening 
of your symptoms, such as the pain caused by your cancer.  Because there is not much information 
about the drug’s effect on your cancer, we do not know if you will benefit from taking part in this 
study, although the knowledge gained from this study may help others in the future who have 
cancer.  
IRB NUMBER: 13C0006
IRB APPROVAL DATE: 01/11/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 12/30/2020
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
ALTERNATIVE APPROACHES OR TREATMENTS
What other choices do I have if I do not take part in this study? 
Instead of being in this study, you have these options:

Getting treatment or care for your cancer without being in a study

Taking part in another study

Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat the 
cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep you 
as active and comfortable as possible.
Please talk to your doctor about these and other options.
STOPPING THERAPY 
Your doctor may decide to take you off this study for the following reasons:
•
if he/she believes that it is in your best interest
•
if your disease comes back during treatment
•
if you have side effects from the treatment that are your doctor thinks are too severe
•
if new information shows that another treatment would be better for you
•
if the study drug, ruxolitinib is no longer available
•
if the FDA, other health authority, or the NIH decide to end the study
•
If you do not follow the study requirements (for instance, if you are not coming for 
your study visits when scheduled).In this case, you will be informed of the reason 
therapy is being stopped.
You can stop taking part in the study at any time. However, if you decide to stop taking part in the 
study, we would like you to talk to the study doctor and your regular doctor first.
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up until that point may still be provided to designated representatives. 
If you withdraw your consent and leave the trial, any samples of yours that have been obtained for 
the study and stored at the NCI can be destroyed upon request. However, any samples and data 
generated from the samples that have already been distributed to other researchers or placed in the 
research databases cannot be recalled and destroyed.
IRB NUMBER: 13C0006
IRB APPROVAL DATE: 01/11/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 12/30/2020
Page 9 of 13
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CONFLICT OF INTEREST
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide.  You may ask your research team 
for a copy of the Protocol Review Guide or for more information.  Members of the research team 
who do not work for NIH are expected to follow these guidelines but they do not need to report 
their personal finances to the NIH.
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies. A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses.  These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes. Your specimens and data will be used for research purposes only and will not benefit 
you.  It is also possible that the stored specimens and data may never be used.  Results of research 
done on your specimens and data will not be available to you or your doctor.  It might help people 
who have cancer and other diseases in the future.  
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers.
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines.
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
On this study, the NCI will cover the cost for some of your expenses.  Some of these costs may be 
paid directly by the NIH and some may be reimbursed after you have paid. The amount and form 
IRB NUMBER: 13C0006
IRB APPROVAL DATE: 01/11/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 12/30/2020
Page 10 of 13
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
of these payments are determined by the NCI Travel and Lodging Reimbursement Policy.   You 
will be given a summary of the policy which provides more information.
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 

You will receive study treatment at no charge to you. This may include surgery, medicines, 
laboratory testing, x-rays or scans done at the Clinical Center, National Institutes of Health 
(NIH), or arranged for you by the research team to be done outside the Clinical Center, 
NIH if the study related treatment is not available at the NIH.

If some tests and procedures are performed outside the NIH Clinical Center, you may have 
to pay for these costs if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
NIH Clinical Center.

Once you have completed taking part in the study, medical care will no longer be provided 
by the NIH Clinical Center.
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
IRB NUMBER: 13C0006
IRB APPROVAL DATE: 01/11/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 12/30/2020
Page 11 of 13
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
IRB NUMBER: 13C0006
IRB APPROVAL DATE: 01/11/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 12/30/2020
Page 12 of 13
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Kevin Conlon, 
M.D., conlonkc@mail.nih.gov, 240-760-6087. You may also call the NIH Clinical Center Patient 
Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you 
have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 13C0006
IRB APPROVAL DATE: 01/11/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 12/30/2020
Page 13 of 13
CC pre rCR ICF template v. 05.05.2020
MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: 
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 13C0006
IRB APPROVAL DATE: 01/11/2021