Clinical trial NCT02400463
Conditions: Hemophagocytic Syndrome (HPS)
Sponsor: University of Michigan Rogel Cancer Center
Start date: 2016-02-05; Completion date: 2020-01-07
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a pilot study to determine the efficacy of Ruxolitinib in secondary hemophagocytic syndrome. The primary objective is to assess the efficacy of ruxolitinib 15 mg PO twice daily in patients with HPS. The primary endpoint is overall survival at two months.

Detailed description:
Hemophagocytic Syndrome (HPS) is a disorder characterized by pathological activation of the immune system resulting in a systemic disorder characterized by excessive cytokine production and macrophage activation, culminating in cytopenias and evidence of hemophagocytosis on tissue specimens. The disorder can be sporadic or familial due to one of several mutations and is primarily seen in the pediatric population, with a reported incidence of 1 case per 3000 admissions. The actual incidence in adults is unknown and can be rarely sporadic, or secondary to viral infections, malignancy, or autoimmune disease.

HPS is a universally fatal disease if untreated. In adults, the median survival has been reported to be less than 2 months if diagnosis and treatment is delayed. Adult patients are treated with pediatric protocols with early institution of etoposide and steroids and consolidation with allogeneic stem cell transplant in appropriately selected patients if a familial form is identified. Other treatment strategies have been attempted, including rituximab, infliximab, entaracept, tocilizumab, and alemtuzumab. These anecdotal reports highlight the therapeutic potential of cytokine-targeted therapies in this disorder.

This is a pilot study to determine the efficacy of Ruxolitinib in secondary hemophagocytic syndrome. The primary objective is to assess the efficacy of ruxolitinib 15 mg PO twice daily in patients with HPS. The primary endpoint is overall survival at two months.

Patients will receive Ruxolitinib at 15 mg twice daily orally either on an empty stomach or with food for 4 weeks (28 days) in a 4 week (28 day) cycle. Ruxolitinib will be administered in continuous 28-day cycles.

In the absence of treatment delays or cessation due to adverse events, treatment may continue indefinitely or until one of the following criteria applies:

* Disease progression.
* Intercurrent illness that prevents further administration of treatment.
* The investigator considers it, for safety reasons, to be in the best interest of the patient.
* Unacceptable adverse events such as any toxicity or other issue that causes a delay of study drug administration by more than 4 weeks.
* General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator.
* Patient decision to withdraw from treatment (partial consent) or from the study (full consent.
* Death.

Patients will be followed for toxicity for 30 days after treatment has been discontinued or until death, whichever occurs first.

Arms: arm 1: Ruxolitinib 15 mg by mouth twice daily.

For patients unable to ingest tablets, ruxolitinib suspended in water may be administered through a nasogastric (NG) or percutaneous endoscopy gastrostomy (PEG) tube.
Interventions: intervention 1: Ruxolitinib
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 






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TABLE OF CONTENTS 
1.
INTRODUCTION ............................................................................................................................................................... 7 
1.1 
HEMOPHAGOCYTIC SYNDROME ......................................................................................................................................................................................... 7 
1.2 
RUXOLITINIB (RUXOLITINIB) ............................................................................................................................................................ 7 
1.2.1 
Preclinical Data ................................................................................................................................................................... 7 
1.2.2 
Clinical Data .......................................................................................................................................................................... 8 
1.2.3 
Clinical Pharmacokinetics ............................................................................................................................................... 9 
1.3 
BACKGROUND AND RATIONALE...................................................................................................................................................................................... 10 
2.
OBJECTIVES .................................................................................................................................................................... 12 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................................................................................................ 12 
2.1.1 
Primary Endpoint ............................................................................................................................................................. 12 
2.2 
SECONDARY OBJECTIVE(S) ..............................................................................................................................................................12 
3.
STUDY DESIGN .............................................................................................................................................................. 13 
3.1 
STUDY DESIGN INCLUDING DOSE ESCALATION / COHORTS ............................................................................................................................... 13 
3.2 
NUMBER OF SUBJECTS ......................................................................................................................................................................................................... 13 
3.3 
REPLACEMENT OF SUBJECTS ............................................................................................................................................................................................ 13 
3.4 
EXPECTED DURATION OF SUBJECT PARTICIPATION ............................................................................................................................................ 13 
3.4.1 
Duration of Therapy ........................................................................................................................................................ 13 
3.4.2 
Duration of Follow Up ..................................................................................................................................................... 14 
4.
PATIENT SELECTION ................................................................................................................................................... 15 
4.1 
INCLUSION CRITERIA ............................................................................................................................................................................................................ 15 
4.2 
EXCLUSION CRITERIA ........................................................................................................................................................................................................... 15 
4.3 
INCLUSION OF WOMEN AND MINORITIES ................................................................................................................................................................. 16 
5.
REGISTRATION ............................................................................................................................................................. 17 
6.
TREATMENT PLAN ....................................................................................................................................................... 18 
6.1 
AGENT ADMINISTRATION .................................................................................................................................................................................................. 18 
6.1.1 
Ruxolitinib Administration ........................................................................................................................................... 18 
6.2 
GENERAL CONCOMITANT MEDICATIONS AND SUPPORTIVE CARE GUIDELINES ................................................................................... 18 
6.3 
DURATION OF FOLLOW UP ............................................................................................................................................................................................... 19 
7.
DOSING DELAYS / DOSE MODIFICATIONS .......................................................................................................... 20 
8.
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ......................................................................... 22 
8.1 
ADVERSE EVENTS AND POTENTIAL RISKS ................................................................................................................................................................ 23 
8.1.1 
Ruxolitinib-related Adverse Effects ........................................................................................................................... 24 
9.
DEFINITIONS .................................................................................................................................................................. 25 
9.1 
ADVERSE EVENTS .................................................................................................................................................................................................................. 25 
9.2 
SERIOUS ADVERSE EVENTS .............................................................................................................................................................................................. 26 
9.3 
EXPECTEDNESS........................................................................................................................................................................................................................ 27 
9.4 
ATTRIBUTION ........................................................................................................................................................................................................................... 27 
9.5 
REPORTING PROCEDURES FOR ALL ADVERSE EVENTS ...................................................................................................................................... 28 
9.5.1 
Serious Adverse Event Reporting Procedures ........................................................................................................ 28 
9.5.2 
Incyte Reporting ................................................................................................................................................................ 28 
9.5.3 
FDA Reporting .................................................................................................................................................................... 29 
10.
PHARMACEUTICAL INFORMATION ....................................................................................................................... 31 


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10.1 
INVESTIGATIONAL AGENT .......................................................................................................................................................................................... 31 
10.1.1 
Ruxolitinib ...................................................................................................................................................................... 31 
11. CORRELATIVE / SPECIAL STUDIES ........................................................................................................................ 33 
11.1 
BACKGROUND ................................................................................................................................................................................................................... 33 
11.2 
RATIONALE FOR ANALYSIS ........................................................................................................................................................................................ 33 
11.3 
COLLECTION OF SPECIMENS ...................................................................................................................................................................................... 33 
12. STUDY PARAMETERS AND CALENDAR ................................................................................................................. 33 
12.1 
STUDY PARAMETERS ..................................................................................................................................................................................................... 34 
12.1.1 
Screening Evaluation ................................................................................................................................................. 34 
12.2 
CALENDAR .......................................................................................................................................................................................................................... 35 
13. MEASUREMENT OF EFFECT ...................................................................................................................................... 36 
13.1 
RESPONSE EVALUATION .............................................................................................................................................................................................. 36 
13.1.1 
Definitions ...................................................................................................................................................................... 36 
13.1.2 
Disease Parameters .................................................................................................................................................... 36 
13.1.3 
Response Criteria ........................................................................................................................................................ 36 
13.1.4 
Duration of Response ................................................................................................................................................. 37 
14. RECORDS TO BE KEPT / REGULATORY CONSIDERATIONS ........................................................................... 37 
14.1 
DATA REPORTING ........................................................................................................................................................................................................... 37 
14.2 
REGULATORY CONSIDERATIONS ............................................................................................................................................................................. 37 
14.2.1 
Written Informed consent ....................................................................................................................................... 37 
14.2.2 
Subject Data Protection............................................................................................................................................ 38 
14.2.3 
Acessing Electronic Medical Records for Universityof Michigan Hospital and Health 
Systems ................................................................................................................................................................................................... 38 
14.2.4 
Retention of records ................................................................................................................................................... 38 
14.2.5 
Audits and inspections .............................................................................................................................................. 38 
14.2.6 
Data Safety and Monitoring Plan ......................................................................................................................... 39 
15. STATISTICAL CONSIDERATIONS............................................................................................................................. 40 
15.1 
SAMPLE SIZE ..................................................................................................................................................................................................................... 40 
15.2 
ANALYSES ........................................................................................................................................................................................................................... 40 
16. REFERENCES .................................................................................................................................................................. 42 
17. APPENDIX A .................................................................................................................................................................... 45 


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SCHEMA 
Pilot study to determine the efficacy of Ruxolitinib in secondary hemophagocytic syndrome. 
 
STUDY SYNOPSIS 
 
Disease : Secondary Hemophagocytic Syndrome (HPS) 
 
Primary objective: To assess the efficacy of ruxolitinib 15 mg PO twice daily in patients with HPS. 
Primary endpoint: Overall survival at 2 months. 
Secondary objectives: 
1) To assess the safety and tolerability of ruxolitinib in patients with HPS. 
2) To determine the response rate, duration of response, progression-free survival, and overall survival in 
ruxolitinib treated subjects. 
Exploratory objectives: 
To assess inflammatory cytokines and markers of T-cell/macrophage activation (i.e. cytokines, sIL-2R, 
sCD163) as predictive biomarkers. 
Inclusion Criteria: 
1) Patients, or their legally authorized representative, must voluntarily provide written IRB-approved 
informed consent. 
2) Males and females, 18 years of age or older at the time of enrollment. 
3) Patients must meet the diagnostic criteria for HPS (at least 5 of the following): 
-fever 
-splenomegaly 
-cytopenia involving ≥2 cell lines (Hemoglobin <9 g/dL; platelets <100,000/µL; absolute 
neutrophil count <1000/µL) 
-hypertriglyceridemia or hypofibrinogenemia 
-tissue demonstration of hemophagocytosis 
-low or absent NK cell activity 
-serum ferritin ≥3000 ug/L 
-soluble IL-2 receptor (CD25) >2400 U/mL. 
4) In the investigator’s opinion, the patient has the ability to participate fully in the study and comply with 
all its requirements. 
Exclusion criteria: 
1) CNS involvement 
2) Malabsorption 
3) Pregnant or lactating female: all females of child-bearing potential must have a negative serum 
pregnancy test within 7 days of treatment 
4) Has received any prior systemic therapy, excluding corticosteroids, within 7 days of treatment. 


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5) Estimated creatinine clearance <15mL/min 
6) No active malignancy at the time of enrollment, except nonmelanoma skin cancers or carcinoma in 
situ. Patients with a prior history of malignancy are eligible if their malignancy has been definitely treated 
or is in remission and does not require ongoing adjuvant or cancer-directed therapies. 
7) Active hepatitis B or hepatitis C or known HIV infection. 
8) Known (and biopsy-confirmed) liver cirrhosis; or, a reported history of liver cirrhosis with a model for 
end-stage liver disease (MELD) score >20. 
 
1. 
INTRODUCTION 
1.1 
Hemophagocytic Syndrome 
Hemophagocytic Syndrome (HPS) is a disorder characterized by pathological activation of 
the immune system resulting in a systemic disorder characterized by excessive cytokine 
production and macrophage activation, culminating in cytopenias and evidence of 
hemophagocytosis on tissue specimens. The disorder can be sporadic or familial due to one 
of several mutations and is primarily seen in the pediatric population, with a reported 
incidence of 1 case per 3000 admissions1. The actual incidence in adults is unknown and can 
be rarely sporadic, or secondary to viral infections, malignancy, or autoimmune disease. 
 
HPS is a universally fatal disease if untreated. In adults, the median survival has been reported to 
be less than 2 months if diagnosis and treatment is delayed2. Adult patients are treated with 
pediatric protocols with early institution of etoposide and steroids and consolidation with 
allogeneic stem cell transplant in appropriately selected patients if a familial form is identified 3. 
Other treatment strategies have been attempted, including rituximab4, infliximab5, entaracept6, 
tocilizumab7, and alemtuzumab8. These anecdotal reports highlight the therapeutic potential of 
cytokine-targeted therapies in this disorder. 
 
1.2 
Ruxolitinib 
 
1.2.1 
Preclinical Data 
 
Ruxolitinib (INCB018424 phosphate, INC424, ruxolitinib phosphate) represents a novel, 
potent, and selective inhibitor of JAK1 (Janus kinase 1) (inhibition concentration 50% 
[IC50]=3.3 ± 1.2 nM) and JAK2 (IC50=2.8 ± 1.2 nM) with modest to marked selectivity 
against TYK2 (tyrosine kinase 2) (IC50=19 ± 3.2 nM) and JAK3 (IC50=428 ± 243 nM), 
respectively. Ruxolitinib interferes with the signaling of a number of cytokines and growth 
factors that are important for hematopoiesis and immune function9-11. 
 
JAK signaling involves recruitment of signal transducers and activators of transcription 
(STATs) to cytokine receptors, activation, and subsequent localization of STATs to the 
nucleus leading to modulation of gene expression. Dysregulation of the JAK-STAT pathway 
has been associated with several types of cancer and increased proliferation and survival of 
malignant cells12-23. In particular, this pathway may be dysregulated in the majority of 


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patients with Philadelphia chromosome negative myeloproliferative neoplasms (MPNs, 
including myelofibrosis [MF] and polycythemia vera [PV]), suggesting that JAK inhibition 
may be efficacious in these diseases. 
 
During the Phase I and Phase II development program, ruxolitinib was assessed in healthy 
volunteers, subjects with various degrees of renal or hepatic impairment, in patients with 
rheumatoid arthritis, prostate cancer, multiple myeloma (MM), MF, PV and essential 
thrombocythemia (ET). Ruxolitinib is currently approved for the treatment of MF/ PV/ET, 
and is currently under development for the treatment of other hematologic malignancies, and 
solid tumors. Two pivotal Phase III trials in MF patients have been completed and one in PV 
patients is ongoing. 
 
 
1.2.2 
Clinical Data 
 
Ruxolitinib is a potent, selective ATP-competitive inhibitor of JAK1 and JAK2 kinases, with an 
IC50 of 3.3nM and 2.8nM, respectively. Ruxolitinib inhibits JAK signaling by targeting the 
cytokines that support transformed cells and are responsible for constitutional symptoms. It 
arrests growth factor signaling by inhibiting downstream STAT phosphorylation. Ruxolitinib has 
been administered to over 180 healthy volunteers as single, repeat single, or multiple doses of up 
to 10 days duration. Ruxolitinib has been administered to approximately 450 subjects with MF 
for periods of up to > 24 months, and over 100 subjects with prostate cancer, multiple myeloma, 
polycythemia vera or essential thrombocythemia for periods of up to > 24 months. In healthy 
volunteer studies, a transient, reversible decrease in neutrophil count has frequently been seen 
following dosing, which reverses after 12 to 24 hours off drug, suggestive that the neutropenia 
may reflect an effect of ruxolitinib blocking IL-6 signaling and causing neutrophil margination 
on blood vessel walls. In a repeat dose healthy volunteer study, neutropenia of any severity grade 
was seen in 22% of placebo subjects, 11% of subjects receiving 50 mg qd, 67% of subjects 
receiving 100 mg qd, 13% of subjects receiving 15 mg bid, 33% of subjects receiving 25 mg bid 
and 67% of subjects receiving 50 mg bid. Importantly, these neutropenia events were of Grade 1 
or Grade 2 severity with a single instance of severe Grade 4 neutropenia that led to 
discontinuation of study drug in 1 subject receiving ruxolitinib at 50 mg bid (highest dose). The 
maximum tolerated dose in healthy volunteers was determined to be 25 mg bid and no dose 
limiting toxicities (DLT) were seen at 100 mg qd. A definitive QT study was carried out in 50 
healthy volunteers, evaluating the effects of single doses of 25 mg or 200 mg ruxolitinib 
compared with placebo and 400 mg moxifloxacin (positive control). The overall conclusion was 
that there appeared to be no adverse impact on ventricular repolarization (no increase in QTcF) 
and little change in heart rate, QRS duration, and a slight, non-clinically significant, increase in 
PR interval with the administration of ruxolitinib. This agent is currently FDA approved for the 
treatment of patients with intermediate to high-risk myelofibrosis, including primary 
myelofibrosis, post-Polycythemia Vera myelofibrosis and Post-Essential Thrombocytopenia 
myelofibrosis based on pre-clinical activity in cellular assays driven by JAK2V617F and on the 
results of the phase III studies COMFORT-1 and COMFORT-2 24,25. In those trials, the agent 
was continuously dosed at 15-20mg PO twice daily (BID); currently, depending on platelet 
count, ruxolitinib is FDA approved from 5 mg BID to a maximum dose of 25mg BID. To further 
demonstrate the tolerability of this agent in other disease settings; pilot studies have 


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demonstrated , ruxolitinib was well tolerated in patients with psoriasis and rheumatoid arthritis 
studies 26. Ruxolitinib use has been associated with myelosuppression, thrombocytopenia, and 
anemia in patients with myelofibrosis. Other documented side effects include dizziness, 
headaches, bruising and tranaminitis. 
 
1.2.3 
Clinical Pharmacokinetics 
 
Twelve Phase I , five Phase II, and two Phase III clinical studies were conducted to explore the 
clinical pharmacology of ruxolitinib in healthy volunteers and in patients with MF, ET, PV, 
subjects with renal or hepatic impairment, prostate cancer, MM or rheumatoid arthritis (RA). 
• 
Oral absorption of ruxolitinib is rapid and nearly complete, with ≥95% absorption 
indicating high in vivo permeability in the human gastrointestinal tract, consistent with a 
Biopharmaceutical Classification System (BCS) Class I compound. Mean peak plasma 
concentrations (Cmax) is achieved 1-2 h post-dose. 
• 
The effect of food on ruxolitinib exposure is minimal and is not expected to be clinically 
significant; as a result, the drug may be administered either with or without food. 
• 
Dose proportional exposure is observed between 5 and 200 mg dose range with linear 
pharmacokinetics (PK). 
• 
Plasma protein binding is approximately 97% in vitro. There is moderate distribution to 
organs and tissues with no long-term retention of drug-related material in preclinical species and 
limited drug penetration into the central nervous system (CNS) or across the blood-brain barrier. 
• 
There is >95% [14C] drug recovery in a mass balance study with 74% and 22% of the 
dose excreted in urine and feces of healthy subjects, respectively. Less than 1% of the 
administered dose is recovered in urine and feces as unchanged parent drug. 
• 
The mean terminal elimination half-life is ~3 h with no appreciable accumulation of 
either parent or metabolites with twice daily dosing. 
• 
Metabolism is predominantly via the cytochrome P450 isozyme CYP3A4 to yield 
oxygenated and subsequent conjugated metabolites. 
• 
Oxidative metabolites of ruxolitinib retain pharmacological activity albeit with one half 
to one fifth of the activity of the parent compound. Ex vivo pharmacokinetic/pharmacodynamic 
(PK/PD) analysis indicates that the sum total of 8 active metabolites contribute to 18% of the 
overall PD activity of ruxolitinib. 
• 
When administering ruxolitinib with strong CYP3A4 inhibitors, the total daily dose 
should be reduced by approximately 50%. 
• 
No dose adjustment is necessary when co-administering ruxolitinib with strong CYP3A4 
inducers. 
• 
In patients with severe [creatinine clearance (Clcr) < 30 mL/min] and moderate renal 
impairment (Clcr = 30 - 49 mL/min), the recommended starting dose based on platelet count 
should be reduced by approximately 50% to be administered twice a day. Patients on 
hemodialysis should initiate ruxolitinib with a single dose of 15 mg or 20 mg based on platelet 
counts with subsequent single doses only on hemodialysis days and following each hemodialysis 
session. Ruxolitinib doses should be titrated based on individual safety and efficacy. 
• 
In patients with mild, moderate or severe hepatic impairment, the recommended starting 
dose based on platelet count should be reduced by approximately 50% with subsequent dose 
titration based on individual safety and efficacy. 


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• 
Baseline elevations in inflammatory markers such as tumor necrosis factor alpha (TNFα), 
interleukin (IL)-6, and C-reactive protein (CRP) noted in subjects with MF were associated with 
constitutional symptoms such as fatigue, pruritus, and night sweats. Decreases were observed in 
these markers over the 24 weeks of treatment with ruxolitinib, with no evidence that subjects 
became refractory to the effects of ruxolitinib treatment. 
 
1.3 
Background and Rationale 
 
Hemophagocytic lymphohistiocytosis (HLH) or hemophagocytic syndrome (HPS) is an 
inflammatory disorder associated with the activation and expansion of reactive (i.e. non- 
clonal) macrophages. Primary HPS is associated with mutations (e.g. ≈50% of familial cases 
are caused by perforin gene mutations) that culminate in defective natural killer (NK) cell 
and cytotoxic T-lymphocyte (CTL) degranulation and impaired killing of target cells. In 
these patients, a triggering event (e.g. viral infection) is associated with immune 
dysregulation that is characterized by the overproduction of proinflammatory cytokines (e.g. 
IL-12 and IFN-γ) and tissue accumulation of activated T-cells and macrophages. 27-31 These 
immunologic changes are associated with protean clinicopathologic manifestations, 
including: fever, hepatosplenomegaly, hyperferritinemia (due to macrophage activation), 
cytopenias (caused by phagocytosis - “hemophagocytosis”- of hematopoietic cells), 
hypofibrinogenemia, and multi-organ failure.32 Predominantly observed in children, primary 
HPS is initially managed with supportive care and chemotherapy, but is only curable in 
approximately 60% of children with allogeneic stem cell transplantation.3,33 In contrast to 
primary HPS, secondary HPS is more common in adults and is associated with a variety of 
triggers, including infection (often viral), autoimmunity, or hematologic malignancies 
(commonly non-Hodgkin lymphomas).32 For many patients, a precipitating cause cannot be 
identified. Apart from disease-specific therapies for patients in which a precipitating cause 
can be identified (e.g. non-Hodgkin lymphoma directed therapies for those with an 
underlying lymphoma), no HPS-specific therapies are currently available for the majority of 
adults with HPS. Therefore, these patients are frequently treated with a regimen originally 
developed for use in children with primary HPS that includes combinations of steroids, 
immunuosuppressive agents (i.e. cyclosporine A), and etoposide. Not surprisingly, secondary 
HPS in adults is associated with high morbidity and mortality. In one of the largest single 
center studies, the overall mortality was 67%, with a median time from diagnosis to death of 
35 (range: 5-160) days.2 Therefore, improved therapeutic strategies for adults with secondary 
HPS are greatly needed. 
Both pre-clinical and clinical data highlight the central role of proinflammatory cytokines, 
particularly IFN-γ, that are dependent upon the JAK/STAT signaling in HPS pathogenesis. 27- 
31 The disease biology and clinical manifestations associated with HPS are driven by this 
underlying “cytokine storm”, culminating in T-cell accumulation and macrophage activation. 
Therefore, inhibition of JAK/STAT signaling may represent a novel therapeutic approach. As 
ruxolitinib inhibits upstream Janus kinases (JAK) at nanomolar concentrations, and is well 
tolerated in myelofibrosis patients (and alleviates signs/symptoms associated with 
hypercytokinemia), we sought to determine whether it inhibits STAT1 phosphorylation in 
IFN-γ treated macrophages. Not surprisingly, ruxolitinib (1 μM) was able to inhibit STAT1 
phosphorylation in treated macrophages. Therefore, ruxolitinib represents a novel therapeutic 


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approach for secondary HPS that has the potential to dramatically change the standard of care 
(and improve outcomes) for these patients. Cytopenias (including thrombocytopenia) 
observed in HPS are secondary to consumption (“hemophagocytosis”) and cytokine- 
mediated suppression, and are not secondary to underlying bone marrow “failure”. Therefore, 
treatment will be initiated at 15 mg po twice daily. 


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2. 
OBJECTIVES 
 
 
2.1 
Primary Objective 
 
To assess the efficacy of ruxolitinib 15 mg PO twice daily in patients with HPS. 
 
2.1.1 
Primary Endpoint 
 
Overall survival at two months. 
 
2.2 
Secondary Objective(s) 
 
To assess the safety and tolerability of ruxolitinib in patients with HPS. 
 
To determine the response rate, duration of response, progression-free survival, and overall 
survival in ruxolitinib treated subjects. 
 
2.3 
Exploratory Objectives 
 
To assess inflammatory cytokines and markers of T-cell/macrophage activation (i.e. 
cytokines, sIL-2R, sCD163) as predictive biomarkers. 


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3. 
STUDY DESIGN 
3.1 
Study design including dose escalation / cohorts 
 
Pilot study to determine the efficacy of Ruxolitinib in secondary hemophagocytic syndrome. 
 
 
3.2 
Number of Subjects 
 
Up to 10 patients meeting the inclusion and exclusion criteria will be enrolled into this pilot 
study. 
 
3.3 
Replacement of Subjects 
 
Subjects who do not receive the first dose of study drug will be replaced. 
 
3.4 
Expected Duration of Subject Participation 
 
3.4.1 
Duration of Therapy 
 
In the absence of treatment delays or cessation due to adverse events, treatment may continue 
indefinitely or until one of the following criteria applies: 
 
• Disease progression. 
 
• Intercurrent illness that prevents further administration of treatment. 
 
• The investigator considers it, for safety reasons, to be in the best interest of the patient. The 
investigator may recommend gradual discontinuation (i.e. ruxolitinib taper) in patients achieving 
a prolonged response (defined as a PR or CR ≥6 months in duration). The rate of a ruxolitinib 
taper, and decisions to dose escalate in the setting of recurrent signs/symptoms, are not specified 
in this protocol, and are at the discretion of the investigator. 
 
• Unacceptable adverse events such as any toxicity or other issue that causes a delay of 
study drug administration by more than 4 weeks. 
 
• General or specific changes in the patient’s condition render the patient unacceptable for 
further treatment in the judgment of the investigator. 
 
• Patient decision to withdraw from treatment (partial consent) or from the study (full 
consent. 
 


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• Death. 
 
• Sponsor reserves the right to temporarily suspend or prematurely discontinue this study. 
 


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The date and reason for discontinuation must be documented. Every effort should be made 
to complete the appropriate assessments. 
 
 
3.4.2 
Duration of Follow Up 
 
Patients will be followed for efficacy and toxicity for 30 days after treatment has been 
discontinued. Thirty days after treatment discontinuation, progression-free and overall 
survival will be collected every 6-12 months by a review of the clinical notes from the 
treating investigator or other provider. Patients will be followed for up to five years or until 
the end of the study or death, whichever occurs first. 
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study 
participation will be recorded and reported immediately per IRB & FDA reporting 
guidelines. 


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4. 
PATIENT SELECTION 
 
A checklist will be used to confirm a patient’s eligibility. The check list will include the 
inclusion and exclusion criteria listed below, and must be completed for each patient and must 
be signed and dated by the treating physician. 
 
 
4.1 
Inclusion Criteria 
 
Patients must meet all of the following inclusion criteria to be eligible for enrollment: 
 
1. Patients, or their legally authorized representative, must voluntarily provide written 
IRB-approved informed consent. 
 
2. Males and females, 18 years of age or older at the time of enrollment. 
 
3. Patients must meet the diagnostic criteria for HPS (at least 5 of the following): 
-fever 
-splenomegaly 
-cytopenia involving ≥2 cell lines (Hemoglobin <9 g/dL; platelets <100,000/µL; absolute 
neutrophil count <1000/µL) 
-hypertriglyceridemia or hypofibrinogenemia 
-tissue demonstration of hemophagocytosis 
-low or absent NK cell activity 
-serum ferritin ≥3000 ug/L 
-soluble IL-2 receptor (CD25) >2400 U/mL. 
 
4. In the investigator’s opinion, the patient has the ability to participate fully in the study 
and comply with all its requirements. 
 
4.2 
Exclusion Criteria 
 
The presence of any of the following will exclude a patient from study enrollment. 
 
1. CNS involvement 
 
2. Malabsorption 
 
3. Known secondary HPS that is otherwise treatable (e.g. non-Hodgkin’s lymphoma). 
 
4. Pregnant or lactating female: all females of child-bearing potential must have a 
negative serum pregnancy test within 7 days of treatment; lactating females must 
discontinue breast feeding. 


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5. Has received any prior systemic therapy, excluding corticosteroids, within 7 days (or 5 
half-lives) of treatment. 
 
6. Estimated creatinine clearance <15 mL/min 
 
7. No active malignancy at the time of enrollment, except nonmelanoma skin cancers or 
carcinoma in situ. Patients with a prior history of malignancy are eligible if their 
malignancy has been definitely treated or is in remission and does not require ongoing 
adjuvant or cancer-directed therapies. 
8. Active hepatitis B or hepatitis C or known HIV infection. 
 
9.  Known (and biopsy-confirmed) liver cirrhosis; or, a reported history of liver cirrhosis 
with a model for end-stage liver disease (MELD) score >20. 
 
 
 
 
4.3 
Inclusion of Women and Minorities 
 
Both men and women and members of all races and ethnic groups are eligible for this trial. 


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5. 
REGISTRATION 
 
All subjects who have been consented are to be registered in an online Database. For those 
subjects who are consented, but not enrolled, the reason for exclusion must be recorded. 


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6. 
TREATMENT PLAN 
 
 
6.1 
Study Drug Administration 
 
Appropriate dose modifications for Ruxolitinib are described in Section 7.0 
 
Reported adverse events and potential risks of Ruxolitinib are described in Section 8.0. 
 
 
TREATMENT REGIMEN DESCRIPTION 
Agent 
Pre-medicate 
/ Precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Ruxolitinib 
None 
15 (mg) 
PO in twice 
daily 
Days 1-28 
28 days 
 
 
6.1.1 
Ruxolitinib Administration 
 
Patients will receive Ruxolitinib at 15 mg twice daily orally either on an empty stomach or 
with food for 4 weeks (28 days) in a 4 week (28 day) cycle. Ruxolitinib will be administered 
in continuous 28-day cycles. For patients unable to ingest tablets, ruxolitinib suspended in 
water may be administered through a nasogastric (NG) or percutaneous endoscopy 
gastrostomy (PEG) tube. Tablets should be suspended (1 tablet in ~40 mL water) in water and 
stirred for 10 minutes and administered within 6 hours of dispersion with an appropriate 
syringe. The NG or PEG tube should be rinsed with ~75 mL water following administration. 
 
 
Ruxolitinib administration must be at least 1 hour before or after any other medications. 
 
 
6.2 
General Concomitant Medications and Supportive Care Guidelines 
 
Because there is a potential for interaction of Ruxolitinib with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must capture 
the concurrent use of all other drugs, over-the-counter medications, or alternative therapies. 
The Principal Investigator should be alerted if the patient is taking any agent known to affect 
CYP3A4. In patients who concurrently take strong CYP3A4 inhibitors and a platelet count of 
at least 50,000 the dose of ruxolitinib should be capped at 10 mg twice daily due to the 
concern for increased serum concentrations of ruxolitinib’s active metabolites. Strong 
CYP3A4 inhibitors, including grapefruit juice, should be avoided whenever possible. 


20 | P a ge  
 
Patients should receive full supportive care, including transfusions of blood and blood products, 
cytokines, antibiotics, anti-emetics, etc when appropriate. 
 
 
6.3 
Duration of Follow Up 
 
Patients will be followed for toxicity for 30 days after treatment has been discontinued or 
until death, whichever occurs first. Patients will be followed for survival for up to five 
years or until the end of the study or death, whichever occurs first. 
 
The clinical course of each event will be followed until resolution, stabilization, or until it 
has been determined that the study treatment or participation is not the cause for a maximum 
of 6 months. 
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study 
participation will be recorded and reported immediately per IRB and FDA reporting 
guidelines. 


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7. 
DOSING DELAYS / DOSE MODIFICATIONS 
 
Ruxolitinib will be dosed twice daily throughout the study. In the event a dose is missed, the 
subject should be instructed to take the next scheduled dose. 
 
Dose Level 
Ruxolitinib 
(BID schedule) 
CrCl ≥60 
CrCl 15-59 
Level 1 (starting dose) 
15 mg 
10 mg 
Level -1 (reduction) 
10 mg 
5 mg 
Level -2 (reduction) 
5 mg 
Hold 
 
Event Name 
Nausea 
Grade of Event 
Management/Next Dose for Ruxolitinib 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1. Resume at same dose level. 
Grade 3 
Hold * until < Grade 2. Resume at one dose level 
lower, if indicated. ** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >4 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management: antiemetics. 
 
 
Event Name 
Vomiting 
Grade of 
Event 
Management/Next Dose for Ruxolitinib 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1. Resume at same dose level. 
Grade 3 
Hold* until < Grade 2. Resume at one dose level 
lower, if indicated. ** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >4 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management: antiemetics; in the event a dose of ruxolitinib is 
vomited, it is recommended that subjects resume ruxolitinib with the next 
scheduled dose. 


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Event Name 
Diarrhea 
Grade of 
Event 
Management/Next Dose for Ruxolitinib 
≤ Grade 1 
No change in dose 
Grade 2 
Hold until ≤ Grade 1. Resume at same dose level. 
Grade 3 
Hold* until < Grade 2. Resume at one dose level 
lower, if indicated. ** 
Grade 4 
Off protocol therapy 
*Patients requiring a delay of >4 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
Recommended management: Loperamide antidiarrheal therapy 
Dosage schedule: 4 mg at first onset, followed by 2 mg with each loose 
motion until diarrhea-free for 12 hours (maximum dosage: 16 mg/24 hours) 
Adjunct anti-diarrheal therapy is permitted and should be recorded when 
used. 
 
 
Event Name 
Thrombocytopenia 
Platelet Count 
Management/Next Dose for Ruxolitinib 
50,000-100,000 
Level 1 Ruxolitinib 
35,000-49,999 
Level -1 (reduction) if determined to be secondary to 
Ruxolitinib per the discretion of the investigator or 
PI. 
20,000-34,999 
Level -2 (reduction) 
Less than 
20,000 
Hold* until platelet count is at least 50,000 then 
resume at one dose level lower if determined to be 
secondary to Ruxolitinib per the discretion of the 
investigator or PI. Transfuse as needed for bleeds. 
*Patients requiring a delay of >4 weeks should go off protocol therapy. 
**Patients requiring > two dose reductions should go off protocol therapy. 
 
Treatment will be discontinued for any patient that experiences a Grade 4 non-hematologic 
toxicity that is possibly related to ruxolitinib. 
 
Dose adjustments for grades 1-3 non-hematologic toxicity that is possibly related to 
ruxolitinib will be at the discretion of the investigator or PI. 


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With the exception of thrombocytopenia (see table above), dose adjustments for grades 1-4 
hematologic toxicity that is possibly related to ruxolitinib will be at the discretion of the 
investigator or PI. 
 
8. 
ADVERSE EVENTS 
 
The clinical database (safety set based on cut-off for COMFORT-II: 04-Jan-2011; cut-off for 
COMFORT-I: 02-Nov-2010) in solid tumor and hematologic malignancies consists of 787 
patients treated in 6 studies evaluating patients with MF (n=679), prostate cancer (n=22), MM 
(n=13), ET and PV (n=73), of whom 617 patients received ruxolitinib: 
• 
Hematologic events are the most frequently reported adverse events (AEs) and include 
thrombocytopenia and anemia. The majority of these AEs are of Grades 1-2, seldom led to study 
drug discontinuation (<1% of patients), and can be usually managed through dose reduction or 
interruption. 
• 
Increased rates of anemia resulted in an increase in packed red blood cell (PRBC) 
transfusion requirements for some ruxolitinib-treated patients. Platelet transfusions while on 
ruxolitinib were rare. 
• 
Biochemistry laboratory abnormalities of alanine aminotransferase (ALT), aspartate 
aminotransferase (AST) and cholesterol were reported. The majority of these increases were 
Grade 1 or 2. No Grade 4 events were reported. 
• 
The Phase III safety dataset in MF patients (COMFORT-I, COMFORT-II) shows that it 
is appropriate to individually adjust doses for patients according to their tolerability and efficacy. 
However, 124 patients (41.2%) required no dose reduction, indicating the 
starting dose was appropriate for these individuals. Of the 177 patients who had dose 
reduction, 91 patients (51%) had only one reduction in dose. Interruptions of dosing were less 
frequent than dose reductions, with 215 patients (71.4%) requiring no dose interruption. Of the 
86 patients who had dose interruptions, 59 patients (19.6%) had only one dose interruption. 
• 
The Phase III data in MF patients (COMFORT-I, COMFORT-II) indicate that the only 
notable imbalances (ruxolitinib versus placebo or best available therapy [BAT]) in AEs related to 
hemorrhagic events were in Grade 1-2 skin and soft tissue bruising which did not lead to dose 
reduction or discontinuation. Similarly, the only notable imbalances (ruxolitinib versus placebo 
or BAT) in AEs related to infections were urinary tract infections and herpes zoster infections. 
Finally, an imbalance between ruxolitinib and BAT was noted in systolic blood pressure with an 
increase of 20 mmHg or more from 
baseline in COMFORT-II (31.5% of patients on at least one visit compared with 19.5% of 
the control-treated patients). 
• 
Cases of tuberculosis have been reported. In addition, one case of progressive multifocal 
leukoencephalopathy has been reported in one patient with myelofibrosis. 
 
The AE profile of the compound has been assessed in 198 healthy volunteers, subjects with 
various degrees of renal (n=32) or hepatic (n=24) impairment, and in patients with RA (n=59) 
receiving ruxolitinib: 
• AEs were, in general, mild and resolved without interventions. 


24 | P a ge  
 
A thorough QT study was conducted in 50 healthy subjects. There was no indication of a 
QT/QTc prolonging effect of ruxolitinib in single doses up to a supra-therapeutic dose of 200 mg 
indicating that ruxolitinib has no effect on cardiac repolarization. 
 
The following is a list of AEs (Section 8.1) and the reporting requirements associated with 
observed AEs (Sections 8.3 and 8.4). 
 
The clinical course of each event will be followed until resolution, stabilization, or until it has 
been determined that the study treatment or participation is not the cause. 
 
Serious adverse events that are still ongoing at the end of the study period will necessitate 
follow-up to determine the final outcome. Any serious adverse event that occurs within 30 days 
after the study period and is considered to be possibly related to the study treatment or study 
participation will be recorded and reported immediately. 
 
8.1 
Adverse Events and Potential Risks 
In a phase III population, the comparison of the control groups to the ruxolitinib patients 
showed that headache was more frequent in ruxolitinib-treated patients (13.6% vs. 6.0% on 
placebo and 5.5% on BAT). Most AEs of headache were Grade 1 or 2. Similarly, dizziness 
(12.0% vs. 6.6% on placebo and 6.8% on BAT) was more frequent in ruxolitinib-treated 
patients, again mostly Grade 1 or 2. When adjusted for patient-year exposure, the differences 
are still present for headache and dizziness. 
 
Weight increase was also more frequent in ruxolitinib-treated patients than in the control 
groups (9.6% vs. 1.3% on placebo and 1.4% on BAT). Although some of these patients had 
co-reported AEs of edema, many had a past medical history of weight loss and the weight 
gain usually gradually accumulated over the course of one year of treatment. The majority of 
weight gain AEs were Grade 1 and 2. It is worth noting that weight gain may be a beneficial 
effect in patients with MF, given the catabolic nature of the disease and the frequency of 
weight loss reported as a constitutional symptom. 
 
Other preferred terms with increased frequency in the ruxolitinib arms included bruising 
(2.6% vs. 1.3% on placebo in COMFORT-I only), contusion (8.6% vs. 5.3% on placebo and 
1.4% on BAT), urinary tract infection (7.3% vs. 4.6% on placebo and 2.7% on BAT), herpes 
zoster (4.0% vs. 0.7% on placebo and 0% on BAT) and flatulence (3.3% vs. 1.3% on placebo 
and 0% on BAT). 
 
Abdominal pain was more frequent in the control groups than in the ruxolitinib group (43% 
on placebo and 13.7% on BAT vs. 12% on ruxolitinib), as were weight decrease (8.6% on 
placebo and 8.2% on BAT vs. 1% on ruxolitinib), early satiety (8.6% on placebo and 0% on 
BAT vs. 0.3% on ruxolitinib) and splenic infarction (6.0% on placebo and 0% on BAT vs. 
1.0% on ruxolitinib). 
 
For COMFORT-I at the Week 144 interim analysis, for subjects initially randomized to 
ruxolitinib, although the frequency of AEs reported increased as expected with increased 


25 | P a ge  
 
duration of exposure and follow-up, the types of TEAEs reported remained consistent with 
what was reported in the initial analysis. Thrombocytopenia/platelet count decrease 
remained the most frequently reported AE (58.1%). Anemia/Hgb decreased was reported in 
84 subjects (54.2%), which was also an expected effect of ruxolitinib. Among the non- 
hematologic TEAEs, the most frequently reported TEAE was fatigue (44.5%) followed by 
diarrhea (35.5%), and peripheral edema (31.0%). 
 
In the ruxolitinib-treated Phase III population, the overall frequency of AEs requiring dose 
reduction or interruption was 59.8%. This frequency was higher than in the control groups 
(placebo: 27.2%, BAT: 15.1%). The most frequently reported AEs requiring dose reduction 
or interruption in ruxolitinib-treated patients were thrombocytopenia (36.9%), platelet count 
decreased (7.6%) and anemia (5.6%). The high frequency for thrombocytopenia is due to 
protocol-mandated dose reductions and interruptions. Although there were no protocol- 
specified guidelines for dose reductions secondary to anemia, some investigators chose to 
reduce a patient’s dose in the setting of anemia to minimize this particular effect of 
ruxolitinib. The frequency of these AEs was higher than in the control groups. All other AEs 
requiring dose reduction or interruption occurred with a frequency of 1.3% or less in the 
ruxolitinib-treated patients. For COMFORT-I at the Week 144 analysis for patients initially 
randomized to ruxolitinib 70 patients (45.2%) had at least 1 AE leading to interruption or 
discontinuation of study drug and 82 (52.9%) had at least 1 AE leading to dose reduction. 
Thrombocytopenia/platelet count decrease was the most common reason for dose reduction 
or discontinuation. 
 
In the Phase III population, at the initial analysis, there were 34 deaths in total, 27 of which 
were on-treatment deaths: 20 deaths in study COMFORT-I (9 in the ruxolitinib group, 11 in 
the placebo group) and 7 deaths in study COMFORT-II (4 in the ruxolitinib group, 3 in the 
BAT group). The reasons for death (infections, intestinal perforation, disease progression and 
events probably due to disease progression, bleedings events) were similar in the ruxolitinib 
and the placebo groups. 
 
8.1.1 
Ruxolitinib-related Adverse Effects 
The following Ruxolitinib side effects are common (occurring in greater than 10%): 
• Cardiovascular: Peripheral edema (22%), elevation in systolic blood 
pressure 
• Central nervous system: Dizziness (15% to 18%), headache (10% to 15%), 
insomnia (12%) 
• Dermatologic: Bruising (19% to 23%) 
• Endocrine & metabolic: Cholesterol increased (17%; grade 2: <1%) 
• Gastrointestinal: Diarrhea (23%), constipation (13%), nausea (13%), 
vomiting (12%) 


26 | P a ge  
 
• Hematologic: Anemia (96%; grade 3: 34%; grade 4: 11%), 
thrombocytopenia due to bone marrow suppression (70%; grade 3: 9%; 
grade 4: 4%), neutropenia (19%; grade 3: 5%; grade 4: 2%) 
• Hepatic: ALT increased (25%; grades 2/3: 2%), AST increased (17%; 
grade 2: <1%) 
The following Ruxolitinib side effects are less common (occurring in less than 
10%): 
• Respiratory: Dyspnea (16%), nasopharyngitis (16%) 
• Gastrointestinal: Flatulence (5%) 
• Genitourinary: Urinary tract infection (9%) 
• Miscellaneous: Herpes zoster infection (2%) 
 
The following Ruxolitinib side effects are rare: 
 
• Cardiac murmur 
• peripheral neuropathy 
• weight gain 
• progressive multifocal leukoencephalopathy (PML) 
• Tuberculosis reactivation 
 
 
 
9. 
DEFINITIONS 
 
 
9.1 
Adverse Events 
 
An adverse event (AE) is any unfavorable or unintended event, physical or psychological, 
associated with a research study, which causes harm or injury to a research participant as a result 
of the participant’s involvement in a research study. The event can include abnormal laboratory 
findings, symptoms, or disease associated with the research study. The event does not necessarily 
have to have a causal relationship with the research, any risk associated with the research, the 
research intervention, or the research assessments. 
 
Adverse events may be the result of the interventions and interactions used in the research; 
the collection of identifiable private information in the research; an underlying disease, 
disorder, or condition of the subject; and/or other circumstances unrelated to the research or 
any underlying disease, disorder, or condition of the subject. In general, adverse events that 


27 | P a ge  
 
are at least partially the result of the interventions and interactions used in the research or the 
collection of identifiable private information in the research;would be considered related to 
the research, whereas adverse events solely related to an underlying disease, disorder, or 
condition of the subject; and/or other circumstances unrelated to the research or any 
underlying disease, disorder, or condition of the subject would be considered unrelated to the 
research. 
 
The significance of an adverse event is used to describe the patient/event outcome or action 
criteria associated with events that pose a threat to a patient’s life or functioning (i.e., 
moderate, severe or life threatening). Based on the National Cancer Institute Guidelines for 
the Cancer Therapy Evaluation Program, severity can be defined by the following grades of 
events: 
 
Grades 1 are mild adverse events. (e.g., minor event requiring no specific medical 
intervention; asymptomatic laboratory findings only; marginal clinical relevance) 
 
Grades 2 are moderate adverse events (e.g., minimal intervention; local intervention; non- 
invasive intervention. 
 
Grades 3 are severe and undesirable adverse events (e.g., significant symptoms requiring 
hospitalization or invasive intervention; transfusion; elective interventional radiological 
procedure; therapeutic endoscopy or operation). 
 
Grades 4 are life threatening or disabling adverse events (e.g., complicated by acute, life- 
threatening metabolic or cardiovascular complications such as circulatory failure, 
hemorrhage, sepsis; life–threatening physiologic consequences; need for intensive care or 
emergent invasive procedure; emergent interventional radiological procedure, therapeutic 
endoscopy or operation). 
 
Grades 5 are fatal adverse event resulting in death. 
 
9.2 
Serious Adverse Events 
A serious adverse event (SAE) is any adverse experience occurring at any dose that results 
in any of the following outcomes: 
• Results in death. 
• Is a life-threatening adverse experience. The term life-threatening in the definition 
of serious refers to an adverse event in which the subject was at risk of death at the 
time of the event. It does not refer to an adverse event which hypothetically might 
have caused death if it were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization.  
Any adverse event leading to hospitalization or prolongation of hospitalization will be 
considered as Serious, UNLESS at least one of the following expectations is met: 
o The admission results in a hospital stay of less than 12 hours OR 


28 | P a ge  
 
o The admission is pre-planned (i.e., elective or scheduled surgery arranged 
prior to the start of the study) OR 
o The admission is not associated with an adverse event (e.g., social 
hospitalization for purposes of respite care. 
However it should be noted that invasive treatment during any hospitalization may 
fulfill the criteria of “medically important” and as such may be reportable as a serious 
adverse event dependent on clinical judgment. In addition where local regulatory 
authorities specifically require a more stringent definition, the local regulation takes 
precedent. 
• Results in persistent or significant disability/incapacity. The definition of 
disability is a substantial disruption of a person’s ability to conduct normal life’s 
functions. 
• Is a congenital anomaly/birth defect. 
• Is an important medical event. Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered a serious 
adverse experience when, based upon appropriate medical judgment, they may 
jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood disease or disorders, or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
9.3 
Expectedness 
Adverse Events can be Expected or Unexpected. 
 
An expected adverse event is an event previously known or anticipated to result from 
participation in the research study or any underlying disease, disorder, or condition of the 
subject. The event is usually listed in the package insert, consent form or research protocol. 
 
An unexpected adverse event is an adverse event not previously known or anticipated to result 
from the research study or any underlying disease, disorder, or condition of the subject. 
 
9.4 
Attribution 
Attribution is the relationship between an adverse event or serious adverse event and the study 
drug. Attribution will be assigned as follows: 
 
• Definite – The AE is clearly related to the study drug. 
• Probable – The AE is likely related to the study drug. 
• Possible – The AE may be related to the study drug. 
• Unlikely – The AE is doubtfully related to the study drug. 
• Unrelated – The AE is clearly NOT related to the study drug. 


29 | P a ge  
 
9.5 
Reporting Procedures for All Adverse Events 
 
All participating investigators will assess the occurrence of AEs throughout the subject’s 
participation in the study. Subjects will be followed for toxicity for 30 days after treatment 
has been discontinued or until death, whichever occurs first. The clinical course of each 
event will be followed until resolution, stabilization, or until it has been determined that the 
study treatment or participation is not the cause. 
 
The investigator is responsible for ensuring that all adverse events observed by the 
investigator or reported by the subject which occur after the subject has been started on the 
investigational agent are fully recorded in the subject’s case report form, subject’s medical 
records, and/or any other institutional requirement. Source documentation must be available 
to support all adverse events. 
 
A laboratory test abnormality considered clinically relevant (e.g., causing the subject to 
withdraw from the study), requiring treatment or causing apparent clinical manifestations, or 
judged relevant by the investigator, should be reported as an adverse event. 
 
The investigator will provide the following for all adverse events: 
• Description of the event 
• Date of onset and resolution 
• Grade of toxicity 
• Attribution of relatedness to the investigational agent 
• Action taken as a result of the event 
• Outcome of event 
 
In this study, descriptions and grading scales found in the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 available at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm will be utilized for 
AE reporting. 
 
 
9.5.1 
Serious Adverse Event Reporting Procedures 
 
Serious adverse events that occur beginning after the subject has been started on the 
investigational agent or within 30 days of the last dose of treatment must be reported to the 
Sponsor Investigator. Serious adverse events will be reported to the IRBMED according to their 
reporting guidelines and to the FDA as detailed in Section 9.5.3. 
 
 
 
9.5.2 
Incyte Reporting 


30 | P a ge  
 
If the SAE is not previously documented in the package insert for the study drug (new 
occurrence) and is thought to be related to the study drug, a manufacturer’s associate may 
urgently require further information from the Investigator or Sponsor for reporting to Health 
Authorities. Incyte will be notified within 24hrs of any IND safety event and will receive a copy 
of the initial and follow up IND Adverse Event reports within 48hrs of submission to regulatory 
authorities. This will be submitted to the following email address: 
IncytePhVOpsIST@incyte.com 
 
9.5.3 
FDA Reporting 
 
The University of Michigan Sponsor Investigator, Ryan Wilcox, as holder of the IND, will be 
responsible for all communication with the FDA. In accordance with 21 CFR 312.32, The 
University of Michigan Sponsor Investigator, Ryan Wilcox is responsible for notifying the FDA 
of SAEs that are serious, unexpected (not listed in the package insert) and judged to be related 
(i.e., possible, probable, definite) to the study drug. Events meeting the following criteria need 
to be submitted to the FDA as Expedited IND Safety Reports. 
 
7 Calendar Day IND Safety Report 
Any unexpected fatal or life-threatening suspected adverse event represent especially important 
safety information and, therefore, must be reported more rapidly to FDA (21 CFR 312.32(c)(2)). 
Any unexpected fatal or life-threatening suspected adverse event must be reported to FDA no 
later than 7 calendar days after the University of Michigan Sponsor Investigator, Ryan Wilcox, 
obtains initial receipt of the information (21 CFR 312.32(c)(2)). The University of Michigan 
Sponsor Investigator, Ryan Wilcox, will complete a Medwatch Form FDA 3500A and notify the 
FDA by telephone or facsimile transmission with the assistance of the Michigan IND/IDE 
Assistance Program (MIAP). 
 
15 Calendar Day IND Safety Report 
The timeframe for submitting an IND safety report to FDA is no later than 15 calendar days after 
the University of Michigan Sponsor Investigator determines that the suspected adverse event or 
other information qualifies for reporting (21 CFR 312.32(c)(1)). This includes any serious, 
unexpected adverse events considered reasonably or possibly related to the investigational agent. 
The University of Michigan Sponsor Investigator, Ryan Wilcox will complete a CTO standard 
SAE Form and notify the FDA by telephone or facsimile transmission with the assistance of 
MIAP. If FDA requests any additional data or information, the University of Michigan Sposor 
Investigator must submit it to FDA as soon as possible, but no later than 15 calendar days after 
receiving the request (21 CFR 312.32(c)(1)(v)). 
 
Follow-up IND Safety Report 
Any relevant additional information that the University of Michigan Sponsor Investigator obtains 
that pertains to a previously submitted IND safety report must be submitted to FDA as a Follow- 
up IND Safety Report without delay, as soon as the information is available (21 CFR 
312.32(d)(2)). The University of Michigan Sponsor Investigator, Ryan Wilcox, will maintain 
records of its efforts to obtain additional information. 


31 | P a ge  
 
 
 
 
 
 
 
 
 
IND Annual Reports 
 
A summary of all IND safety reports submitting during the previous year will be reported to the 
FDA in the annual report by The University of Michigan Sponsor Investigator, Ryan Wilcox, as 
holder of the IND. 
Reporting Serious Problems to FDA 
Medwatch Form FDA 3500A: 
http://www.fda.gov/Safety/MedWatch/HowToReport/DownloadForms/default.htm 
Telephone: 1-800-332-1088 
Fax: 1-800-FDA-0178 


32 | P a ge  
 
10. 
PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or 
commercial agents administered in this study can be found in Section 8. 
 
10.1 
Investigational Agent 
 
Agents are listed in alphabetical order. 
 
10.1.1 
Ruxolitinib 
 
Chemical Name: 
(R)-3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-3- 
cyclopentylpropanenitrile phosphate 
Other Names: 
Ruxolitinib 
 
Classification: 
selective JAK1 and JAK2 inhibitor 
 
Molecular Formula: 
 
Mode of Action: 
Inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 
which mediate the signaling of a number of cytokines and 
growth factors that are important for hematopoiesis and immune 
function 
 
Metabolism: 
In vitro studies suggest that CYP3A4 is the major enzyme 
responsible for metabolism of ruxolitinib. Ruxolitinib is the 
predominant entity in humans representing approximately 60% 
of the drug-related material in circulation. Two major and active 
metabolites were identified in plasma of healthy subjects 
representing 25% and 11% of parent AUC. These two 
metabolites have one-fifth and one-half of ruxolitinib’s 
pharmacological activity, respectively. The sum total of all active 
metabolites contributes 18% of the overall pharmacodynamics of 
ruxolitinib. 


33 | P a ge  
 
Product description: 
Ruxolitinib (ruxolitinib) Tablets are for oral administration. The 
tablet contains ruxolitinib phosphate equivalent to 5 mg of 
ruxolitinib free base together with Microcrystalline cellulose, 
lactose monohydrate, magnesium stearate, colloidal silicon 
dioxide, sodium starch glycolate, povidone and hydroxypropyl 
cellulose. 
 
Solution preparation: 
Not applicable 
 
Storage requirements: 
Store at room temperature 20°C to 25°C (68°F to 77°F); excursions 
permitted between 15°C and 30°C (59°F and 86°F) 
 
Stability: 
Not applicable 
 
Route of administration: Ruxolitinib is dosed orally and can be administered with or 
without food. 
 
Drug Procurement: Ruxolitinib will be supplied for this study by Incyte. Once notified by 
Incyte of IST support, Principal Investigator or study staff will contact Incyte’s Medical Affairs 
Operations and Program Manager or Medical Science Liaison to inform them of the amount 
of study drug needed to conduct the study. The Medical Affairs Operations and Program 
Manager at Incyte will generate a requisition for Investigational Product (IP) supplies and 
manage shipments through a third party vendor. 
 
 
Drug Accountability: The investigator or designated study personnel are responsible for 
maintaining accurate dispensing records of the study drug. All study 
drugs must be accounted for, including study drug accidentally or 
deliberately destroyed. Under no circumstances will the investigator 
allow the investigational drug to be used other than as directed by the 
protocol. Drug storage, drug dispensing, and drug accountability will 
be performed by the UM Research Pharmacy. Final drug 
accountability will be made to Incyte. Drug Destruction: At the 
completion of the study, there will be a final reconciliation of drug 
shipped, drug consumed, and drug remaining. This reconciliation will 
be logged on the drug reconciliation form, signed and dated. Any 
discrepancies noted will be investigated, resolved, and documented 
prior to return or destruction of unused study drug. Drug destroyed on 
site will be documented in the study files. Final drug accountability 
certificate will be provided to Incyte at the end of the study. 


34 | P a ge  
 
11. 
CORRELATIVE / SPECIAL STUDIES 
11.1 
Background 
 
Hemophagocytic syndrome is driven by inflammatory cytokines, including interferon-γ, that 
culminate in STAT1 phosphorylation, activated T-cell accumulation, and macrophage 
activation. 
 
11.2 
Rationale for Analysis 
 
We will utilize immunofluorescent staining (by flow cytometry) to test the hypothesis that 
ruxolitinib inhibits Stat1 activation in HPS. We will evaluate the expression of Stat1 and 
pStat1 in peripheral blood T-cells and monocytes pre- and post-treatment. The post- 
treatment analysis will be conducted 7 (+/- 3) days following treatment initiation. T-cell (sIL- 
2R) and macrophage (soluble CD163) activation markers will be serially analyzed by ELISA 
in patient plasma. Plasma samples will by obtained weekly and cryopreserved for analysis of 
relevant cytokines (including interferon-γ) by ELISA. We will test the hypothesis that 
ruxolitinib decreases inflammatory markers (e.g. soluble CD163) associated with 
macrophage activation. 
 
11.3 
Collection of Specimens 
 
Research blood samples (≈20 mL) will be obtained prior to treatment, and every 7 days (+/-2 
days) thereafter. 
 
Handling of Specimens 
 
All specimens are to be shipped to the Wilcox laboratory at the address below. Lab 
personnel will re-label the specimen using a code specific for this trial. Peripheral blood 
mononuclear cells will be isolated by density centrifugation and viably frozen using 
laboratory standard operating procedures. Platelet-poor plasma will be isolated using 
laboratory standard operating procedures and cryopreserved. 
 
Wilcox laboratory 
1400 E. Medical Center Drive 
4431 Cancer Center 
Ann Arbor, MI 48109 
 
 
12. 
STUDY PARAMETERS AND CALENDAR 


35 | P a ge  
 
12.1 
Study Parameters 
 
12.1.1 
Screening Evaluation 
 
Screening studies and evaluations will be used to determine the eligibility of each subject for 
study inclusion. All evaluations must be completed no longer than 14 days prior to 
administration of protocol therapy. 
 
• Informed Consent 
• Medical History 
• Complete physical examination 
• Vital signs including: blood pressure, pulse, respiratory rate, weight and temperature 
• Concomitant Medications Assessment including prescription and herbal supplements 
• Laboratory Studies: 
• Complete Blood Count (CBC) with differential and platelets. 
• Serum Chemistries: albumin, alkaline phosphatase, total bilirubin, 
bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium. 
• ß-HCG for women of childbearing potential at time of study entry 
• Ferritin 
• Lipids (Triglycerides) 
• Fibrinogen 
• Soluble IL-2 receptor 
• NK cell activity 


36 | P a ge  
 
 
12.2 
Calendar 
 
 
Enrollment 
(within 14 days 
of treatment) 
Pre-treatment 
(within 48 hours 
of treatment) 
Weekly 
(weeks 1-5)4 
(beginning day 
7, +/- 2 days) 
q14 days 
+/- 3 days 
(weeks 6-12)4 
q28 days 
+/- 3 days 
(>12 weeks)4 
Informed consent 
X 
H&P (including medication review) 
X 
X 
X 
X 
X 
CBC1 
X 
X 
X 
X 
X 
Serum Chemistries (including 
AST/ALT) 
X 
X 
X 
X 
X 
Pregnancy test5 
X 
Ferritin 
X 
X 
X 
X 
X 
Lipids 
X 
X 
X 
X 
Fibrinogen 
X 
X 
X 
X 
sIL-2 Receptor 
X 
X 
X 
X 
NK cell activity2 
X 
X 
X 
Research blood draw3 
X 
X 
Collect Adverse Events 
X 
X 
X 
X 
X 
1Performed at least every 72 hours for weeks 1-5 of treatment. 2May be performed every 7-14 
days. If total lymphocytes are insufficient to measure NK cell activity during enrollment, 
repeat testing is not required. 3Four heparin tubes (≈20 mL total volume) will be collected. 
Peripheral blood mononuclear cells and platelet-poor plasma will be obtained and 
cryopreserved for ancillary studies. Research blood draws will cease 14 days after a CR is 
achieved or after 5 weeks of treatment, whichever comes first. 4Study procedures required for 
response assessments and toxicity monitoring will be performed every two weeks (Bi-weekly) 
for patients who remain on treatment >6 weeks. For patients who remain on treatment >12 
weeks, the following procedures will be performed monthly: H&P, CBC, serum chemistries, 
ferritin, and adverse events. 5Pregnancy testing will be performed every 6 weeks (+/- 7 days) 
in women of child-bearing potential. 


37 | P a ge  
 
13. 
MEASUREMENT OF EFFECT 
 
13.1 
Response evaluation 
 
13.1.1 
Definitions 
 
Evaluable for toxicity. All patients will be evaluable for toxicity from the time of their first 
treatment with Ruxolitinib. 
 
Evaluable for objective response. Only those patients who received at least 7 days of therapy, 
and have had their disease re-evaluated will be considered evaluable for response. These 
patients will have their response classified according to the definitions stated below. 
 
 
13.1.2 
Disease Parameters 
• Fever 
• Splenomegaly (by physical examination or radiographic imaging). 
• Cytopenias involving ≥2 cell lines 
• Ferritin 
• Triglycerides 
• Fibrinogen 
• Soluble IL-2 receptor 
• NK cell activity 
 
13.1.3 
Response Criteria 
 
Evaluation of Response 
 
Response 
Evaluation of Target Lesions 
Complete Response (CR) 
Complete normalization of all quantifiable signs and 
laboratory abnormalities included in the diagnostic criteria 
for HPS. 
Partial Response (PR) 
At least a 25% improvement in two or more quantifiable 
signs/laboratory markers. 
Progressive Disease (PD) 
At least a 50% worsening in two or more quantifiable 
signs/laboratory markers. 
Stable Disease (SD) 
Neither sufficient improvement to qualify for CR/PR, 
nor sufficient worsening to qualify for PD. 


38 | P a ge  
 
13.1.4 
Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented. The duration of overall CR 
is measured from the time criteria are first met for CR until the first date that progressive 
disease is objectively documented. 
 
Duration of stable disease: Stable disease is measured from the start of the treatment until 
the criteria for progression are met. 
 
 
14. 
RECORDS TO BE KEPT / REGULATORY CONSIDERATIONS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 8.0 
(Adverse Events: List and Reporting Requirements). 
 
14.1 
Data Reporting 
 
The Velos Database will be utilized, as required by the UNIVERSITY OF MICHIGAN 
COMPREHENSIVE CANCER CENTER, to provide data collection for both accrual entry 
and trial data management. Velos is designed with the capability for study setup, activation, 
tracking, reporting, data monitoring and review, and eligibility verification. This study will 
utilize electronic Case Report Form completion in the Velos database. A calendar of events 
and required forms are available in Velos. 
 
14.2 
Regulatory Considerations 
 
The study will be conducted in compliance with ICH guidelines and with all applicable federal 
(including 21 CFR parts 56 & 50), state or local laws. 
 
14.2.1 
Written Informed consent 
Provision of written informed consent must be obtained prior to any study-related procedures. 
The Principal Investigator will ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study as well as the 
subject’s financial responsibility. Subjects must also be notified that they are free to discontinue 
from the study at any time. The subject should be given the opportunity to ask questions and 
allowed time to consider the information provided. 
The original, signed written Informed Consent Form must be kept with the Research Chart in 
conformance with the institution’s standard operating procedures. A copy of the signed written 
Informed Consent Form must be given to the subject. 


39 | P a ge  
 
14.2.2 
Subject Data Protection 
In accordance with the Health Information Portability and Accountability Act (HIPAA), a 
subject must sign an authorization to release medical information to the manufacturer and/or 
allow the manufacturer, a regulatory authority, or Institutional Review Board access to subject’s 
medical information that includes all hospital records relevant to the study, including subjects’ 
medical history. 
 
14.2.3 
Accessing Electronic Medical Records for University of Michigan Hospital and 
Health Systems 
 
This study will access electronic medical records systems to obtain medical information for 
the subjects enrolled to this study. 
 
In order to insure patient safety, investigators and study personnel must have up-to-the- 
minute health information for subjects enrolled to this study. Therefore, electronic medical 
records must be utilized to obtain medical information in a timely manner. 
 
The following electronic systems will be used: MiChart to access scheduling information; 
MiChart and Careweb to access lab results and physician notes; MiChart and Careweb as 
necessary to locate archived medical records; PACS to access radiological imaging results. 
 
Access to these systems is required for the life of this research study. 
 
Information obtained from electronic systems will be copied into the University of Michigan 
Cancer Center Clinical Trials Unit research chart and/or printed (lab results, physician notes, 
etc.) and stored in the research chart. Research charts are kept secure and destroyed 
according to UH policy. 
 
Study data will be obtained by the PI, co-investigators, study coordinator, and/or data 
manager for this study via password-protected login. All study personnel involved in this 
research will adhere to the UH policies regarding confidentiality and Protected Health 
Information. 
 
14.2.4 
Retention of records 
 
The Principal Investigator of The UNIVERSITY OF MICHIGAN COMPREHENSIVE 
CANCER CENTER supervises the retention of all documentation of adverse events, records of 
study drug receipt and dispensation, and all IRB correspondence for as long as needed to comply 
with national and international regulations. No records will be destroyed until the Principal 
Investigator confirms destruction is permitted. 
 
14.2.5 
Audits and inspections 
Authorized representatives of the manufacturer, a regulatory authority, an Independent Ethics 
Committee (IEC) or an Institutional Review Board (IRB) may visit the Center to perform audits 


40 | P a ge  
 
or inspections, including source data verification. The purpose of an audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analysed, and 
accurately reported according to the protocol, Good Clinical Practice (GCP), and any applicable 
regulatory requirements. 
14.2.6 
Data Safety and Monitoring Plan 
 
This protocol will adhere to the policies of the UNIVERSITY OF MICHIGAN 
COMPREHENSIVE CANCER CENTER Data and Safety Monitoring Plan in accordance with 
NCI regulations. 
 
This trial will be monitored in accordance with the NCI approved University of Michigan 
Comprehensive Cancer Center Data and Safety Monitoring Plan. The study specific Data and 
Safety Monitoring Committee (DSMC), consisting of the protocol investigators, data manager or 
designee, and other members of the study team involved with the conduct of the trial, will meet 
quarterly or more frequently depending on the activity of the protocol. The discussion will include 
matters related to the safety of study participants (SAE/UaP reporting), validity and integrity of 
the data, enrollment rate relative to expectations, characteristics of participants, retention of 
participants, adherence to the protocol (potential or real protocol deviations) and data 
completeness. At the regular DSMC meetings, the protocol specific Data and Safety Monitoring 
Report form will be completed. The report will be signed by the Principal Investigator or by one 
of the co-investigators. Data and Safety Monitoring Reports will be submitted to the University of 
Michigan Comprehensive Cancer Center Data and Safety Monitoring Board (DSMB) on a 
quarterly basis for independent review. 


41 | P a ge  
 
 
 
15. 
STATISTICAL CONSIDERATIONS 
 
 
15.1 
Sample Size 
We will accrue and treat 10 patients on this pilot trial. We expect a 2-month survival rate 
approximating 15% in patients meeting the inclusion criteria with current standard of care. As 
we believe ruxolitinib may be highly active in this disease and change the current treatment 
paradigm, we believe the majority of treated patients will be alive at 2 months. Therefore, if 4 or 
more patients are alive 2 months following diagnosis, this would provide sufficient evidence to 
pursue ruxolitinib in an expanded cohort of patients in a future study. This design has 80% 
power to detect a survival rate of 60% versus an estimated survival rate of 15% using a 2-sided 
test, with 5% type 1error. The operating characteristics for design are given in the table below for 
a range of true values for the probability of survival at 2 months, with at least 4 responders the 
critical value. 
 
Probability of survival at 2 months following 
  
diagnosis 
Probability therapy is deemed effective 
0.05 
0.010 
0.15 
0.050 
0.25 
0.228 
0.35 
0.488 
0.45 
0.738 
0.55 
0.901 
0.65 
0.978 
 
 
15.2 
Analyses 
 
Primary: 
The primary analysis is the count of patients alive after 2 months since study entry. If 4 or 
more patients are alive at the 2 months assessment, the null hypothesis of a 15% survival 
probability at 2 months will be rejected in favor or our alternative hypothesis of a 60% 
survival probability. Ninety-five percent confidence intervals will be constructed based upon 
the exact binomial confidence interval. No loss-to-follow-up or censoring is expected prior 
to the study’s primary endpoint assessment. 
Secondary: 
There are no formal response criteria for secondary HPS. Therefore, efficacy assessments 
(including appropriate laboratory studies) will be performed weekly (weeks 1-5), and every 
two weeks (weeks 6-12), and monthly (after 12 weeks), and responses determined as 
previously reported in a retrospective study.8 Briefly, a complete response is defined as 


42 | P a ge  
 
complete normalization of all quantifiable symptoms and laboratory abnormalities (described 
in the diagnostic criteria for HPS, above). A partial response is defined as at least a 25% 
improvement in two or more quantifiable symptoms/laboratory markers following the 
initiation of treatment. The best overall response is the best response recorded from the start 
of the treatment until disease progression/recurrence 
Follow-up time will be calculated from the first administration of ruxolitinib, until death for 
OS or until disease-progression or death for PFS. Patients lost to follow-up will be censored 
on the date of their last known clinical assessment. Specifically for DOR, only patients 
having at least a PR to therapy are evaluable. Duration will be calculated from the date of 
the determination of partial response or better until the date of progression, death, or 
additional non-protocol therapy. Again, for patients lost to follow-up, duration will be 
censored at the time of last clinical assessment. The count and percentage of the number 
having an objective response (CR, CRu, or PR) will be reported along with confidence 
intervals. Product-limit estimates of Kaplan and Meier will be used to estimate OS, PFS, and 
DOR. The likelihood of loss to follow-up is expected to be extremely low.  
Exploratory: 
Plasma will be obtained before treatment and weekly thereafter, and cryopreserved for 
future corollary studies (e.g. cytokine27,28 and soluble CD163 determination34). We will 
compare cytokine, soluble IL-2R and soluble CD163 levels pre-treatment and post 
treatment. We seek to correlate change in expression (decrease) with positive response 
(complete vs. partial vs. stable) to therapy via regression models that appropriately account 
for the serial correlation of repeated measures within a patient. Inference from these models 
would be hypothesis generating. 


43 | P a ge  
 
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Catlett-Falcone R, Landowski TH, Oshiro MM, et al. Constitutive activation of 
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46 | P a ge  
 
17. 
APPENDIX A 
 
POTENTIAL CYP3A4 INTERACTIONS 
 
CYP3A4 Substrates 
Albuterol 
Alfentanil 
Alprazolam 
Amiodarone 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Budesonide 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazepine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cilostazol 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Dasatinib (1) 
Delvirdine 
Diazepam 
Dihydroergotamine 
Diltiazem 
Disopyramide 
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, 
conj., synthetic 
Estrogens, 
conj., equine 
Estrogens, 
conj., esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Exemastane 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fluticasone 
Fosamprenavir 
Gefitinib 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavair 
Irinotecan 
Isosorbide 
Isosorbide, dinitrate 
Isosorbide mononitrate 
Isradipine 
Itraconazole 
Ketamine 
Ketoconazole 
Lansoprazole 
Letrozole 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Pipotiazine 
Primaquine 
Progesterone 
Quetiapine 
Quinidine 
Rabeprazole 
Ranolazine 
Repaglinide 
Rifabutin 
Ritonavir 
Salmetrol 
Saquinavir 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Spiramycin 
Sufentanil 
Sunitinib 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tipranavir 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamide 
Zopiclone 


47 | P a ge  
 
APPENDIX A (continued) 
POTENTIAL CYP3A4 INTERACTIONS 
CYP3A4 Inhibitors 
Acetaminophen 
Acetazolamide 
Amiodarone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffeine 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetidine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Danazol 
Dasatinib (1) 
Delvirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit Juice(2) 
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavair 
Irbesartan 
Isoniazid 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan 
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarapine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol 
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Ranolazine 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic Acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Voriconazole 
Zafirlukast 
Ziprasidone 


48 | P a ge  
 
APPENDIX A (continued) 
POTENTIAL CYP3A4 INTERACTIONS 
 
CYP3A4 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin 
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin 
Rifapentine 
St. John’s Wort (3) 
 
 
Note: Adapted from Cytochrome P450 Enzymes: Substrates, Inhibitors, and Inducers. In: Lacy CF, Armstrong 
LL, Goldman MP, Lance LL eds. Drug Information Handbook 15TH ed. Hudson, OH; LexiComp Inc. 2007: 
1899-1912. 
Only major substrates and effective inducers are listed. 
Additional information for drug interactions with cytochrome P450 isoenzymes can be found at 
http://medicine.iupui.edu/flockhart/. 
 
(1) Investigator’s Brochure: Dasatinib (BMS 354825). Bristol-Myers Squibb. October 2006. 
 
(2) Malhotra et al. (2001). Clin Pharmacol Ther. 69:14-23. 
 
(3) Mathijssen et al. (2002). J Natl Cancer Inst. 94:1247-1249. 
 
(4) Frye et al. (2004). Clin Pharmacol Ther. 76:323-329. 
 
Updated on May 1, 2007