A Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and Efficacy of Ruxolitinib

• Sponsor: H. Lee Moffitt Cancer Center and Research Institute (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01776723
• Collaborator: Incyte Corporation (Industry)
• Enrollment: 50
• Locations: 6
• Arms: 2
• Anticipated Duration (Months): 117.3
• Patients Per Site: 8.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to find out if treating Chronic Myelomonocytic Leukemia (CMML) with a study drug [ruxolitinib] can improve outcomes of patients with CMML. The first step of the study is to learn the dose of ruxolitinib that is tolerable (bearable). It has already been studied in a number of patients with different bone marrow diseases and is approved for the treatment of a disease called Myelofibrosis; however, it is not approved for treatment of CMML. It is given orally (by mouth). Most people tolerate it well but the tolerability has not been determined in patients with CMML. We will be testing different doses to determine how much of the medication people can tolerate (bear) before they develop side effects.

Condition or Disease	Intervention/Treatment	Phase
Myelomonocytic Leukemia	Drug: Ruxolitinib	Phase 1/Phase 2

Detailed Description

This is a phase 1/2, two-stage, sequential cohort dose escalation study. If dose escalation is completed as planned, no more than 53 subjects are expected to enroll onto this study at a rate of approximately 3 subjects every month. For the Phase 2 study the Simon's optimal two-stage design will be employed to test the null hypothesis that response rate (RR) equals to 10% versus the alternative that RR equals to 30%.

Demographic and clinical variables for the study patients will be summarized using descriptive statistics (mean, standard deviation, median, inter-quartile range, range, and frequency counts and percentages). Safety and efficacy data will be analyzed overall as well as separately for each dose cohort when appropriate.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Sequential Two-Stage Dose Escalation Study to Evaluate the Safety and Efficacy of Ruxolitinib for the Treatment of Chronic Myelomonocytic Leukemia (CMML) and Cataloging the Molecular Consequences of JAK2 Inhibition in Chronic Myelomonocytic Leukemia: A Correlative Study Identifying Targetable CMML Sub-Clones by Leveraging GM-CSF Dependent pSTAT Hypersensitivity
• Actual Study Start Date: Feb 20, 2013
• Actual Primary Completion Date: Nov 28, 2018
• Anticipated Study Completion Date: Dec 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: I: Dose Escalation - Ruxolitinib Phase I: Dose Escalation. In Phase I, participants will be allocated to dose levels starting at 10 mg/d (twice a day [BID] dosing) according to the "rolling six" Phase I design.	Drug: Ruxolitinib; In Phase I, participants will be allocated to twice a day (BID) doses of 10 mg/d up to 40mg/d. The starting dose will be 10 mg/d (5mg BID). Each cohort will include up to 6 subjects. Once MTD is reached, 10 additional participants will be treated during the first stage of Phase II (stage 1) at the MTD.; Other Names: Jakafi® INCB-018424 Kinase Inhibitor
Experimental: II: Maximum Tolerated Dose - Ruxolitinib Phase II: Treatment at Maximum Tolerated Dose (MTD).	Drug: Ruxolitinib; In Phase I, participants will be allocated to twice a day (BID) doses of 10 mg/d up to 40mg/d. The starting dose will be 10 mg/d (5mg BID). Each cohort will include up to 6 subjects. Once MTD is reached, 10 additional participants will be treated during the first stage of Phase II (stage 1) at the MTD.; Other Names: Jakafi® INCB-018424 Kinase Inhibitor

Outcome Measures

Primary Outcome Measures

1. The Maximum Tolerated Dose (MTD) of Ruxolitinib for the Treatment of Myelomonocytic Leukemia (CMML) [17 weeks]

   Phase I - The MTD is defined as the highest dose where less than 33% of participants experience a drug related predefined dose limited toxicity (DLT). Dose-limiting toxicity (DLT) is defined as any grade 4 hematologic toxicity and any grade 3 or greater non-hematologic toxicity except nausea that is controlled by antiemetic therapy based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3 metabolic/electrolyte abnormalities that are not clinically significant, and are adequately controlled within 72 hours are not to be considered a DLT.

2. Occurrence of Clinical Response [Up to 2 years]

   Phase II - Proportion of participants achieving clinical benefit defined as hematologic improvement, complete remission (CR), partial remission (PR), marrow complete remission (Marrow CR) or stable disease (SD) by the International Working Group (IWG) 2006 criteria. Erythroid Response for pretreatment hemoglobin < 11 g/dl; Platelet response for subjects with a pre-treatment platelet count < 50 x 10^9/L; Neutrophil response with pretreatment absolute neutrophil count (ANC) < 1 x 10^9/L.

Secondary Outcome Measures

1. Percentage of Participants With Acute Myeloid Leukemia (AML) Transformation [Up to 2 years]

   Phase II - To determine the time to AML transformation of participants on Ruxolitinib. Acute myeloid leukemia (AML) transformation according to World Health Organization (WHO) criteria. CMML-1: peripheral blood <5% blasts, bone marrow <10% myeloblast. CMML-2: peripheral blood <19 percent blasts persistent monocytosis >1000/ul +/- cytopenias Leukocytosis frequent, bone marrow <19 percent blasts >10% dysplasia in affected lineage, Auer Rods.

2. Median Overall Survival (OS) [Up to 2 years]

   Phase II - To determine the median overall survival.

3. Duration of Response in Days [3.5 years]

   Phase II - To determine the duration of response achieved as in secondary endpoint one. The duration of response is measured from the time measurement criteria are met for major or complete platelet response (which ever is first recorded) until the first date that disease progression defined by the bone marrow response outlined above, progression/relapse following a CR, marrow CR or PR, or progressions/relapse following hematological improvement (HI) as outlined above.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed diagnosis of CMML using the World Health Organization (WHO) classification

• Age >18 years at the time of obtaining informed consent

• Must be able to adhere to the study visit schedule and other protocol requirements

• Must be able to provide adequate bone marrow (BM) aspirate and biopsy specimens for histopathological analysis and standard cytogenetic analysis during the screening procedure

• An Eastern Cooperative Oncology Group (ECOG) performance status score of 0,1, or 2

• Women of childbearing potential must have a negative pregnancy test at time of screening and baseline visits and agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse 1) for at least 28 days before starting study drug; 2) while participating in the study; and

1. for at least 28 days after discontinuation from the study.

• Must understand and voluntarily sign an informed consent form

• Must have a life expectancy of greater than 3 months at time of screening

Exclusion Criteria:

• Platelet count of less than 35,000/uL

• Absolute Neutrophil Count (ANC) of less than 250/uL

• Serum Creatinine >2.0

• Serum total bilirubin >1.5 x upper limit of normal (ULN)

• Use of cytotoxic chemotherapeutic agents, or experimental agents (agents that are not commercially available) for the treatment of CMML within 28 days of the first day of study drug treatment

• Any serious medical condition or psychiatric illness that will prevent the subject from signing the informed consent form or will place the subject at unacceptable risk if he/she participates in the study

• Concurrent use of Granulocyte/macrophage colony stimulating factor (GM-CSF). Granulocyte colony-stimulating factor (G-CSF) could be used for the short-term management of neutropenic infection. Stable doses of erythropoietin stimulating agents that were started >8 weeks from first ruxolitinib dose or corticosteroids that were being administered prior to screening are allowed.

• Uncontrolled current illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women are excluded from this study because ruxolitinib has not been studied in pregnant subjects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with ruxolitinib, breastfeeding should be discontinued if the mother is treated with ruxolitinib.

• Patients who have participated in other interventional (treatment-related) clinical trials within 30 days of enrollment are excluded.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
2	Johns Hopkins Sidney Kimmel Comprehensive Cancer Center	Baltimore	Maryland	United States	21287
3	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115
4	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
5	Weill Medical College of Cornell	New York	New York	United States	10021
6	Cleveland Clinic	Cleveland	Ohio	United States	44106

Sponsors and Collaborators

• H. Lee Moffitt Cancer Center and Research Institute
• Incyte Corporation

Investigators

• Principal Investigator: Eric Padron, M.D., H. Lee Moffitt Cancer Center and Research Institute

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 28, 2016

More Information

Additional Information:

• Moffitt Cancer Center Clinical Trials website

Publications

None provided.

• Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• ClinicalTrials.gov Identifier: NCT01776723
• Other Study ID Numbers: MCC-17259
• First Posted: Jan 28, 2013
• Last Update Posted: Jun 3, 2022
• Last Verified: Jun 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by H. Lee Moffitt Cancer Center and Research Institute: Chronic Myelomonocytic Leukemia; CMML; Leukemia
• Additional relevant MeSH terms: Leukemia; Leukemia, Myelomonocytic, Acute; Leukemia, Myelomonocytic, Chronic; Leukemia, Myelomonocytic, Juvenile

Study Results

Participant Flow

Arm/Group Title	Phase 1, Level 1: Ruxolitinib 10 mg	Phase 1 Level 2: Ruxolitinib 20 mg	Phase 1 Level 3: Ruxolitinib 30 mg	Phase 1 Level 4: 40 mg Ruxolitinib	Phase 2: Maximum Tolerated Dose - Ruxolitinib
Arm/Group Description	Phase 1, Level 1: Ruxolitinib 5 mg twice daily	Phase 1 Level 2: Ruxolitinib 10 mg twice daily	Phase 1 Level 3: Ruxolitinib 15 mg twice daily	Phase 1 Level 4: 20 mg Ruxolitinib twice daily	Phase II: Treatment at Maximum Tolerated Dose (MTD).
Period Title: Overall Study
STARTED	6	4	5	5	30
COMPLETED	6	4	5	5	30
NOT COMPLETED	0	0	0	0	0

Baseline Characteristics

Arm/Group Title	Phase 1, Level 1: Ruxolitinib 10 mg	Phase 1, Level 2: Ruxolitinib 20 mg	Phase 1, Level 3: Ruxolitinib 30 mg	Phase 1, Level 4: Ruxolitinib 40 mg	Phase 2: Maximum Tolerated Dose - Ruxolitinib	Total
Arm/Group Description	Phase 1 Level 1: Ruxolitinib 5 mg twice daily	Phase 1 Level 2: Ruxolitinib 10 mg twice daily	Phase 1 Level 3: Ruxolitinib 15 mg twice daily	Phase 1 Level 4: Ruxolitinib 20 mg twice daily	Phase 2: Treatment at Maximum Tolerated Dose (MTD).	Total of all reporting groups
Overall Participants	6	4	5	5	30	50
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	2 33.3%	1 25%	3 60%	0 0%	8 26.7%	14 28%
>=65 years	4 66.7%	3 75%	2 40%	5 100%	22 73.3%	36 72%
Sex: Female, Male (Count of Participants)
Female	1 16.7%	2 50%	2 40%	0 0%	14 46.7%	19 38%
Male	5 83.3%	2 50%	3 60%	5 100%	16 53.3%	31 62%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	1 20%	4 13.3%	5 10%
Not Hispanic or Latino	6 100%	4 100%	4 80%	4 80%	26 86.7%	44 88%
Unknown or Not Reported	0 0%	0 0%	1 20%	0 0%	0 0%	1 2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
White	6 100%	4 100%	5 100%	5 100%	29 96.7%	49 98%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	1 3.3%	1 2%
Region of Enrollment (participants) [Number]
United States	6 100%	4 100%	5 100%	5 100%	30 100%	50 100%

Outcome Measures

1. Primary Outcome

Title	The Maximum Tolerated Dose (MTD) of Ruxolitinib for the Treatment of Myelomonocytic Leukemia (CMML)
Description	Phase I - The MTD is defined as the highest dose where less than 33% of participants experience a drug related predefined dose limited toxicity (DLT). Dose-limiting toxicity (DLT) is defined as any grade 4 hematologic toxicity and any grade 3 or greater non-hematologic toxicity except nausea that is controlled by antiemetic therapy based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3 metabolic/electrolyte abnormalities that are not clinically significant, and are adequately controlled within 72 hours are not to be considered a DLT.
Time Frame	17 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	I: Dose Escalation - Ruxolitinib
Arm/Group Description	Phase I: Dose Escalation. In Phase I, participants will be allocated to dose levels starting at 10 mg/d (twice a day [BID] dosing) according to the "rolling six" Phase I design. Ruxolitinib: In Phase I, participants will be allocated to twice a day (BID) doses of 10 mg/d up to 40mg/d. The starting dose will be 10 mg/d (5mg BID). Each cohort will include up to 6 subjects. Once MTD is reached, 10 additional participants will be treated during the first stage of Phase II (stage 1) at the MTD.
Measure Participants	20
Number [mg]	40

2. Primary Outcome

Title	Occurrence of Clinical Response
Description	Phase II - Proportion of participants achieving clinical benefit defined as hematologic improvement, complete remission (CR), partial remission (PR), marrow complete remission (Marrow CR) or stable disease (SD) by the International Working Group (IWG) 2006 criteria. Erythroid Response for pretreatment hemoglobin < 11 g/dl; Platelet response for subjects with a pre-treatment platelet count < 50 x 10^9/L; Neutrophil response with pretreatment absolute neutrophil count (ANC) < 1 x 10^9/L.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

All participants who received ruxolitinib therapy

Arm/Group Title	II: Maximum Tolerated Dose - Ruxolitinib
Arm/Group Description	Phase II: Treatment at Maximum Tolerated Dose (MTD). Ruxolitinib: In Phase I, participants will be allocated to twice a day (BID) doses of 10 mg/d up to 40mg/d. The starting dose will be 10 mg/d (5mg BID). Each cohort will include up to 6 subjects. Once MTD is reached, 10 additional participants will be treated during the first stage of Phase II (stage 1) at the MTD.
Measure Participants	30
Number [participants]	18 300%

3. Secondary Outcome

Title	Percentage of Participants With Acute Myeloid Leukemia (AML) Transformation
Description	Phase II - To determine the time to AML transformation of participants on Ruxolitinib. Acute myeloid leukemia (AML) transformation according to World Health Organization (WHO) criteria. CMML-1: peripheral blood <5% blasts, bone marrow <10% myeloblast. CMML-2: peripheral blood <19 percent blasts persistent monocytosis >1000/ul +/- cytopenias Leukocytosis frequent, bone marrow <19 percent blasts >10% dysplasia in affected lineage, Auer Rods.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Participants
Arm/Group Description	All participants who received at least one dose of Ruxuxolitinib
Measure Participants	30
Number [percentage of patients]	14

4. Secondary Outcome

Title	Median Overall Survival (OS)
Description	Phase II - To determine the median overall survival.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

All participants who received ruxolitinib therapy

Arm/Group Title	II: Maximum Tolerated Dose - Ruxolitinib
Arm/Group Description	Phase II: Treatment at Maximum Tolerated Dose (MTD).
Measure Participants	30
Median (95% Confidence Interval) [months]	23.7

5. Secondary Outcome

Title	Duration of Response in Days
Description	Phase II - To determine the duration of response achieved as in secondary endpoint one. The duration of response is measured from the time measurement criteria are met for major or complete platelet response (which ever is first recorded) until the first date that disease progression defined by the bone marrow response outlined above, progression/relapse following a CR, marrow CR or PR, or progressions/relapse following hematological improvement (HI) as outlined above.
Time Frame	3.5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase 1, Level 1: Ruxolitinib 10 mg	Phase 1, Level 2: Ruxolitinib 20 mg	Phase 1, Level 3: Ruxolitinib 30 mg	Phase 1, Level 4: Ruxolitinib 40 mg	Maximum Tolerated Dose - Ruxolitinib
Arm/Group Description	Phase 1, Level 1: Ruxolitinib 5 mg twice daily	Phase 1, Level 2: Ruxolitinib 10 mg twice daily	Phase 1 Level 3: Ruxolitinib 15 mg twice daily	Phase 1, Level 4: Ruxolitinib 20 mg twice daily	Treatment at Maximum Tolerated Dose (MTD).
Measure Participants	6	4	5	5	30
Mean (Full Range) [days]	104	446.25	718	331.25	263.5

Adverse Events

Time Frame	Adverse Events collected from time of consent through follow-up, up to 2 years
Arm/Group Title	Phase 1, Level 1: Ruxolitinib 10 mg		Phase 1, Level 2: Ruxolitinib 20 mg		Phase 1, Level 3: Ruxolitinib 30 mg		Phase 1, Level 4: Ruxolitinib 40 mg		II: Maximum Tolerated Dose - Ruxolitinib
Arm/Group Description	Phase 1, Level 1: Ruxolitinib 5 mg twice daily		Phase 1, Level 1: Ruxolitinib 10 mg twice daily		Phase 1, Level 1: Ruxolitinib 15 mg twice daily		Phase 1, Level 1: Ruxolitinib 20 mg twice daily		Phase II: Treatment at Maximum Tolerated Dose (MTD).
All Cause Mortality
	Phase 1, Level 1: Ruxolitinib 10 mg		Phase 1, Level 2: Ruxolitinib 20 mg		Phase 1, Level 3: Ruxolitinib 30 mg		Phase 1, Level 4: Ruxolitinib 40 mg		II: Maximum Tolerated Dose - Ruxolitinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		4/4 (100%)		1/5 (20%)		1/5 (20%)		13/30 (43.3%)
Serious Adverse Events
	Phase 1, Level 1: Ruxolitinib 10 mg		Phase 1, Level 2: Ruxolitinib 20 mg		Phase 1, Level 3: Ruxolitinib 30 mg		Phase 1, Level 4: Ruxolitinib 40 mg		II: Maximum Tolerated Dose - Ruxolitinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		4/4 (100%)		1/5 (20%)		1/5 (20%)		15/30 (50%)
Blood and lymphatic system disorders
Anemia	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Spleen disorder	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Cardiac disorders
Heart failure	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Cardiac arrest	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Gastrointestinal disorders
Diarrhea	0/6 (0%)	0	2/4 (50%)	2	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Dehydration	0/6 (0%)	0	1/4 (25%)	2	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Edema limbs	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Abdominal pain	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Gastrointestinal disorders - other	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
General disorders
Death NOS	6/6 (100%)	6	4/4 (100%)	4	1/5 (20%)	1	1/5 (20%)	1	13/30 (43.3%)	13
Fatigue	0/6 (0%)	0	2/4 (50%)	2	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Multi-organ failure	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Flu like symptoms	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Infections and infestations
Lung infection	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	2/30 (6.7%)	2
Infections and infestations - other	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Sepsis	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Injury, poisoning and procedural complications
Fall	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Postoperative hemorrhage	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Investigations
Creatinine increased	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Metabolism and nutrition disorders
Hyperglycemia	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Tumor lysis syndrome	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Hyponatremia	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness lower limb	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Generalized muscle weakness	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Nervous system disorders
Facial muscle weakness	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Nervous system disorders - other	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Syncope	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/30 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary hypertension	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Dyspnea	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Respiratory failure	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/30 (0%)	0
Respiratory, thoracic and mediastinal disorders - other	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Surgical and medical procedures
Surgical and medical procedures -other	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Surgical and medical procedures - other	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Vascular disorders
Vascular disorders -Other	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Headache	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Other (Not Including Serious) Adverse Events
	Phase 1, Level 1: Ruxolitinib 10 mg		Phase 1, Level 2: Ruxolitinib 20 mg		Phase 1, Level 3: Ruxolitinib 30 mg		Phase 1, Level 4: Ruxolitinib 40 mg		II: Maximum Tolerated Dose - Ruxolitinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		4/4 (100%)		5/5 (100%)		5/5 (100%)		30/30 (100%)
Blood and lymphatic system disorders
Anemia	0/6 (0%)	0	2/4 (50%)	4	3/5 (60%)	4	2/5 (40%)	2	17/30 (56.7%)	24
Leukocytosis	1/6 (16.7%)	1	2/4 (50%)	2	2/5 (40%)	3	0/5 (0%)	0	9/30 (30%)	9
Disseminated intravascular coagulation	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Blood and lymphatic system disorders - other	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	2	0/5 (0%)	0	4/30 (13.3%)	4
Cardiac disorders
Atrial fibillation	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	3/30 (10%)	3
Sinus tachycardia	2/6 (33.3%)	2	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Heart failure	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	1/30 (3.3%)	1
Palpitations	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Supraventricular tachycardia	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Atrial flutter	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Cardiac arrest	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Chest pain - cardiac	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Sinus bradycardia	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Ventricular tachycardia	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Cardiac disorders - Other	0/6 (0%)	0	2/4 (50%)	2	0/5 (0%)	0	0/5 (0%)	0	3/30 (10%)	4
Ear and labyrinth disorders
Ear pain	0/6 (0%)	0	0/4 (0%)	0	2/5 (40%)	2	0/5 (0%)	0	0/30 (0%)	0
Middle ear inflammation	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	4/30 (13.3%)	4
Vertigo	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	2
Ear and labyrinth disorders -Other	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	4/30 (13.3%)	4
Eye disorders
Blurred vision	0/6 (0%)	0	1/4 (25%)	2	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Cataract	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Conjunctivitis	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/30 (0%)	0
Dry eye	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Watering eyes	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/30 (0%)	0
Eye disorders -Other	1/6 (16.7%)	1	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Gastrointestinal disorders
Diarrhea	2/6 (33.3%)	2	3/4 (75%)	11	2/5 (40%)	5	2/5 (40%)	3	5/30 (16.7%)	5
Nausea	2/6 (33.3%)	2	2/4 (50%)	2	1/5 (20%)	1	0/5 (0%)	0	6/30 (20%)	6
Abdominal Pain	1/6 (16.7%)	1	0/4 (0%)	0	2/5 (40%)	2	2/5 (40%)	2	6/30 (20%)	8
Vomitting	3/6 (50%)	3	2/4 (50%)	2	1/5 (20%)	1	0/5 (0%)	0	3/30 (10%)	3
Constipation	2/6 (33.3%)	2	1/4 (25%)	1	0/5 (0%)	0	1/5 (20%)	1	4/30 (13.3%)	5
Mucositis oral	1/6 (16.7%)	1	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	5/30 (16.7%)	6
Abdominal distension	2/6 (33.3%)	2	0/4 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	3/30 (10%)	3
Gastroesophageal reflux disease	1/6 (16.7%)	1	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	3/30 (10%)	3
Dyspepsia	1/6 (16.7%)	1	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Bloating	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Ascites	2/6 (33.3%)	2	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Colitis	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Dental caries	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Gastroparesis	0/6 (0%)	0	1/4 (25%)	2	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	2
Hemorrhoids	1/6 (16.7%)	1	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Dry mouth	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Duodenal ulcer	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Esophageal ulcer	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Esophagitis	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Fecal incontinence	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Gastric ulcer	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Gastritis	0/6 (0%)	0	1/4 (25%)	2	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Gastrointestinal pain	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	2
Malabsorption	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Oral hemorrhage	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Rectal hemorrhate	1/6 (16.7%)	1	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Upper gastrointestinal hemorrhage	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/30 (0%)	0
Gastrointestinal disorders - other	1/6 (16.7%)	2	1/4 (25%)	2	2/5 (40%)	3	0/5 (0%)	0	4/30 (13.3%)	6
General disorders
Fatigue	3/6 (50%)	3	3/4 (75%)	5	4/5 (80%)	4	1/5 (20%)	1	10/30 (33.3%)	11
Edema limbs	3/6 (50%)	4	3/4 (75%)	4	1/5 (20%)	1	1/5 (20%)	1	4/30 (13.3%)	4
Fever	0/6 (0%)	0	2/4 (50%)	2	0/5 (0%)	0	1/5 (20%)	2	8/30 (26.7%)	8
Pain	1/6 (16.7%)	1	1/4 (25%)	2	2/5 (40%)	4	0/5 (0%)	0	4/30 (13.3%)	6
Chills	3/6 (50%)	3	0/4 (0%)	0	0/5 (0%)	0	1/5 (20%)	2	2/30 (6.7%)	2
Non-cardiac chest pain	1/6 (16.7%)	1	1/4 (25%)	1	1/5 (20%)	1	0/5 (0%)	0	4/30 (13.3%)	5
Flu-like symptoms	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	3/30 (10%)	3
Edema trunk	1/6 (16.7%)	1	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Gait disturbance	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Irritability	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Malaise	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Multi-organ failure	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Toothache	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
General disorders and administration site conditions - other	1/6 (16.7%)	1	0/4 (0%)	0	3/5 (60%)	4	0/5 (0%)	0	2/30 (6.7%)	2
Immune system disorders
Immune system disorders -Other	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/30 (0%)	0
Infections and infestations
Upper respiratory infection	0/6 (0%)	0	2/4 (50%)	7	2/5 (40%)	6	1/5 (20%)	1	7/30 (23.3%)	12
Urinary tract infection	0/6 (0%)	0	1/4 (25%)	2	1/5 (20%)	1	0/5 (0%)	0	6/30 (20%)	10
Bronchial infection	0/6 (0%)	0	1/4 (25%)	1	1/5 (20%)	1	0/5 (0%)	0	1/30 (3.3%)	1
Sepsis	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	3/30 (10%)	4
Sinusitis	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	2/30 (6.7%)	2
Skin Infection	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	3	0/5 (0%)	0	2/30 (6.7%)	3
Bladder infection	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Papulopustular rash	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	1/5 (20%)	1	0/30 (0%)	0
Pleural infection	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	1/5 (20%)	1	0/30 (0%)	0
Vaginal infection	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	2	0/5 (0%)	0	1/30 (3.3%)	1
Abdominal infection	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Hepatic infection	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Laryngitis	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Mucosal infection	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Ottis media	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/30 (0%)	0
Pharyngitis	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Tooth infection	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Infections and infestations - Other	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	6/30 (20%)	9
Injury, poisoning and procedural complications
Bruising	1/6 (16.7%)	1	2/4 (50%)	2	0/5 (0%)	0	1/5 (20%)	1	7/30 (23.3%)	7
Fall	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	3/30 (10%)	3
Fracture	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Burn	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Postoperative hemorrhage	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Injury, poisoning and procedures complications - Other	1/6 (16.7%)	3	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Investigations
Platelet count decreased	1/6 (16.7%)	2	2/4 (50%)	3	2/5 (40%)	2	1/5 (20%)	1	11/30 (36.7%)	17
Aspartate aminotransferase increased	0/6 (0%)	0	1/4 (25%)	3	3/5 (60%)	6	0/5 (0%)	0	7/30 (23.3%)	11
Creatinine increased	0/6 (0%)	0	2/4 (50%)	4	2/5 (40%)	3	0/5 (0%)	0	5/30 (16.7%)	8
Alanine aminotransferase increased	0/6 (0%)	0	1/4 (25%)	2	3/5 (60%)	4	0/5 (0%)	0	3/30 (10%)	5
Alkaline phosphatase increased	0/6 (0%)	0	0/4 (0%)	0	2/5 (40%)	4	0/5 (0%)	0	4/30 (13.3%)	4
Neutrophil count decreased	0/6 (0%)	0	1/4 (25%)	1	1/5 (20%)	1	0/5 (0%)	0	2/30 (6.7%)	5
Weight gain	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
White blood cell decreased	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	1/30 (3.3%)	1
Blood bilirubin increased	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	4	0/5 (0%)	0	1/30 (3.3%)	1
Cardiac troponin I increased	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Investigations - Other	0/6 (0%)	0	1/4 (25%)	1	1/5 (20%)	1	0/5 (0%)	0	0/30 (0%)	0
Metabolism and nutrition disorders
Hyperglycemia	0/6 (0%)	0	2/4 (50%)	2	3/5 (60%)	5	0/5 (0%)	0	6/30 (20%)	9
Anorexia	2/6 (33.3%)	2	2/4 (50%)	2	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Hyperkalemia	0/6 (0%)	0	2/4 (50%)	3	1/5 (20%)	1	0/5 (0%)	0	3/30 (10%)	4
Hyperuricemia	0/6 (0%)	0	2/4 (50%)	5	2/5 (40%)	3	0/5 (0%)	0	2/30 (6.7%)	2
Hypocalcemia	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	5/30 (16.7%)	11
Hypokalemia	1/6 (16.7%)	1	0/4 (0%)	0	0/5 (0%)	0	1/5 (20%)	2	3/30 (10%)	3
Dehydration	0/6 (0%)	0	1/4 (25%)	1	1/5 (20%)	1	0/5 (0%)	0	1/30 (3.3%)	1
Hypoalbuminemia	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	4
Hyponatremia	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	1/5 (20%)	1	0/30 (0%)	0
Acideosis	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Hypercalcemia	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Hypomagnesemia	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Tumor lysis syndrome	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Metabolism and nutrition disorders -Other	1/6 (16.7%)	1	3/4 (75%)	7	2/5 (40%)	4	0/5 (0%)	0	1/30 (3.3%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	1/6 (16.7%)	1	1/4 (25%)	2	1/5 (20%)	3	2/5 (40%)	2	5/30 (16.7%)	9
Back pain	0/6 (0%)	0	1/4 (25%)	2	0/5 (0%)	0	1/5 (20%)	1	7/30 (23.3%)	8
Generalized muscle weakness	1/6 (16.7%)	1	2/4 (50%)	2	0/5 (0%)	0	0/5 (0%)	0	3/30 (10%)	3
Myalgia	1/6 (16.7%)	1	1/4 (25%)	1	1/5 (20%)	1	2/5 (40%)	2	1/30 (3.3%)	1
Bone pain	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	4/30 (13.3%)	4
Flank pain	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Muscle weakness left-sided	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Muscle weakness lower limb	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Arthritis	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/30 (0%)	0
Muscle weakness upper limb	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Neck pain	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Musculoskeletal and connective tissue disorder -Other	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	1/5 (20%)	1	2/30 (6.7%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant or unspecified -Other	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Nervous system disorders
Dizziness	0/6 (0%)	0	0/4 (0%)	0	2/5 (40%)	4	0/5 (0%)	0	9/30 (30%)	15
Headache	2/6 (33.3%)	2	1/4 (25%)	1	2/5 (40%)	3	0/5 (0%)	0	7/30 (23.3%)	9
Syncope	1/6 (16.7%)	2	0/4 (0%)	0	1/5 (20%)	1	2/5 (40%)	2	2/30 (6.7%)	2
Peripheral sensory neuropathy	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	1/5 (20%)	1	3/30 (10%)	5
Parathesia	1/6 (16.7%)	1	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	3/30 (10%)	3
Movements involuntary	1/6 (16.7%)	1	2/4 (50%)	2	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Brachial plexopathy	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Concentration impairment	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/5 (20%)	2	1/30 (3.3%)	1
Dysesthesia	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Dysgeusia	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Encephalopathy	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Facial muscle weakness	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	2
Meningismus	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Somnolence	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Spasticity	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	0/30 (0%)	0
Nervous system disorders -Other	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Psychiatric disorders
Anxiety	0/6 (0%)	0	2/4 (50%)	2	2/5 (40%)	3	0/5 (0%)	0	6/30 (20%)	7
Insomnia	3/6 (50%)	3	1/4 (25%)	1	1/5 (20%)	2	0/5 (0%)	0	5/30 (16.7%)	6
Depression	1/6 (16.7%)	1	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Confusion	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Delirium	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Psychiatric disorders -Other	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	3
Renal and urinary disorders
Acute kidney injury	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	4/30 (13.3%)	5
Urinary frequency	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	3/30 (10%)	3
Urinary urgency	1/6 (16.7%)	1	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Hematuria	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	3
Urine discoloration	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	1/30 (3.3%)	1
Renal calculi	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/30 (0%)	0
Urinary tract obstruction	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Renal and urinary disorders -Other	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Reproductive system and breast disorders
Pelvic pain	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Testicular disorder	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	5/6 (83.3%)	5	3/4 (75%)	6	2/5 (40%)	2	1/5 (20%)	1	8/30 (26.7%)	11
Cough	2/6 (33.3%)	2	2/4 (50%)	8	2/5 (40%)	5	0/5 (0%)	0	9/30 (30%)	11
Nasal congestion	1/6 (16.7%)	1	0/4 (0%)	0	1/5 (20%)	1	2/5 (40%)	2	4/30 (13.3%)	6
Sore throat	0/6 (0%)	0	1/4 (25%)	5	1/5 (20%)	2	1/5 (20%)	2	4/30 (13.3%)	4
Productive cough	1/6 (16.7%)	1	1/4 (25%)	2	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Hypoxia	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Pleural effusion	2/6 (33.3%)	2	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Respiratory failure	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	3/30 (10%)	3
Epistaxis	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	1/30 (3.3%)	1
Hoarseness	1/6 (16.7%)	1	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Pneumonitis	0/6 (0%)	0	1/4 (25%)	2	0/5 (0%)	0	1/5 (20%)	1	0/30 (0%)	0
Postnasal drip	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	1/5 (20%)	1	1/30 (3.3%)	1
Pulmonary edema	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2
Adult respiratory distress syndrome	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Bronchial stricture	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Laryngeal hemorrhage	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Pleuritic pain	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/30 (0%)	0
Pulmonary fibrosis	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Pulmonary hypertension	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Sneezing	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/30 (0%)	0
Voice alteration	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Wheezing	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Respiratory, thoracic and mediastinal disorders - other	1/6 (16.7%)	1	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	5/30 (16.7%)	5
Skin and subcutaneous tissue disorders
Pruritus	0/6 (0%)	0	1/4 (25%)	1	2/5 (40%)	2	0/5 (0%)	0	5/30 (16.7%)	5
Rash maculo-papular	1/6 (16.7%)	1	0/4 (0%)	0	1/5 (20%)	2	0/5 (0%)	0	3/30 (10%)	4
Hyperhidrosis	0/6 (0%)	0	2/4 (50%)	4	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Alopecia	0/6 (0%)	0	1/4 (25%)	1	1/5 (20%)	1	0/5 (0%)	0	0/30 (0%)	0
Rash acneiform	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	1/30 (3.3%)	1
Erythroderma	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Hypohidrosis	1/6 (16.7%)	1	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	0/30 (0%)	0
Pain of skin	0/6 (0%)	0	0/4 (0%)	0	1/5 (20%)	1	0/5 (0%)	0	0/30 (0%)	0
Skin ulceration	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Skin and subcutaneous tissue disorders -other	0/6 (0%)	0	1/4 (25%)	2	1/5 (20%)	5	0/5 (0%)	0	6/30 (20%)	7
Surgical and medical procedures
Surgical and medical procedures - Other	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	3
Vascular disorders
Hot flashes	0/6 (0%)	0	1/4 (25%)	1	1/5 (20%)	1	0/5 (0%)	0	2/30 (6.7%)	2
Hypotension	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	5/30 (16.7%)	5
Hematoma	1/6 (16.7%)	1	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	3
Hypertension	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	3/30 (10%)	3
Flushing	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Lymphedema	0/6 (0%)	0	0/4 (0%)	0	0/5 (0%)	0	0/5 (0%)	0	1/30 (3.3%)	1
Vascular disorders - Other	0/6 (0%)	0	1/4 (25%)	1	0/5 (0%)	0	0/5 (0%)	0	2/30 (6.7%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.