Phase I Trial of Vorinostat (MK-0683, SAHA) in Combination With Decitabine in Patients With AML or MDS (MK-0683-055 EXT1)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00479232
• Collaborator: (none)
• Enrollment: 71
• Arms: 2
• Duration (Months): 57

Study Details

Study Description

Brief Summary

This study is to evaluate the safety and tolerability of vorinostat in combination with decitabine as well as the in vivo molecular and biological effects of vorinostat in patients with refractory or relapsed Acute Myelogenous Leukemia (AML) and intermediate or high risk as defined by International Prognostic Scoring System (IPSS) Myelodysplastic Syndrome (MDS). Participants with Acute Myelogenous Leukemia or Myelodysplastic Syndrome are eligible.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Myelocytic, Acute Myelodysplastic Syndromes; Myelodysplastic Syndromes	Drug: vorinostat; Drug: decitabine	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Clinical Trial of Vorinostat in Combination With Decitabine in Patients With Acute Myelogenous Leukemia or Myelodysplastic Syndrome
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Apr 1, 2010
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1: Vorinostat (sequential) Vorinostat 400 mg capsules once daily given 7, 10 or 14 days in 28 day cycles. Up to 24 months of treatment. Decitabine IV 20 mg/m^2 daily for 5 days in each 28 day cycle. Up to 24 months of treatment.	Drug: vorinostat; Other Names: MK-0683 SAHA ; Drug: decitabine; Other Names: Dacogen
Experimental: Cohort 2: Vorinostat (concurrent) Vorinostat 400 mg capsules once daily given 7 days, 14 days with 8 day break after first 7 days or 14 days without break, out of 28 day cycles. Decitabine IV 20 mg/m^2 daily for 5 days in each 28 day cycle. Up to 24 months of treatment.	Drug: vorinostat; Other Names: MK-0683 SAHA ; Drug: decitabine; Other Names: Dacogen

Outcome Measures

Primary Outcome Measures

1. Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events [Day 1 to 28 of Cycle 1]

   Participants who received at least one dose of vorinostat in combination with decitabine intravenous (IV) at a dose of 20 mg/m^2 daily for 5 days along with oral vorinostat 400 mg once daily for 7 to 14 days in a 28-day cycle concurrently or sequentially, were evaluated to determine the maximum tolerable dose (MTD) determined by the number of participants experiencing dose limiting toxicity (DLT) events defined as any Grade 3 or 4 non-hematological toxicity (reported adverse event) and/or myelosuppression lasting >42 days.

Other Outcome Measures

1. Objective Response Rate in Participants Treated With Vorinostat + Decitabine With Refractory or Relapse Acute Myelogenous Leukemia (AML) [Approximately 6 months]

   Objective Response Rate was measured in participants with refractory or relapse AML (acute myelogenous leukemia) in combination with Decitabine who were treated with vorinostat and decitabine on either a concurrent or sequential regimen. The Objective response was defined as any confirmed complete remission or any confirmed partial remission for AML participants and complete remission, confirmed partial remission or confirmed hematologic improvement for Myelodysplastic Syndrome (MDS) participants.

2. Objective Response Rate in Participants Treated With Vorinostat + Decitabine With Intermediate-high Risk Myelodysplastic Syndrome (MDS) or Untreated Acute Myelogenous Leukemia (AML) [Approximately 6 months]

   Objective Response Rate was measured in participants with intermediate-high risk MDS or untreated AML who were treated with vorinostat and decitabine either on a concurrent or sequential regimen. The Objective response was defined as any confirmed complete remission or any confirmed partial remission for AML participants and complete remission, confirmed partial remission or confirmed hematologic improvement for MDS participants.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patient is at least 18 years old with refractory/relapsed AML

• If untreated AML, patient is older than 60 years old and not a candidate for standard chemotherapy

• Patient is at least 4 weeks from prior treatment and has recovered from all prior treatment side effects

• Patient has no known liver or kidney problems

• Patient knows of no reason they can not receive transfusions of blood clotting cells (platelets)

• Patient is able to swallow capsules

• Patients both male and female are willing to practice birth control during the study

Exclusion Criteria:

• Patient has received prior treatment with valproic acid, decitabine or azacitidine

• Being is less than 18 years of age or if patient has untreated AML is below 60 years of age

• Patient is a women who is pregnant or breastfeeding. Patient has an active infection that requires antibiotics

• Patient has uncontrolled illness including but not limited to the following: heart problems (congestive heart failure, unstable angina pectoris, cardiac arrhythmia), inflammation of the pancreas; a mental or social condition that may interfere with patient following study procedures

• Patient has known human immunodeficiency virus (HIV) infection or HIV-related malignancy. Patient has a known history of hepatitis B or C infection

• Patient currently has another active cancer other than certain types of skin cancer

• Patient is heterosexual and able to have a child and is unwilling to practice birth control during the study

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Monitor, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT00479232
• Other Study ID Numbers: 0683-055; 2007_500
• First Posted: May 28, 2007
• Last Update Posted: Sep 21, 2015
• Last Verified: Sep 1, 2015

• Keywords provided by Merck Sharp & Dohme LLC: Leukemia; Myelocytic; Acute Myelodysplastic Syndromes
• Additional relevant MeSH terms: Leukemia; Preleukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Syndrome; Decitabine; Vorinostat

Study Results

Participant Flow

Arm/Group Title	Concurrent, Vorinostat 400mg qd x 7d/4wk + Decitabine	Concurrent, Vorinostat 400mg qd x 7d/2wk + Decitabine	Concurrent, Vorinostat 400mg qd x 14d/4wk + Decitabine (MTD)	Sequential, Vorinostat 400mg qd x 7d/4wk + Decitabine	Sequential, Vorinostat 400mg qd x 10d/4wk + Decitabine	Sequential, Vorinostat 400mg qd x 14d/4wk + Decitabine (MTD)
Arm/Group Description	(concurrent) vorinostat 400 mg capsules given once daily (qd) on Days 1 to 7 in a 28 day cycle, along with decitabine intravenous (IV) 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.	(concurrent) vorinostat 400 mg capsules given qd on Days 1 to 7 and Days 15 to 21 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.	(concurrent) vorinostat 400 mg capsules given qd on Days 1 to 14 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.	(sequential) vorinostat 400 mg capsules given qd on Days 6 to 12 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.	(sequential) vorinostat 400 mg capsules given qd on Days 6 to 15 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.	(sequential) vorinostat 400 mg capsules given qd on Days 6 to 19 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.
Period Title: Overall Study
STARTED	3	3	28	3	4	30
COMPLETED	0	0	0	0	0	0
NOT COMPLETED	3	3	28	3	4	30

Baseline Characteristics

Arm/Group Title	Vorinostat + Decitabine, Concurrent	Vorinostat + Decitabine, Sequential	Total
Arm/Group Description	(concurrent) Vorinostat 400 mg capsules once daily given 7 days, 14 days with 8 day break after first 7 days or 14 days without break, out of 28 day cycles along with decitabine IV 20 mg/m^2 daily for 5 days in each 28 day cycle. Up to 24 months of treatment.	(sequential) Vorinostat 400 mg capsules once daily given 7, 10 or 14 days in 28 day cycles along with decitabine IV 20 mg/m^2 daily for 5 days in each 28 day cycle. Up to 24 months of treatment.	Total of all reporting groups
Overall Participants	34	37	71
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63.9 (13.0)	66.6 (13.8)	65.3 (13.4)
Sex: Female, Male (Count of Participants)
Female	11 32.4%	18 48.6%	29 40.8%
Male	23 67.6%	19 51.4%	42 59.2%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Experiencing Dose Limiting Toxicity (DLT) Events
Description	Participants who received at least one dose of vorinostat in combination with decitabine intravenous (IV) at a dose of 20 mg/m^2 daily for 5 days along with oral vorinostat 400 mg once daily for 7 to 14 days in a 28-day cycle concurrently or sequentially, were evaluated to determine the maximum tolerable dose (MTD) determined by the number of participants experiencing dose limiting toxicity (DLT) events defined as any Grade 3 or 4 non-hematological toxicity (reported adverse event) and/or myelosuppression lasting >42 days.
Time Frame	Day 1 to 28 of Cycle 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Concurrent, Vorinostat 400mg qd x 7d/4wk + Decitabine	Concurrent, Vorinostat 400mg qd x 7d/2wk + Decitabine	Concurrent, Vorinostat 400mg qd x 14d/4wk + Decitabine (MTD)	Sequential, Vorinostat 400mg qd x 7d/4wk + Decitabine	Sequential, Vorinostat 400mg qd x 10d/4wk + Decitabine	Sequential, Vorinostat 400mg qd x 14d/4wk + Decitabine (MTD)
Arm/Group Description	(concurrent) vorinostat 400 mg capsules given once daily on Days 1 to 7 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.	(concurrent) vorinostat 400 mg capsules given once daily on Days 1 to 7 and Days 15 to 21 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.	(concurrent) vorinostat 400 mg capsules given once daily on Days 1 to 14 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.	(sequential) vorinostat 400 mg capsules given once daily on Days 6 to 12 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.	(sequential) vorinostat 400 mg capsules given once daily on Days 6 to 15 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.	(sequential) vorinostat 400 mg capsules given once daily on Days 6 to 19 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.
Measure Participants	3	3	28	3	4	30
Number [participants]	0 0%	0 0%	0 0%	0 NaN	0 NaN	1 NaN

2. Other Pre-specified Outcome

Title	Objective Response Rate in Participants Treated With Vorinostat + Decitabine With Refractory or Relapse Acute Myelogenous Leukemia (AML)
Description	Objective Response Rate was measured in participants with refractory or relapse AML (acute myelogenous leukemia) in combination with Decitabine who were treated with vorinostat and decitabine on either a concurrent or sequential regimen. The Objective response was defined as any confirmed complete remission or any confirmed partial remission for AML participants and complete remission, confirmed partial remission or confirmed hematologic improvement for Myelodysplastic Syndrome (MDS) participants.
Time Frame	Approximately 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Refractory or Relapsed AML, Concurrent	Refractory or Relapsed AML, Sequential
Arm/Group Description	Participants with Refractory or Relapsed AML who were treated with vorinostat and Decitabine concurrently.	Participants with Refractory or Relapsed AML who were treated with vorinostat and Decitabine sequentially.
Measure Participants	14	15
Number [percentage of participants]	7.1 (0) 20.9%	0.0 (NA) 0%

3. Other Pre-specified Outcome

Title	Objective Response Rate in Participants Treated With Vorinostat + Decitabine With Intermediate-high Risk Myelodysplastic Syndrome (MDS) or Untreated Acute Myelogenous Leukemia (AML)
Description	Objective Response Rate was measured in participants with intermediate-high risk MDS or untreated AML who were treated with vorinostat and decitabine either on a concurrent or sequential regimen. The Objective response was defined as any confirmed complete remission or any confirmed partial remission for AML participants and complete remission, confirmed partial remission or confirmed hematologic improvement for MDS participants.
Time Frame	Approximately 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Untreated AML or Intermediate, Concurrent	Untreated AML or Intermediate, Sequential
Arm/Group Description	Participants with Untreated AML or Intermediate-High Risk MDS who were treated with vorinostat and Decitabine concurrently.	Participants with Untreated AML or Intermediate-High Risk MDS who were treated with vorinostat and Decitabine sequentially.
Measure Participants	20	22
Number [percentage of participants]	35.0 (170.3) 102.9%	13.6 (119.2) 36.8%

Adverse Events

Arm/Group Title	Concurrent, Vorinostat 400 mg qd x 7d/4wk + Decitabine		Concurrent, Vorinostat 400 mg qd x 7d/2wk + Decitabine		Concurrent, Vorinostat 400 mg qd x 14d/4wk + Decitabine (MTD)		Sequential, Vorinostat 400 mg qd x 7d/4wk + Decitabine		Sequential, Vorinostat 400 mg qd x 10d/4wk + Decitabine		Sequential,Vorinostat 400 mg qd x 14d/4wk + Decitabine (MTD)
Arm/Group Description	(concurrent) vorinostat 400 mg capsules given once daily on Days 1 to 7 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.		(concurrent) vorinostat 400 mg capsules given once daily on Days 1 to 7 and Days 15 to 21 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.		(concurrent) vorinostat 400 mg capsules given once daily on Days 1 to 14 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.		(sequential) vorinostat 400 mg capsules given once daily on Days 6 to 12 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.		(sequential) vorinostat 400 mg capsules given once daily on Days 6 to 15 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.		(sequential) orinostat 400 mg capsules given once daily on Days 6 to 19 in a 28 day cycle, along with decitabine IV 20mg/m^2 daily for 5 days in each 28 day cycle, up to 24 months of treatment.
All Cause Mortality
	Concurrent, Vorinostat 400 mg qd x 7d/4wk + Decitabine		Concurrent, Vorinostat 400 mg qd x 7d/2wk + Decitabine		Concurrent, Vorinostat 400 mg qd x 14d/4wk + Decitabine (MTD)		Sequential, Vorinostat 400 mg qd x 7d/4wk + Decitabine		Sequential, Vorinostat 400 mg qd x 10d/4wk + Decitabine		Sequential,Vorinostat 400 mg qd x 14d/4wk + Decitabine (MTD)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Concurrent, Vorinostat 400 mg qd x 7d/4wk + Decitabine		Concurrent, Vorinostat 400 mg qd x 7d/2wk + Decitabine		Concurrent, Vorinostat 400 mg qd x 14d/4wk + Decitabine (MTD)		Sequential, Vorinostat 400 mg qd x 7d/4wk + Decitabine		Sequential, Vorinostat 400 mg qd x 10d/4wk + Decitabine		Sequential,Vorinostat 400 mg qd x 14d/4wk + Decitabine (MTD)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		1/3 (33.3%)		21/28 (75%)		2/3 (66.7%)		4/4 (100%)		25/31 (80.6%)
Blood and lymphatic system disorders
Febrile neutropenia	1/3 (33.3%)	2	1/3 (33.3%)	1	12/28 (42.9%)	16	1/3 (33.3%)	1	1/4 (25%)	1	7/31 (22.6%)	8
Leukopenia	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Neutropenia	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	4	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Thrombocytosis	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Cardiac disorders
Acute myocardial infarction	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Atrial fibrillation	2/3 (66.7%)	2	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Cardiac arrest	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Myocardial infarction	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Pericardial effusion	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Sinus bradycardia	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Tachycardia	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Gastrointestinal disorders
Caecitis	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/31 (0%)	0
Diarrhoea	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Haematemesis	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Nausea	1/3 (33.3%)	1	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Pancreatitis	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Small intestinal obstruction	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Vomiting	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
General disorders
Death	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Multi-organ failure	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Pyrexia	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	1/3 (33.3%)	1	0/4 (0%)	0	3/31 (9.7%)	5
Hepatobiliary disorders
Cholecystitis	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Infections and infestations
Bacterial sepsis	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Cellulitis	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	1/3 (33.3%)	1	0/4 (0%)	0	2/31 (6.5%)	2
Clostridium bacteraemia	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Enterococcal bacteraemia	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Enterococcal infection	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Gastroenteritis clostridial	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Klebsiella infection	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Klebsiella sepsis	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Lung infection	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Oesophageal candidiasis	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Perirectal abscess	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Pneumonia	3/3 (100%)	3	0/3 (0%)	0	6/28 (21.4%)	7	0/3 (0%)	0	2/4 (50%)	4	1/31 (3.2%)	1
Pneumonia fungal	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Pneumonia primary atypical	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Sepsis	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/31 (3.2%)	1
Staphylococcal bacteraemia	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Streptococcal bacteraemia	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Urinary tract infection	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Urosepsis	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Injury, poisoning and procedural complications
Spinal compression fracture	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Investigations
Electrocardiogram QT prolonged	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Metabolism and nutrition disorders
Dehydration	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Hyponatraemia	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Musculoskeletal and connective tissue disorders
Myositis	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/3 (33.3%)	1	0/3 (0%)	0	2/28 (7.1%)	2	1/3 (33.3%)	1	1/4 (25%)	1	3/31 (9.7%)	3
Myelofibrosis	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Squamous cell carcinoma	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Nervous system disorders
Cerebral infarction	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Cerebrovascular accident	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Dizziness	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Syncope	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Psychiatric disorders
Mental status changes	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Renal and urinary disorders
Haematuria	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Renal failure	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Renal failure acute	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Pulmonary embolism	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Respiratory failure	1/3 (33.3%)	1	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Skin and subcutaneous tissue disorders
Erythema	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Rash	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Vascular disorders
Deep vein thrombosis	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Orthostatic hypotension	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Thrombophlebitis	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Other (Not Including Serious) Adverse Events
	Concurrent, Vorinostat 400 mg qd x 7d/4wk + Decitabine		Concurrent, Vorinostat 400 mg qd x 7d/2wk + Decitabine		Concurrent, Vorinostat 400 mg qd x 14d/4wk + Decitabine (MTD)		Sequential, Vorinostat 400 mg qd x 7d/4wk + Decitabine		Sequential, Vorinostat 400 mg qd x 10d/4wk + Decitabine		Sequential,Vorinostat 400 mg qd x 14d/4wk + Decitabine (MTD)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		3/3 (100%)		27/28 (96.4%)		3/3 (100%)		4/4 (100%)		29/31 (93.5%)
Blood and lymphatic system disorders
Anaemia	2/3 (66.7%)	2	1/3 (33.3%)	3	3/28 (10.7%)	6	2/3 (66.7%)	2	1/4 (25%)	1	3/31 (9.7%)	3
Febrile neutropenia	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	1/3 (33.3%)	2	0/4 (0%)	0	3/31 (9.7%)	4
Granulocytopenia	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	1/3 (33.3%)	4	0/4 (0%)	0	0/31 (0%)	0
Leukopenia	2/3 (66.7%)	2	2/3 (66.7%)	10	8/28 (28.6%)	17	2/3 (66.7%)	4	1/4 (25%)	1	3/31 (9.7%)	5
Lymphadenopathy	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Neutropenia	0/3 (0%)	0	3/3 (100%)	6	9/28 (32.1%)	20	0/3 (0%)	0	0/4 (0%)	0	6/31 (19.4%)	12
Thrombocytopenia	0/3 (0%)	0	1/3 (33.3%)	5	11/28 (39.3%)	31	1/3 (33.3%)	2	1/4 (25%)	1	8/31 (25.8%)	20
Cardiac disorders
Arrhythmia	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	0/31 (0%)	0
Palpitations	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Sinus bradycardia	0/3 (0%)	0	1/3 (33.3%)	1	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Sinus tachycardia	3/3 (100%)	4	0/3 (0%)	0	1/28 (3.6%)	1	1/3 (33.3%)	1	1/4 (25%)	1	0/31 (0%)	0
Tachycardia	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	2
Ear and labyrinth disorders
Ear pain	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	2
Vertigo	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/31 (3.2%)	1
Eye disorders
Cataract	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Conjunctivitis	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Retinopathy	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Vision blurred	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/31 (3.2%)	1
Vitreous floaters	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Gastrointestinal disorders
Abdominal discomfort	0/3 (0%)	0	0/3 (0%)	0	3/28 (10.7%)	3	0/3 (0%)	0	1/4 (25%)	1	3/31 (9.7%)	3
Abdominal distension	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	1/3 (33.3%)	1	1/4 (25%)	1	3/31 (9.7%)	3
Abdominal pain	1/3 (33.3%)	1	1/3 (33.3%)	1	7/28 (25%)	7	1/3 (33.3%)	1	1/4 (25%)	3	3/31 (9.7%)	3
Abdominal pain lower	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/31 (3.2%)	1
Abdominal pain upper	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	2/31 (6.5%)	2
Cheilitis	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Constipation	2/3 (66.7%)	2	0/3 (0%)	0	16/28 (57.1%)	24	1/3 (33.3%)	2	3/4 (75%)	5	11/31 (35.5%)	15
Diarrhoea	2/3 (66.7%)	3	3/3 (100%)	4	16/28 (57.1%)	25	1/3 (33.3%)	1	3/4 (75%)	3	15/31 (48.4%)	21
Dry mouth	0/3 (0%)	0	0/3 (0%)	0	3/28 (10.7%)	3	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	3
Dyspepsia	1/3 (33.3%)	1	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	3/4 (75%)	3	1/31 (3.2%)	1
Eructation	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Flatulence	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	3
Gastrooesophageal reflux disease	1/3 (33.3%)	1	0/3 (0%)	0	1/28 (3.6%)	1	1/3 (33.3%)	1	1/4 (25%)	1	0/31 (0%)	0
Gingival bleeding	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Gingivitis	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Haemorrhoids	0/3 (0%)	0	0/3 (0%)	0	5/28 (17.9%)	5	0/3 (0%)	0	1/4 (25%)	1	3/31 (9.7%)	3
Lip dry	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Melaena	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Mouth haemorrhage	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	2
Nausea	2/3 (66.7%)	3	1/3 (33.3%)	2	17/28 (60.7%)	29	3/3 (100%)	3	3/4 (75%)	4	20/31 (64.5%)	25
Oral pain	1/3 (33.3%)	1	1/3 (33.3%)	1	2/28 (7.1%)	3	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Proctalgia	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	3/31 (9.7%)	3
Rectal haemorrhage	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Vomiting	1/3 (33.3%)	1	1/3 (33.3%)	1	10/28 (35.7%)	15	2/3 (66.7%)	2	2/4 (50%)	3	11/31 (35.5%)	12
General disorders
Asthenia	0/3 (0%)	0	0/3 (0%)	0	7/28 (25%)	7	0/3 (0%)	0	2/4 (50%)	2	4/31 (12.9%)	4
Catheter site erythema	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Catheter site pain	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Chest discomfort	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	2
Chest pain	1/3 (33.3%)	1	0/3 (0%)	0	2/28 (7.1%)	3	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	2
Chills	0/3 (0%)	0	1/3 (33.3%)	1	11/28 (39.3%)	12	1/3 (33.3%)	1	1/4 (25%)	2	2/31 (6.5%)	3
Fatigue	3/3 (100%)	3	1/3 (33.3%)	1	11/28 (39.3%)	20	2/3 (66.7%)	2	3/4 (75%)	4	19/31 (61.3%)	24
Gait disturbance	0/3 (0%)	0	0/3 (0%)	0	3/28 (10.7%)	4	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Influenza like illness	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	1/4 (25%)	1	1/31 (3.2%)	1
Infusion site pain	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Injection site pruritus	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Mucosal inflammation	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	2	1/3 (33.3%)	1	1/4 (25%)	1	2/31 (6.5%)	2
Oedema	0/3 (0%)	0	1/3 (33.3%)	1	1/28 (3.6%)	1	1/3 (33.3%)	1	1/4 (25%)	1	2/31 (6.5%)	2
Oedema peripheral	1/3 (33.3%)	1	0/3 (0%)	0	5/28 (17.9%)	6	0/3 (0%)	0	1/4 (25%)	1	7/31 (22.6%)	9
Pain	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	4/31 (12.9%)	4
Pyrexia	0/3 (0%)	0	1/3 (33.3%)	1	7/28 (25%)	9	0/3 (0%)	0	0/4 (0%)	0	5/31 (16.1%)	5
Hepatobiliary disorders
Hyperbilirubinaemia	0/3 (0%)	0	0/3 (0%)	0	7/28 (25%)	10	1/3 (33.3%)	1	0/4 (0%)	0	0/31 (0%)	0
Infections and infestations
Cellulitis	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	1/3 (33.3%)	1	0/4 (0%)	0	2/31 (6.5%)	2
Diverticulitis	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/31 (0%)	0
Folliculitis	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Oral herpes	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Paronychia	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Upper respiratory tract infection	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	3/31 (9.7%)	3
Urinary tract infection	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	3/31 (9.7%)	3
Vulvovaginal mycotic infection	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/3 (0%)	0	1/3 (33.3%)	1	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Excoriation	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	1/4 (25%)	2	0/31 (0%)	0
Wound	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Investigations
Alanine aminotransferase increased	1/3 (33.3%)	1	0/3 (0%)	0	4/28 (14.3%)	5	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	17
Aspartate aminotransferase increased	1/3 (33.3%)	1	0/3 (0%)	0	3/28 (10.7%)	5	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	7
Blood alkaline phosphatase increased	2/3 (66.7%)	2	0/3 (0%)	0	2/28 (7.1%)	2	1/3 (33.3%)	2	0/4 (0%)	0	1/31 (3.2%)	3
Blood bicarbonate decreased	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	2	1/3 (33.3%)	2	1/4 (25%)	1	0/31 (0%)	0
Blood calcium decreased	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Blood creatinine increased	0/3 (0%)	0	0/3 (0%)	0	4/28 (14.3%)	6	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	4
Blood glucose increased	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Blood potassium decreased	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Electrocardiogram QT prolonged	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	2
Gamma-glutamyltransferase increased	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	3/31 (9.7%)	6
Granulocyte count decreased	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/31 (0%)	0
Haemoglobin decreased	1/3 (33.3%)	2	1/3 (33.3%)	1	0/28 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	1/31 (3.2%)	2
Neutrophil count decreased	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Platelet count decreased	1/3 (33.3%)	1	1/3 (33.3%)	1	0/28 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/31 (0%)	0
Prothrombin time prolonged	0/3 (0%)	0	0/3 (0%)	0	3/28 (10.7%)	3	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Weight decreased	0/3 (0%)	0	0/3 (0%)	0	4/28 (14.3%)	4	1/3 (33.3%)	1	0/4 (0%)	0	1/31 (3.2%)	1
Weight increased	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
White blood cell count decreased	1/3 (33.3%)	1	1/3 (33.3%)	1	0/28 (0%)	0	2/3 (66.7%)	3	0/4 (0%)	0	0/31 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	1/3 (33.3%)	1	2/3 (66.7%)	2	9/28 (32.1%)	14	2/3 (66.7%)	2	1/4 (25%)	1	10/31 (32.3%)	13
Dehydration	1/3 (33.3%)	1	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	3/31 (9.7%)	3
Diabetes mellitus	1/3 (33.3%)	1	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Fluid retention	1/3 (33.3%)	1	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Haemosiderosis	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Hyperglycaemia	1/3 (33.3%)	1	0/3 (0%)	0	5/28 (17.9%)	6	2/3 (66.7%)	4	1/4 (25%)	2	2/31 (6.5%)	2
Hyperkalaemia	1/3 (33.3%)	1	1/3 (33.3%)	1	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Hypermagnesaemia	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Hypoalbuminaemia	2/3 (66.7%)	2	0/3 (0%)	0	5/28 (17.9%)	6	2/3 (66.7%)	2	1/4 (25%)	1	2/31 (6.5%)	4
Hypocalcaemia	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	3/3 (100%)	5	0/4 (0%)	0	2/31 (6.5%)	6
Hypokalaemia	0/3 (0%)	0	0/3 (0%)	0	7/28 (25%)	13	2/3 (66.7%)	2	1/4 (25%)	1	6/31 (19.4%)	8
Hypomagnesaemia	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	3/31 (9.7%)	5
Hyponatraemia	0/3 (0%)	0	0/3 (0%)	0	5/28 (17.9%)	8	2/3 (66.7%)	2	1/4 (25%)	1	4/31 (12.9%)	5
Hypophagia	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Hypophosphataemia	2/3 (66.7%)	2	1/3 (33.3%)	1	4/28 (14.3%)	5	3/3 (100%)	4	2/4 (50%)	2	1/31 (3.2%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/3 (33.3%)	1	1/3 (33.3%)	1	6/28 (21.4%)	6	1/3 (33.3%)	1	0/4 (0%)	0	3/31 (9.7%)	10
Back pain	0/3 (0%)	0	1/3 (33.3%)	1	5/28 (17.9%)	6	0/3 (0%)	0	0/4 (0%)	0	3/31 (9.7%)	4
Bone pain	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	0/31 (0%)	0
Muscle spasms	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Muscular weakness	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Musculoskeletal pain	0/3 (0%)	0	0/3 (0%)	0	3/28 (10.7%)	5	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Myalgia	0/3 (0%)	0	1/3 (33.3%)	1	4/28 (14.3%)	4	0/3 (0%)	0	1/4 (25%)	1	1/31 (3.2%)	1
Neck pain	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Pain in extremity	0/3 (0%)	0	2/3 (66.7%)	2	3/28 (10.7%)	3	1/3 (33.3%)	1	0/4 (0%)	0	4/31 (12.9%)	8
Pain in jaw	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	1/3 (33.3%)	1	0/4 (0%)	0	0/31 (0%)	0
Rhabdomyolysis	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Nervous system disorders
Dizziness	1/3 (33.3%)	1	0/3 (0%)	0	11/28 (39.3%)	16	0/3 (0%)	0	1/4 (25%)	1	7/31 (22.6%)	9
Dysgeusia	0/3 (0%)	0	0/3 (0%)	0	3/28 (10.7%)	4	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Headache	3/3 (100%)	3	2/3 (66.7%)	3	7/28 (25%)	9	1/3 (33.3%)	1	0/4 (0%)	0	5/31 (16.1%)	6
Hypoaesthesia	0/3 (0%)	0	0/3 (0%)	0	3/28 (10.7%)	4	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	2
Neuropathy peripheral	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	2
Paraesthesia	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	1/3 (33.3%)	1	0/4 (0%)	0	1/31 (3.2%)	1
Somnolence	1/3 (33.3%)	1	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	2
Tremor	0/3 (0%)	0	0/3 (0%)	0	4/28 (14.3%)	4	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Psychiatric disorders
Agitation	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Anxiety	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Confusional state	1/3 (33.3%)	1	0/3 (0%)	0	4/28 (14.3%)	6	0/3 (0%)	0	1/4 (25%)	1	1/31 (3.2%)	1
Depression	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	4/31 (12.9%)	4
Hallucination, visual	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	2
Insomnia	0/3 (0%)	0	1/3 (33.3%)	1	4/28 (14.3%)	5	1/3 (33.3%)	1	1/4 (25%)	1	4/31 (12.9%)	4
Renal and urinary disorders
Bladder spasm	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Dysuria	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	2/31 (6.5%)	2
Haematuria	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	3
Pollakiuria	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Urinary hesitation	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Urinary incontinence	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	2/31 (6.5%)	2
Reproductive system and breast disorders
Testis discomfort	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Vulvovaginal pruritus	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	2/3 (66.7%)	3	1/3 (33.3%)	1	6/28 (21.4%)	6	1/3 (33.3%)	1	2/4 (50%)	2	9/31 (29%)	9
Dyspnoea	1/3 (33.3%)	1	0/3 (0%)	0	3/28 (10.7%)	3	0/3 (0%)	0	2/4 (50%)	3	3/31 (9.7%)	3
Dyspnoea exertional	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	4	1/3 (33.3%)	1	1/4 (25%)	1	2/31 (6.5%)	2
Epistaxis	1/3 (33.3%)	2	0/3 (0%)	0	3/28 (10.7%)	4	0/3 (0%)	0	1/4 (25%)	1	1/31 (3.2%)	1
Haemoptysis	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	1/31 (3.2%)	1
Oropharyngeal pain	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	3	0/3 (0%)	0	0/4 (0%)	0	6/31 (19.4%)	6
Painful respiration	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Pleuritic pain	1/3 (33.3%)	1	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	1/4 (25%)	2	2/31 (6.5%)	3
Pulmonary oedema	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Respiratory distress	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Respiratory failure	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	2
Rhinitis allergic	0/3 (0%)	0	1/3 (33.3%)	1	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Rhinorrhoea	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Sinus congestion	0/3 (0%)	0	1/3 (33.3%)	1	2/28 (7.1%)	5	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Wheezing	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	1/4 (25%)	1	1/31 (3.2%)	1
Skin and subcutaneous tissue disorders
Dry skin	0/3 (0%)	0	0/3 (0%)	0	3/28 (10.7%)	3	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	2
Ecchymosis	0/3 (0%)	0	0/3 (0%)	0	3/28 (10.7%)	5	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Erythema	0/3 (0%)	0	0/3 (0%)	0	3/28 (10.7%)	3	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	2
Hyperhidrosis	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	3/31 (9.7%)	3
Increased tendency to bruise	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	1/31 (3.2%)	1
Night sweats	0/3 (0%)	0	1/3 (33.3%)	1	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	2
Petechiae	2/3 (66.7%)	2	0/3 (0%)	0	1/28 (3.6%)	1	1/3 (33.3%)	1	1/4 (25%)	1	3/31 (9.7%)	3
Pruritus	1/3 (33.3%)	1	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	2
Rash	0/3 (0%)	0	2/3 (66.7%)	2	4/28 (14.3%)	5	0/3 (0%)	0	0/4 (0%)	0	4/31 (12.9%)	4
Rash generalised	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	1/4 (25%)	1	0/31 (0%)	0
Rash macular	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Vascular disorders
Deep vein thrombosis	0/3 (0%)	0	0/3 (0%)	0	2/28 (7.1%)	2	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Flushing	0/3 (0%)	0	0/3 (0%)	0	1/28 (3.6%)	1	0/3 (0%)	0	1/4 (25%)	1	1/31 (3.2%)	1
Haematoma	1/3 (33.3%)	1	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	0/31 (0%)	0
Hypertension	1/3 (33.3%)	1	0/3 (0%)	0	2/28 (7.1%)	4	0/3 (0%)	0	0/4 (0%)	0	4/31 (12.9%)	6
Hypotension	1/3 (33.3%)	1	1/3 (33.3%)	1	1/28 (3.6%)	1	0/3 (0%)	0	0/4 (0%)	0	3/31 (9.7%)	3
Thrombosis	0/3 (0%)	0	0/3 (0%)	0	0/28 (0%)	0	0/3 (0%)	0	0/4 (0%)	0	2/31 (6.5%)	3

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the SPONSOR as confidential must be deleted prior to submission. Sponsor review can be expedited to meet publication guidelines.