Bortezomib (Velcade) With Standard Chemotherapy for Relapsed or Refractory Follicular Lymphoma

• Sponsor: Duke University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00510887
• Collaborator: Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 14
• Location: 1
• Arm: 1
• Duration (Months): 80
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the effectiveness and safety of combining bortezomib (Velcade) with rituximab, fludarabine, mitoxantrone, and dexamethasone in treating patients with follicular cell lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Follicular	Drug: Bortezomib; Drug: Rituximab; Drug: Fludarabine; Drug: Mitoxantrone; Drug: Dexamethasone	Phase 2

Detailed Description

This is a phase II study using the combination of bortezomib, rituximab, fludarabine, mitoxantrone and dexamethasone. The combination will given over a 28 day cycle. In addition each patient will receive Pneumocystis carinii Pneumonia (PCP) prophylaxis with Trimethoprim/sulfamethoxazole (TMP/Sulfa) or equivalent agent. On day 4 the physician has the option of starting granulocyte colony-stimulating factor (GCSF), granulocyte macrophage colony-stimulating factor (GMCSF), or pegylated GCSF.

All patients who receive at least one dose of the drug will be evaluated for toxicity. Patients will be treated with the agent for at least 2 cycles to be considered eligible for evaluation of response. The chemotherapy dosing will continue until there is evidence of disease progression, a second recurrence of unacceptable toxicity, or a maximum of 8 courses of therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Bortezomib in Combination With Rituximab, Fludarabine, Mitoxantrone, and Dexamethasone (VR-FND) for Relapsed or Refractory Follicular Lymphoma
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Sep 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: VR-FND Bortezomib (VELCADER) 1.6 mg/m2 IV days 1 and 8 Rituximab 375 mg/m2 IV on day 1 Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone 20 mg orally on days 1,2,3,4,5 On day 1 the sequence of drug administration will be Bortezomib followed by Fludarabine followed by Rituximab. Each cycle will be repeated every 28 days for 8 cycles maximum.	Drug: Bortezomib; Bortezomib 1.6 mg/m2 on days 1 and 8 of each 28-day cycle; Other Names: Velcade ; Drug: Rituximab; Rituximab 375 mg/m2 IV on day 1; Drug: Fludarabine; Fludarabine 25 mg/m2 IV on days 1,2,3; Drug: Mitoxantrone; Mitoxantrone 10 mg/m2 IV on day 2; Other Names: Novantrone ; Drug: Dexamethasone; Dexamethasone 20 mg orally on days 1,2,3,4,5

Outcome Measures

Primary Outcome Measures

1. Complete and Partial Response [1 year]

   Complete Response: Complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms and normalization of biochemical abnormalities (eg. LDH) definitely assignable to follicular lymphoma. Partial Response requires the following: greater than or equal to 50% decrease in the SPD of the 6 largest dominant nodes of nodal masses. No increase in size of other nodes, liver, or spleen. Splenic and hepatic nodes must regress by at least 50% in sum of the products (SPD). Bone marrow assessment in irrelevant for determination of Partial Response since it is not measurable disease; however, if positive the type of cell should be reported. No new lesions.

Secondary Outcome Measures

1. Duration of Response [up to 4 years]

   Duration of response is measured from time of treatment to time of disease progression

2. Percentage of Subjects Experiencing Progression Free Survival [up to 2 years]

   Progression free survival is measured from treatment to progression or death, whichever comes first. Progressive disease is measured as: 50% or greater increase from nadir in the sum of the products (SPD) of any previously identified abnormal node and the appearance of any new lesions during or at the end of treatment.

3. Percentage of Subjects Experiencing Overall Survival [up to 2 years]

   Overall survival is from the day of enrollment to date of death from any cause.

4. Number of Participants With a Grade 3-4 Hematologic Toxicity. [up to 1 year]

   Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria (CTC).

5. Number of Participants With Neuropathy, Any Grade [up to 1 year]

   Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria (CTC).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Diagnosis of grade 1-3 follicular lymphoma with persistent, relapsed, or refractory disease to at least one prior regimen.

• No prior bortezomib therapy.

• Voluntary written informed consent.

• Female subject is either post-menopausal or surgically sterilized or willing to use an acceptable method of birth control.

• Male subject agrees to use an acceptable method for contraception for the duration of the study therapy.

• 18 years of age or older.

• aspartate aminotransferase (AST),alanine aminotransferase (ALT), total bilirubin < 3 times the upper limit of normal unless documented by the treating physician to be secondary to underlying lymphoma.

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

Exclusion Criteria:

• Platelet count of < 50,000 within 14 days before enrollment unless documented by the treating physician to be due to the disease.

• Absolute neutrophil count of < 1000 within 14 days before enrollment unless documented by the treating physician to be due to disease.

• Estimated or measured creatinine clearance of less than 30 ml/min within 14 days before enrollment.

• ≥Grade 2 peripheral neuropathy within 14 days before enrollment.

• Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia.

• Patient has hypersensitivity to boron, mannitol or any drug included in the current protocol.

• Female subject is pregnant or lactating.

• Received other investigational drugs for this disease within 14 days of enrollment

• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.

• Known HIV+ status.

• Cardiac ejection fraction less than 35% at study entry measured by echocardiogram, Multigated Acquisition (MUGA) or cardiac MRI.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Duke University
• Millennium Pharmaceuticals, Inc.

Investigators

• Principal Investigator: David A Rizzieri, MD, Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Duke University
• ClinicalTrials.gov Identifier: NCT00510887
• Other Study ID Numbers: Pro00008487; 8785
• First Posted: Aug 2, 2007
• Last Update Posted: May 12, 2014
• Last Verified: Apr 1, 2014

• Keywords provided by Duke University: follicular lymphoma; Velcade; VR-FND
• Additional relevant MeSH terms: Lymphoma; Lymphoma, Follicular; Dexamethasone; Rituximab; Fludarabine; Bortezomib; Mitoxantrone

Study Results

Participant Flow

Pre-assignment Detail	Of the 14 subjects consented, 2 were screen failures so only 12 subjects received the study drug.

Arm/Group Title	VR-FND
Arm/Group Description	Bortezomib (VELCADE) 1.6 mg/m2 IV days 1 and 8 Rituximab 375 mg/m2 IV on day 1 Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone 20 mg orally on days 1,2,3,4,5 On day 1 the sequence of drug administration will be Bortezomib followed by Fludarabine followed by Rituximab. Each cycle will be repeated every 28 days for 8 cycles maximum. Bortezomib: Bortezomib 1.6 mg/m2 on days 1 and 8 of each 28-day cycle Rituximab: Rituximab 375 mg/m2 IV on day 1 Fludarabine: Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone: Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone: Dexamethasone 20 mg orally on days 1,2,3,4,5
Period Title: Overall Study
STARTED	12
COMPLETED	11
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	VR-FND
Arm/Group Description	Bortezomib (VELCADER) 1.6 mg/m2 IV days 1 and 8 Rituximab 375 mg/m2 IV on day 1 Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone 20 mg orally on days 1,2,3,4,5 On day 1 the sequence of drug administration will be Bortezomib followed by Fludarabine followed by Rituximab. Each cycle will be repeated every 28 days for 8 cycles maximum. Bortezomib: Bortezomib 1.6 mg/m2 on days 1 and 8 of each 28-day cycle Rituximab: Rituximab 375 mg/m2 IV on day 1 Fludarabine: Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone: Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone: Dexamethasone 20 mg orally on days 1,2,3,4,5
Overall Participants	14
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 71.4%
>=65 years	4 28.6%
Sex: Female, Male (Count of Participants)
Female	4 28.6%
Male	10 71.4%
Region of Enrollment (participants) [Number]
United States	14 100%

Outcome Measures

1. Primary Outcome

Title	Complete and Partial Response
Description	Complete Response: Complete disappearance of all detectable clinical and radiographic evidence of disease, disappearance of all disease-related symptoms and normalization of biochemical abnormalities (eg. LDH) definitely assignable to follicular lymphoma. Partial Response requires the following: greater than or equal to 50% decrease in the SPD of the 6 largest dominant nodes of nodal masses. No increase in size of other nodes, liver, or spleen. Splenic and hepatic nodes must regress by at least 50% in sum of the products (SPD). Bone marrow assessment in irrelevant for determination of Partial Response since it is not measurable disease; however, if positive the type of cell should be reported. No new lesions.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	VR-FND
Arm/Group Description	Bortezomib (VELCADE) 1.6 mg/m2 IV days 1 and 8 Rituximab 375 mg/m2 IV on day 1 Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone 20 mg orally on days 1,2,3,4,5 On day 1 the sequence of drug administration will be Bortezomib followed by Fludarabine followed by Rituximab. Each cycle will be repeated every 28 days for 8 cycles maximum. Bortezomib: Bortezomib 1.6 mg/m2 on days 1 and 8 of each 28-day cycle Rituximab: Rituximab 375 mg/m2 IV on day 1 Fludarabine: Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone: Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone: Dexamethasone 20 mg orally on days 1,2,3,4,5
Measure Participants	11
Number [percentage of participants]	64 457.1%

2. Secondary Outcome

Title	Duration of Response
Description	Duration of response is measured from time of treatment to time of disease progression
Time Frame	up to 4 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	VR-FND
Arm/Group Description	Bortezomib (VELCADE) 1.6 mg/m2 IV days 1 and 8 Rituximab 375 mg/m2 IV on day 1 Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone 20 mg orally on days 1,2,3,4,5 On day 1 the sequence of drug administration will be Bortezomib followed by Fludarabine followed by Rituximab. Each cycle will be repeated every 28 days for 8 cycles maximum. Bortezomib: Bortezomib 1.6 mg/m2 on days 1 and 8 of each 28-day cycle Rituximab: Rituximab 375 mg/m2 IV on day 1 Fludarabine: Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone: Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone: Dexamethasone 20 mg orally on days 1,2,3,4,5
Measure Participants	7
Mean (Full Range) [months]	16.47143

3. Secondary Outcome

Title	Percentage of Subjects Experiencing Progression Free Survival
Description	Progression free survival is measured from treatment to progression or death, whichever comes first. Progressive disease is measured as: 50% or greater increase from nadir in the sum of the products (SPD) of any previously identified abnormal node and the appearance of any new lesions during or at the end of treatment.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	VR-FND
Arm/Group Description	Bortezomib (VELCADE) 1.6 mg/m2 IV days 1 and 8 Rituximab 375 mg/m2 IV on day 1 Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone 20 mg orally on days 1,2,3,4,5 On day 1 the sequence of drug administration will be Bortezomib followed by Fludarabine followed by Rituximab. Each cycle will be repeated every 28 days for 8 cycles maximum. Bortezomib: Bortezomib 1.6 mg/m2 on days 1 and 8 of each 28-day cycle Rituximab: Rituximab 375 mg/m2 IV on day 1 Fludarabine: Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone: Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone: Dexamethasone 20 mg orally on days 1,2,3,4,5
Measure Participants	11
Number [percentage of participants]	17 121.4%

4. Secondary Outcome

Title	Percentage of Subjects Experiencing Overall Survival
Description	Overall survival is from the day of enrollment to date of death from any cause.
Time Frame	up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	VR-FND
Arm/Group Description	Bortezomib (VELCADE) 1.6 mg/m2 IV days 1 and 8 Rituximab 375 mg/m2 IV on day 1 Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone 20 mg orally on days 1,2,3,4,5 On day 1 the sequence of drug administration will be Bortezomib followed by Fludarabine followed by Rituximab. Each cycle will be repeated every 28 days for 8 cycles maximum. Bortezomib: Bortezomib 1.6 mg/m2 on days 1 and 8 of each 28-day cycle Rituximab: Rituximab 375 mg/m2 IV on day 1 Fludarabine: Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone: Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone: Dexamethasone 20 mg orally on days 1,2,3,4,5
Measure Participants	11
Number [percentage of participants]	27 192.9%

5. Secondary Outcome

Title	Number of Participants With a Grade 3-4 Hematologic Toxicity.
Description	Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria (CTC).
Time Frame	up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	VR-FND
Arm/Group Description	Bortezomib (VELCADE) 1.6 mg/m2 IV days 1 and 8 Rituximab 375 mg/m2 IV on day 1 Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone 20 mg orally on days 1,2,3,4,5 On day 1 the sequence of drug administration will be Bortezomib followed by Fludarabine followed by Rituximab. Each cycle will be repeated every 28 days for 8 cycles maximum. Bortezomib: Bortezomib 1.6 mg/m2 on days 1 and 8 of each 28-day cycle Rituximab: Rituximab 375 mg/m2 IV on day 1 Fludarabine: Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone: Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone: Dexamethasone 20 mg orally on days 1,2,3,4,5
Measure Participants	11
Number [participants]	7 50%

6. Secondary Outcome

Title	Number of Participants With Neuropathy, Any Grade
Description	Before each drug dose, the patient will be evaluated for possible toxicities that may have occurred after the previous dose(s). Toxicities are to be assessed according to the NCI Common Toxicity Criteria (CTC).
Time Frame	up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	VR-FND
Arm/Group Description	Bortezomib (VELCADE) 1.6 mg/m2 IV days 1 and 8 Rituximab 375 mg/m2 IV on day 1 Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone 20 mg orally on days 1,2,3,4,5 On day 1 the sequence of drug administration will be Bortezomib followed by Fludarabine followed by Rituximab. Each cycle will be repeated every 28 days for 8 cycles maximum. Bortezomib: Bortezomib 1.6 mg/m2 on days 1 and 8 of each 28-day cycle Rituximab: Rituximab 375 mg/m2 IV on day 1 Fludarabine: Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone: Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone: Dexamethasone 20 mg orally on days 1,2,3,4,5
Measure Participants	11
Number [participants]	6 42.9%

Adverse Events

Time Frame	From first dose of study drug to 30 days after the last dose of study drug
Adverse Event Reporting Description	All adverse events are reported whether or not they are considered attributable to the study treatment.
Arm/Group Title	VR-FND
Arm/Group Description	Bortezomib (VELCADE) 1.6 mg/m2 IV days 1 and 8 Rituximab 375 mg/m2 IV on day 1 Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone 20 mg orally on days 1,2,3,4,5 On day 1 the sequence of drug administration will be Bortezomib followed by Fludarabine followed by Rituximab. Each cycle will be repeated every 28 days for 8 cycles maximum. Bortezomib: Bortezomib 1.6 mg/m2 on days 1 and 8 of each 28-day cycle Rituximab: Rituximab 375 mg/m2 IV on day 1 Fludarabine: Fludarabine 25 mg/m2 IV on days 1,2,3 Mitoxantrone: Mitoxantrone 10 mg/m2 IV on day 2 Dexamethasone: Dexamethasone 20 mg orally on days 1,2,3,4,5
All Cause Mortality
	VR-FND
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	VR-FND
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Other (Not Including Serious) Adverse Events
	VR-FND
	Affected / at Risk (%)	# Events
Total	12/12 (100%)
Blood and lymphatic system disorders
Blood / Bone Marrow - Other	2/12 (16.7%)	2
Febrile neutropenia (fever of unknown origin without documented infection)	1/12 (8.3%)	1
Low Hemoglobin	8/12 (66.7%)	9
Ear and labyrinth disorders
Auditory / Ear	1/12 (8.3%)	1
Eye disorders
Vision - blurred vision	2/12 (16.7%)	2
Gastrointestinal disorders
Constipation	5/12 (41.7%)	9
Diarrhea	4/12 (33.3%)	4
Dry mouth / salivary gland (xerostomia)	1/12 (8.3%)	1
Flatulence	1/12 (8.3%)	1
Heartburn / dyspepsia	1/12 (8.3%)	1
Mucositis / Stomatitis (clinical exam)	1/12 (8.3%)	3
Nausea	8/12 (66.7%)	10
Pain - Abdomen NOS	3/12 (25%)	3
Pain - Anus	1/12 (8.3%)	1
Pain - Dental / teeth / peridontal	1/12 (8.3%)	1
Vomiting	5/12 (41.7%)	9
General disorders
Constitutional Symptoms - Other	2/12 (16.7%)	2
Edema: head and neck	1/12 (8.3%)	1
Edema: limb	5/12 (41.7%)	5
Fatigue (asthenia, lethargy, malaise)	10/12 (83.3%)	17
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	2/12 (16.7%)	2
Pain - Chest / thorax NOS	2/12 (16.7%)	2
Rigors / chills	3/12 (25%)	3
Hepatobiliary disorders
Pain - Gallbladder	1/12 (8.3%)	1
Infections and infestations
Infection - Other	1/12 (8.3%)	1
Infection with normal ANC or Grade 1 or 2 neutrophils	1/12 (8.3%)	1
Infection with unknown ANC - Mucosa	1/12 (8.3%)	1
Injury, poisoning and procedural complications
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	1/12 (8.3%)	1
Investigations
High Alkaline phosphatase	4/12 (33.3%)	4
High AST, SGOT (serum glutamic oxaloacetic transaminase)	2/12 (16.7%)	2
Bilirubin (hyperbilirubinemia)	1/12 (8.3%)	1
High Creatinine	3/12 (25%)	3
Low Leukocytes (total WBC)	10/12 (83.3%)	15
Lymphopenia	5/12 (41.7%)	5
Metabolic / Laboratory - Other	3/12 (25%)	4
Low Neutrophils / granulocytes (ANC / AGC)	7/12 (58.3%)	11
Low Platelets	9/12 (75%)	10
Weight loss	2/12 (16.7%)	2
Metabolism and nutrition disorders
Albumin, serum-low (hypoalbuminemia)	2/12 (16.7%)	2
Anorexia	6/12 (50%)	10
Calcium, serum-low (hypocalcemia)	5/12 (41.7%)	7
Dehydration	1/12 (8.3%)	1
Glucose, serum-high (hyperglycemia)	6/12 (50%)	9
Glucose, serum-low (hypoglycemia)	1/12 (8.3%)	1
Magnesium, serum-low (hypomagnesemia)	3/12 (25%)	3
Sodium, serum-low (hyponatremia)	2/12 (16.7%)	2
Tumor lysis syndrome	1/12 (8.3%)	1
Uric Acid, serum-high (hyperuricemia)	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
Joint-function	2/12 (16.7%)	2
Musculoskeletal - Flank pain	1/12 (8.3%)	1
Pain - Back	5/12 (41.7%)	5
Pain - Bone	1/12 (8.3%)	3
Pain - Extremity-limb	1/12 (8.3%)	2
Pain - Joint	3/12 (25%)	4
Nervous system disorders
Dizziness	3/12 (25%)	3
Neuropathy: motor	1/12 (8.3%)	1
Neuropathy: sensory	5/12 (41.7%)	5
Pain - Head / headache	3/12 (25%)	3
Taste Alteration (dysgeusia)	2/12 (16.7%)	2
Psychiatric disorders
Insomnia	3/12 (25%)	3
Mood Alteration - Agitation	1/12 (8.3%)	1
Renal and urinary disorders
Pain - Kidney	1/12 (8.3%)	1
Renal / Genitourinary - Other	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	3/12 (25%)	3
Dyspnea (shortness of breath)	4/12 (33.3%)	4
Hiccoughs (hiccups, singultus)	4/12 (33.3%)	4
Pain - Throat / pharynx / larynx	3/12 (25%)	4
Skin and subcutaneous tissue disorders
Dry Skin	1/12 (8.3%)	1
Nail Changes	2/12 (16.7%)	2
Petechiae / purpura (hemorrhage / bleeding into skin or mucosa)	1/12 (8.3%)	1
Pruritus / itching	3/12 (25%)	3
Rash / desquamation	4/12 (33.3%)	6
Sweating (diaphoresis)	5/12 (41.7%)	6
Vascular disorders
Hypotension	2/12 (16.7%)	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.