Bevacizumab, Lenalidomide, and Dexamethasone in Patients With Relapsed or Refractory Stage II or III Multiple Myeloma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00410605
• Collaborator: (none)
• Enrollment: 39
• Locations: 2
• Arm: 1
• Duration (Months): 91
• Patients Per Site: 19.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This phase II trial is studying how well giving bevacizumab together with lenalidomide and dexamethasone works in treating patients with relapsed or refractory stage II or stage III multiple myeloma. Monoclonal antibodies, such as bevacizumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Bevacizumab and lenalidomide may stop the growth of multiple myeloma by blocking blood flow to the cancer. Dexamethasone may stimulate the immune system in different ways and stop cancer cells from growing. Giving bevacizumab together with lenalidomide and dexamethasone may kill more cancer cells.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma in Relapse; Stage II Multiple Myeloma; Stage III Multiple Myeloma	Biological: bevacizumab; Drug: lenalidomide; Drug: dexamethasone	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Determine the overall response rate (complete response and partial response) in patients with relapsed or refractory stage II or III multiple myeloma treated with bevacizumab, lenalidomide, and dexamethasone.

SECONDARY OBJECTIVES:

1. Determine time to progression in these patients. II. Determine the toxicity and tolerability of this regimen. III. Determine the effect of bevacizumab and lenalidomide on markers of myeloma activity in myeloma cells and stromal cells, including interleukin-6, macrophage inflammatory protein-1α, vascular endothelial growth factor, and STAT3.

2. Assess local cytokine milieu using tissue microarrays of bone marrow biopsy specimens.

OUTLINE: This is a multicenter, open-label study.

Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and before courses 2 and 4. Blood samples are examined for vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) polymorphisms by pyrosequencing and VEGF, VEGFR1, VEGFR2, interleukin-6, and macrophage inflammatory protein 1 by immunoenzyme techniques. Relationships between plasma cell myeloma and stroma and the effect of study treatment on these relationships are examined in tissue sections of bone marrow before and after treatment utilizing microvessel density measurements, VEGF staining, and STAT3 staining (by immunohistochemistry and fluorescent in situ hybridization [FISH]).

After completion of study treatment, patients are followed periodically for at least 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 39 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Bevacizumab Combined With Lenalidomide and Dexamethasone (BEV/REV/DEX) in Relapsed or Refractory Multiple Myeloma
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Dec 1, 2011
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.	Biological: bevacizumab; Given IV; Other Names: anti-VEGF humanized monoclonal antibody anti-VEGF monoclonal antibody Avastin rhuMAb VEGF ; Drug: lenalidomide; Given orally; Other Names: CC-5013 IMiD-1 Revlimid ; Drug: dexamethasone; Given orally; Other Names: Aeroseb-Dex Decaderm Decadron DM DXM

Outcome Measures

Primary Outcome Measures

1. Confirmed Anti-tumor Response Rate (Complete Response and Partial Response) to the Combination of Bevacizumab and Lenalidomide [Up to 5 years]

   Patient response to the treatment were determined by the definitions for complete response, partial response, marginal response, stable disease, and progressive disease outlined by IMBTR/ABMTR (Blade criteria). Responses were analyzed by descriptive statistics and summarized in tabular format (frequency tables). Furthermore, two-sided 95% confidence intervals for the proportions of subjects with a confirmed anti-tumor response were computed using the method proposed by Chang, which takes into account the multiplicity problem associated with the two-stage testing procedure. The objective response rate was estimated by using Whitehead's bias-adjustment approach.

2. Progression Free Survival (Time to Progression) [up to five years]

   Patient response to the treatment were determined by the definitions for complete response, partial response, marginal response, stable disease, and progressive disease outlined by IMBTR/ABMTR (Blade criteria). Progression free survival was summarized using point estimates of the median time to progression and associated 95% confidence intervals. The data was presented graphically using Kaplan-Meier plots. Exploratory analysis, including multivariate Cox regression with demographic variables and markers of myeloma activity as covariates was performed.

Secondary Outcome Measures

1. Toxicity and Tolerability of the Bevacizumab and Lenalidomide Combination [Up to 5 years]

   Adverse events/toxicities were collected during regular clinical visits. Confidence intervals for the estimate of the true number of patients suffereing from grade 3 or 4 toxicities per common terminology criteria were calculated using the Wilson interval. Ninety-five percent confidence intervals for the proportions of patients with complications (grade 3 or higher toxicities) were constructed.

2. Effect of Bev/Rev on Markers of Myeloma Activity in Myeloma Cells and Stromal Cells at Baseline [Baseline]

   A Wilconxon signed-rank test conducted to determine if biomarker levels differed between baseline levels and those after three full cycles of treatment for all patients.

3. Local Cytokine Milieu Using Tissue Micro Arrays of Bone Marrow Biopsy Specimens [Up to 5 years]

4. Effect of Bev/Rev on Markers of Myeloma Activity in Myeloma Cells and Stromal Cells at 3 Months Post-baseline [Up to Course 4 Day 1 (3 Months Post-baseline)]

   A Wilconxon signed-rank test conducted to determine if biomarker levels differed between baseline levels and those after three full cycles of treatment for all patients.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically or cytologically confirmed symptomatic multiple myeloma:

• Stage II or III disease

• Relapsed or refractory disease after >= 2 courses of prior chemotherapy

• Measurable levels of monoclonal protein (M protein) > 1.0 g/dL by serum protein electrophoresis OR > 200 mg of monoclonal light chain by 24-hour urine protein electrophoresis

• Measurable bone disease, defined as >= 1 unidimensionally measurable lesion (longest diameter to be recorded) >= 20 mm with conventional techniques OR >= 10 mm with spiral CT scan (for patients with lytic bone disease)

• No known brain metastases

• ECOG performance status (PS) 0-2 OR Karnofsky PS 70-100%

• Patients with PS of 3 are eligible if it is due to pain that is likely to improve with treatment

• Life expectancy > 6 months

• No known HIV positivity

• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months

• No active infections requiring oral or intravenous antibiotics within the past week

• No proteinuria (i.e., albuminuria) > 1,000 mg/24 hours unless related to the diagnosis of multiple myeloma

• Patients with light chain (i.e., "Bence-Jones") proteinuria are still eligible if the non-light chain component of protein is < 1,000 mg/24 hours

• No serious nonhealing wound or ulcer

• No blood pressure > 150/90 mm Hg (even with medication)

• No significant traumatic injury within the past 28 days

• No clinically significant peripheral vascular disease

• No evidence of bleeding diathesis or coagulopathy

• No unstable angina or myocardial infarction within the past 6 months

• No stroke within the past 6 months

• No New York Heart Association class III or IV heart failure

• No secondary malignancy within the past 2 years except squamous cell or basal cell carcinoma of the skin or carcinoma in situ of the cervix

• Hemoglobin > 9 g/dL (may be supported by transfusion or growth factors)

• WBC >= 2,000/mm^3

• Absolute neutrophil count >= 1,000/mm^3

• Platelet count >= 75,000/mm^3

• Bilirubin =< 2.5 mg/dL

• At least 4 weeks since prior chemotherapy or radiotherapy and recovered

• More than 7 days since prior minor surgical procedures, fine-needle aspirations, or core biopsies:

More than 24 hours since prior bone marrow biopsy or central veinous access placement

• More than 28 days since prior major surgical procedure or open biopsy

• At least 4 weeks since prior and no concurrent participation in another experimental drug study

• Prior autologous peripheral blood stem cell transplantation allowed

• No prior lenalidomide

• Concurrent full-dose anticoagulants allowed provided all of the following criteria are met:

• No active bleeding or pathological condition that carries a high risk of bleeding (e.g., tumor involving major vessels or known varices)

• No thrombocytopenia requiring transfusion

• Platelet count > 75,000/mm3

• INR 2-3 and stable

• No concurrent major surgery

• No concurrent sargramostim (GM-CSF)

• No other concurrent investigational agents

• No other concurrent anticancer agents or therapies

• AST and ALT =< 5 times upper limit of normal

• Creatinine < 2.5 mg/dL

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use 2 methods of effective contraception 4 weeks before, during, and 4 weeks after completion of study treatment

• No history of allergic reactions attributed to compounds of similar chemical or biological composition to lenalidomide and/or bevacizumab or other agents used in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pittsburgh Cancer Institute	Pittsburgh	Pennsylvania	United States	15232
2	University of Wisconsin Hospital and Clinics	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Natalie Callander, University of Wisconsin, Madison

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00410605
• Other Study ID Numbers: NCI-2009-00150; NCI-2009-00150; H-2006-0269; CDR0000521546; HO06401; 7313; U01CA062491; P30CA014520; NCT00406328
• First Posted: Dec 13, 2006
• Last Update Posted: Sep 1, 2017
• Last Verified: Aug 1, 2017

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Dexamethasone; Bevacizumab; Antineoplastic Agents, Immunological; Lenalidomide; Antibodies; Immunoglobulins; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	Participants were recruited from the University of Wisconsin (UW) Hospital and Clinics, the UW 1 South Park Clinic, and the Wisconsin Oncology Network (WON) clinics between November 2006 and March 2011.
Pre-assignment Detail	No events between enrollment and group assignment. All subjects enrolled are immediately assigned to Arm 1, "Bevacizumab, Dexamethasone, and Lenalidomide."

Arm/Group Title	Bevacizumab, Dexamethasone, and Lenalidomide
Arm/Group Description	Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV lenalidomide: Given orally dexamethasone: Given orally
Period Title: Overall Study
STARTED	39
COMPLETED	14
NOT COMPLETED	25

Baseline Characteristics

Arm/Group Title	Bevacizumab, Dexamethasone, and Lenalidomide
Arm/Group Description	Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV lenalidomide: Given orally dexamethasone: Given orally
Overall Participants	39
Age, Customized (participants) [Number]
40-49 years	2 5.1%
50-59 years	4 10.3%
60-69 years	15 38.5%
70-79 years	15 38.5%
80-89 years	3 7.7%
Sex: Female, Male (Count of Participants)
Female	15 38.5%
Male	24 61.5%
Region of Enrollment (participants) [Number]
United States	39 100%

Outcome Measures

1. Primary Outcome

Title	Confirmed Anti-tumor Response Rate (Complete Response and Partial Response) to the Combination of Bevacizumab and Lenalidomide
Description	Patient response to the treatment were determined by the definitions for complete response, partial response, marginal response, stable disease, and progressive disease outlined by IMBTR/ABMTR (Blade criteria). Responses were analyzed by descriptive statistics and summarized in tabular format (frequency tables). Furthermore, two-sided 95% confidence intervals for the proportions of subjects with a confirmed anti-tumor response were computed using the method proposed by Chang, which takes into account the multiplicity problem associated with the two-stage testing procedure. The objective response rate was estimated by using Whitehead's bias-adjustment approach.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab, Dexamethasone, and Lenalidomide
Arm/Group Description	Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV lenalidomide: Given orally dexamethasone: Given orally
Measure Participants	39
Number (95% Confidence Interval) [percentage of participants]	64 164.1%

2. Primary Outcome

Title	Progression Free Survival (Time to Progression)
Description	Patient response to the treatment were determined by the definitions for complete response, partial response, marginal response, stable disease, and progressive disease outlined by IMBTR/ABMTR (Blade criteria). Progression free survival was summarized using point estimates of the median time to progression and associated 95% confidence intervals. The data was presented graphically using Kaplan-Meier plots. Exploratory analysis, including multivariate Cox regression with demographic variables and markers of myeloma activity as covariates was performed.
Time Frame	up to five years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab, Dexamethasone, and Lenalidomide
Arm/Group Description	Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV lenalidomide: Given orally dexamethasone: Given orally
Measure Participants	39
Median (95% Confidence Interval) [months]	9

3. Secondary Outcome

Title	Toxicity and Tolerability of the Bevacizumab and Lenalidomide Combination
Description	Adverse events/toxicities were collected during regular clinical visits. Confidence intervals for the estimate of the true number of patients suffereing from grade 3 or 4 toxicities per common terminology criteria were calculated using the Wilson interval. Ninety-five percent confidence intervals for the proportions of patients with complications (grade 3 or higher toxicities) were constructed.
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab, Dexamethasone, and Lenalidomide
Arm/Group Description	Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV lenalidomide: Given orally dexamethasone: Given orally
Measure Participants	39
Number (95% Confidence Interval) [percentage of participants]	72 184.6%

4. Secondary Outcome

Title	Effect of Bev/Rev on Markers of Myeloma Activity in Myeloma Cells and Stromal Cells at Baseline
Description	A Wilconxon signed-rank test conducted to determine if biomarker levels differed between baseline levels and those after three full cycles of treatment for all patients.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab, Dexamethasone, and Lenalidomide
Arm/Group Description	Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV lenalidomide: Given orally dexamethasone: Given orally
Measure Participants	34
IL-6 level range	17.2 (65.1)
MIP-1 level range	0.039 (0.025)
VEGF level range	0.084 (0.066)
VEGFR1 level range	0.12 (0.11)
VEGFR2 level range	8.85 (2.08)

5. Secondary Outcome

Title	Local Cytokine Milieu Using Tissue Micro Arrays of Bone Marrow Biopsy Specimens
Time Frame	Up to 5 years

Outcome Measure Data

Analysis Population Description

Outcome measure data were not collected.

Arm/Group Title	Bevacizumab, Dexamethasone, and Lenalidomide
Arm/Group Description	Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV lenalidomide: Given orally dexamethasone: Given orally
Measure Participants	0

6. Secondary Outcome

Title	Effect of Bev/Rev on Markers of Myeloma Activity in Myeloma Cells and Stromal Cells at 3 Months Post-baseline
Description	A Wilconxon signed-rank test conducted to determine if biomarker levels differed between baseline levels and those after three full cycles of treatment for all patients.
Time Frame	Up to Course 4 Day 1 (3 Months Post-baseline)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab, Dexamethasone, and Lenalidomide
Arm/Group Description	Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV lenalidomide: Given orally dexamethasone: Given orally
Measure Participants	34
IL-6 level range	5.5 (3.4)
MIP-1 level range	0.047 (0.044)
VEGF level range	0.054 (0.042)
VEGFR1 level range	0.12 (0.088)
VEGFR2 level range	8.17 (2.29)

Adverse Events

Arm/Group Title	Bevacizumab, Dexamethasone, and Lenalidomide
Arm/Group Description	Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral lenalidomide on days 1-21, and oral dexamethasone on days 1, 8, 15, and 22. Courses repeat every 4 weeks in the absence of disease progression or unacceptable toxicity. bevacizumab: Given IV lenalidomide: Given orally dexamethasone: Given orally
All Cause Mortality
	Bevacizumab, Dexamethasone, and Lenalidomide
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Bevacizumab, Dexamethasone, and Lenalidomide
	Affected / at Risk (%)	# Events
Total	22/39 (56.4%)
Cardiac disorders
Atrial fibrillation	3/39 (7.7%)
Atrial flutter	1/39 (2.6%)
Heart failure	1/39 (2.6%)
Left Ventricular Systolic Dysfunction	1/39 (2.6%)
Endocrine disorders
Hypothyroidism	1/39 (2.6%)
Eye disorders
Retinal Detachment	1/39 (2.6%)
Gastrointestinal disorders
Abdominal Pain	2/39 (5.1%)
Colonic Perforation	1/39 (2.6%)
Diarrhea	1/39 (2.6%)
Dry Mouth	1/39 (2.6%)
Duodenal Hemorrhage	1/39 (2.6%)
Ileus	1/39 (2.6%)
Mucositis Oral	1/39 (2.6%)
Small Intestinal Perforation	2/39 (5.1%)
General disorders
Death NOS	2/39 (5.1%)
Edema Limbs	2/39 (5.1%)
Fever	1/39 (2.6%)
Infections and infestations
Infections and Infestations, Other	1/39 (2.6%)
Lung Infection	2/39 (5.1%)
Mucosal Infection	1/39 (2.6%)
Upper Respiratory Infection	1/39 (2.6%)
Investigations
Blood Bilirubin Increased	1/39 (2.6%)
Cardiac Troponin T Increased	2/39 (5.1%)
Lymphocyte Count Decreased	1/39 (2.6%)
Neutrophil Count Decreased	2/39 (5.1%)
White Blood Cell Decreased	1/39 (2.6%)
Metabolism and nutrition disorders
Anorexia	1/39 (2.6%)
Hypercalcemia	1/39 (2.6%)
Hyperglycemia	1/39 (2.6%)
Hyperuricemia	1/39 (2.6%)
Hyponatremia	1/39 (2.6%)
Musculoskeletal and connective tissue disorders
Back Pain	1/39 (2.6%)
Chest Wall Pain	1/39 (2.6%)
Myalgia	1/39 (2.6%)
Pain in Extremity	1/39 (2.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment Related Secondary Malignancy - Chronic Lymphocytic Leukemia	1/39 (2.6%)
Nervous system disorders
Dysgeusia	1/39 (2.6%)
Peripheral Sensory Neuropathy	2/39 (5.1%)
Psychiatric disorders
Confusion	1/39 (2.6%)
Depression	1/39 (2.6%)
Renal and urinary disorders
Acute Kidney Injury	3/39 (7.7%)
Respiratory, thoracic and mediastinal disorders
Cough	1/39 (2.6%)
Dyspnea	4/39 (10.3%)
Pneumonitis	1/39 (2.6%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	1/39 (2.6%)
Vascular disorders
Hypertension	1/39 (2.6%)
Thromboembolic Event	4/39 (10.3%)
Other (Not Including Serious) Adverse Events
	Bevacizumab, Dexamethasone, and Lenalidomide
	Affected / at Risk (%)	# Events
Total	39/39 (100%)
Blood and lymphatic system disorders
Anemia	21/39 (53.8%)
Eye disorders
Blurred vision	5/39 (12.8%)
Gastrointestinal disorders
Abdominal Pain	3/39 (7.7%)
Constipation	8/39 (20.5%)
Diarrhea	20/39 (51.3%)
Dry mouth	2/39 (5.1%)
Dyspepsia	4/39 (10.3%)
Dysphagia	2/39 (5.1%)
Flatulence	2/39 (5.1%)
Hemorrhoids	2/39 (5.1%)
Mucositis oral	16/39 (41%)
Nausea	10/39 (25.6%)
Vomiting	5/39 (12.8%)
General disorders
Chills	4/39 (10.3%)
Edema limbs	8/39 (20.5%)
Fatigue	26/39 (66.7%)
Fever	4/39 (10.3%)
Infections and infestations
Gum infection	2/39 (5.1%)
Mucosal infection	3/39 (7.7%)
Sinusitis	2/39 (5.1%)
Skin infection	2/39 (5.1%)
Tooth infection	2/39 (5.1%)
Upper respiratory infection	8/39 (20.5%)
Urinary Tract Infection	2/39 (5.1%)
Injury, poisoning and procedural complications
Bruising	5/39 (12.8%)
Investigations
Alanine aminotransferase increased	4/39 (10.3%)
Alkaline Phosphatase Increased	4/39 (10.3%)
Aspartate aminotransferase increased	2/39 (5.1%)
Blood bilirubin increased	3/39 (7.7%)
Creatinine increased	6/39 (15.4%)
Lymphocyte count decreased	15/39 (38.5%)
Neutrophil count decreased	29/39 (74.4%)
Platelet count decreased	27/39 (69.2%)
Weight loss	10/39 (25.6%)
White blood cell decreased	26/39 (66.7%)
Metabolism and nutrition disorders
Anorexia	14/39 (35.9%)
hyperglycemia	20/39 (51.3%)
Hyperkalemia	8/39 (20.5%)
Hypoalbuminemia	14/39 (35.9%)
Hypocalcemia	17/39 (43.6%)
Hypokalemia	5/39 (12.8%)
Hyponatremia	10/39 (25.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	4/39 (10.3%)
Back pain	8/39 (20.5%)
Bone pain	5/39 (12.8%)
generalized muscle weakness	4/39 (10.3%)
Muscle weakness lower limb	2/39 (5.1%)
Myalgia	4/39 (10.3%)
Pain in extremity	5/39 (12.8%)
Nervous system disorders
Dizziness	4/39 (10.3%)
Dysgeusia	6/39 (15.4%)
Headache	11/39 (28.2%)
Peripheral sensory neuropathy	15/39 (38.5%)
Tremor	5/39 (12.8%)
Psychiatric disorders
Anxiety	4/39 (10.3%)
Confusion	2/39 (5.1%)
Depression	2/39 (5.1%)
Insomnia	9/39 (23.1%)
Personality change	2/39 (5.1%)
Renal and urinary disorders
Urinary frequency	2/39 (5.1%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	3/39 (7.7%)
Cough	8/39 (20.5%)
Dyspnea	15/39 (38.5%)
Epistaxis	12/39 (30.8%)
Pharyngolaryngeal pain	4/39 (10.3%)
Sinus disorder	5/39 (12.8%)
Voice alteration	8/39 (20.5%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	7/39 (17.9%)
Pruritus	2/39 (5.1%)
Rash maculo-papular	10/39 (25.6%)
Vascular disorders
Flushing	3/39 (7.7%)
Hypertension	7/39 (17.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.