Bortezomib, Thalidomide, and Dexamethasone After Melphalan and Stem Cell Transplant in Treating Patients With Stage I-III Multiple Myeloma

• Sponsor: City of Hope Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00792142
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 45
• Location: 1
• Arm: 1
• Duration (Months): 75.1
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

RATIONALE: Bortezomib and thalidomide may stop the growth of multiple myeloma by blocking blood flow to the cancer. Bortezomib may also stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving bortezomib together with thalidomide and dexamethasone may kill any cancer cells that remain after high-dose melphalan and stem cell transplant in patients with multiple myeloma.

PURPOSE: This phase II trial is studying the side effects of giving bortezomib together with thalidomide and dexamethasone after melphalan and stem cell transplant and to see how well it works in treating patients with stage I-III multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm; Neurotoxicity	Drug: bortezomib; Drug: dexamethasone; Drug: melphalan; Drug: thalidomide; Genetic: cytogenetic analysis; Genetic: fluorescence in situ hybridization; Other: laboratory biomarker analysis; Other: questionnaire administration; Procedure: autologous hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation	Phase 2

Detailed Description

OBJECTIVES:

Primary

• To assess the feasibility and toxicities of maintenance therapy with sequential bortezomib, thalidomide, and dexamethasone after high-dose melphalan and autologous peripheral blood stem cell transplantation in patients with multiple myeloma.

• To assess whether administration of sequential bortezomib, thalidomide, and dexamethasone can improve progression-free survival of these patients.

Secondary

• To assess whether administration of sequential bortezomib, thalidomide, and dexamethasone can increase complete remission rate and duration of response in these patients.

• To assess the impact of maintenance therapy with sequential bortezomib, thalidomide, and dexamethasone after transplantation on overall survival of these patients.

• To evaluate the influence of cytogenetic abnormalities (e.g., chromosome 13 deletion, 14 q32 abnormality, t [4;14], chromosome 1 q21 amplification, and chromosome 17 deletion) on outcome by performing conventional cytogenetic study and fluorescence in situ hybridization (FISH) studies on baseline and post-transplant bone marrow specimens.

OUTLINE:

• High-dose melphalan and autologous peripheral blood stem cell transplantation (PBSCT): Patients receive high-dose melphalan IV over 30 minutes on days -2 and -1 and undergo autologous PBSCT on day 0. Patients receive filgrastim (G-CSF) IV or subcutaneously beginning on day 5 and continuing until blood counts recover.

• Maintenance therapy: Beginning 4-8 weeks after transplantation, patients receive bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive oral dexamethasone on days 1-4; treatment with dexamethasone repeats every month for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after completion of bortezomib, patients receive oral thalidomide once daily until disease progression.

Patients complete the FACT-GOG neurotoxicity questionnaire periodically. Bone marrow samples are collected at baseline and post-transplant for cytogenetic analysis by FISH.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Maintenance Treatment With Sequential Bortezomib, Thalidomide and Dexamethasone Following Autologous Peripheral Blood Stem Cell Transplant in Patients With Multiple Myeloma
• Study Start Date: Jan 16, 2008
• Actual Primary Completion Date: Apr 21, 2014
• Actual Study Completion Date: Apr 21, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (stem cell transplant, maintenance treatment) Patients receive high-dose melphalan IV over 30 minutes on days -2 and -1 and undergo autologous peripheral blood stem cell transplantation on day 0. Patients receive filgrastim IV or SC beginning on day 5 and continuing until blood counts recover. Beginning 4 to 8 weeks after transplantation, patients receive maintenance therapy comprising bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive oral dexamethasone on days 1 to 4. Treatment with dexamethasone repeats every month for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after completion of bortezomib, patients receive oral thalidomide once daily until disease progression.

Drug: bortezomib; Given IV; Drug: dexamethasone; Given orally; Drug: melphalan; Given IV; Drug: thalidomide; Given orally; Genetic: cytogenetic analysis; Performed on baseline and post transplant bone marrow specimens; Genetic: fluorescence in situ hybridization; Performed on baseline and post transplant bone marrow specimens; Other: laboratory biomarker analysis; Baseline, post transplant and prior to start of bortezomib, every 3 months post transplant for the first year, after 6 cycles of bortezomib, every year after transplant for 2-4 years.; Other: questionnaire administration; Completed at baseline (within 6 weeks prior to enrollment) and at 2 months post transplant and once a month after that for the first year. For the second year the questionnaire will be completed every 3 months as long as on thalidomide for the duration of the study.; Procedure: autologous hematopoietic stem cell transplantation; Minimum dose of 2 X 10(6) CD34 + cells/kg day 0 after two days of treatment with Melphalan; Procedure: peripheral blood stem cell transplantation; Minimum dose of 2 X 10(6) CD34 + cells/kg day 0 after two days of treatment with Melphalan

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events [After 4 months of maintenance therapy]

   All grade 3 and above treatment-related adverse events (AEs) during bortezomib/dexamethasone treatment cycles.

2. One Year Overall Survival [From date of treatment initiation until death from any cause, assessed up to one year.]

   One year overall survival estimated using the product-limit method of Kaplan and Meier. Defined as the percentage of patients alive at year one after starting treatment.

Secondary Outcome Measures

1. Count of Response in Patients Started on Maintenance Therapy [Post-Thalidomide at 1 year.]

   Complete Response (CR): Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level < 100mg per 24-h. Partial Response (PR): > 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by > 90% or to < 200mg per 24-h In addition to the above listed criteria, if present at baseline, a . 50% reduction in the size of soft tissue plasmacytomas is also required. Stable Disease (SD): Not meeting criteria for CR, VGPR, PR or progressive disease. Relapse: Any of the following: Reappearance of serum or urine M-protein by immunofixation or electrophoresis Development of > 5% plasma cells in the bone marrow. Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion)

2. One Year Progression-free Survival (PFS) [From start of treatment initiation until disease progression, relapse or death from any cause, assessed up to 1 year.]

   PFS estimated using the product-limit method of Kaplan and Meier. Defined as the percentage of patients progression-free at year one after starting treatment. International Myeloma Working Group uniform response criteria for disease progression: Increase of > 25% from baseline in Serum M-component and/or (the absolute increase must be > 0.5 g/dl); Urine M-component and/or (the absolute increase must be > 200 mg/24 h; Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels. The absolute increase must be >l0mg/dl. Bone marrow plasma cell percentage: the absolute % must be > 10%C; Definite development of new bone lesions or soft tissue plasmacytomas. or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcemia (corrected serum calcium >11.5 mg/dl or 2.65 mmol/l) that can be attributed solely to the plasma cell proliferative disorder.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Multiple Myeloma patients with symptomatic disease, stage II or III at diagnosis or progressive stage I requiring chemotherapy and/or radiation therapy (by Salmon-Durie classification), who are not eligible for tandem transplant study using TMI; because of previous radiation or eligibility criteria; documentation of disease staging by both Salmon-Durie classification and International Staging System (ISS) is required

• Patients with non-secretory myeloma should have measurable serum free-light chain protein by the Free-lite test or measurable disease such as a soft tissue myeloma

• A minimum of 4 x 10^6 of CD 34 Positive cell/kg has been harvested

• A Karnofsky performance status (KPS) of >= 70% is required unless the KPS is impaired due to bone disease

• No contraindication to the collection of a minimum of 4 x 10^6 CD34+ cells/kg by apheresis

• All patients must have signed a voluntary, informed consent in accordance with institutional and federal guidelines

• Bilirubin =< 1.5 mg/dl

• Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvate transaminase (SGPT) < 2.5 x upper limits of normal

• Creatinine clearance of >= 40cc/min

• Absolute neutrophil count of > 1000/ul

• Platelet count of > 100,000/ul

• Cardiac ejection fraction >= 45% by multigated acquisition (MUGA) scan and/or by echocardiogram

• Diffusing capacity of the lung for carbon monoxide (DLCO) >= 50% of predicted lower limit

• Human immunodeficiency virus (HIV) antibody tests negative

• No other medical, or psychosocial problems which in the opinion of the primary physician or principal investigator would place the patient at unacceptably high risk from this treatment regimen

Exclusion Criteria:

• Presence of peripheral neuropathy >= grade II

• Patients with evidence of disease progression (with >= 25% increase in M protein) on bortezomib and or thalidomide therapy prior to transplant

• Pregnant or nursing women, as well as women of child bearing age, who are unwilling to use a dual method of contraception and men who are unwilling to use condom

• Patients with history of hypersensitivity to bortezomib, boron or mannitol

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Medical Center	Duarte	California	United States	91010-3000

Sponsors and Collaborators

• City of Hope Medical Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Firoozeh Sahebi, MD, City of Hope Medical Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - May 27, 2014

More Information

Publications

None provided.

• Responsible Party: City of Hope Medical Center
• ClinicalTrials.gov Identifier: NCT00792142
• Other Study ID Numbers: 06143; P30CA033572; CHNMC-06143; MILLENNIUM-06143; CDR0000624513
• First Posted: Nov 17, 2008
• Last Update Posted: Aug 19, 2021
• Last Verified: Jan 1, 2020

• Keywords provided by City of Hope Medical Center: neurotoxicity; stage I multiple myeloma; stage II multiple myeloma; stage III multiple myeloma
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Neurotoxicity Syndromes; Thalidomide; Dexamethasone; Bortezomib; Melphalan

Study Results

Participant Flow

Arm/Group Title	Treatment (Stem Cell Transplant, Maintenance Treatment)
Arm/Group Description	Patients receive high-dose melphalan IV 200mg/m^2 over 30 minutes on days -2 and -1 and undergo autologous peripheral blood stem cell transplantation (Minimum dose of 2 X 10(6) CD34 + cells/kg ) on day 0. Patients receive filgrastim 5ug/kg IV or SQ beginning on day 5 and continuing until blood counts recover. Beginning 4 to 8 weeks after transplantation, patients receive maintenance therapy comprising 1.3 mg/m^2 of bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive 40mg of oral dexamethasone on days 1 to 4. Treatment with dexamethasone repeats every month for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after completion of bortezomib, patients receive 50mg/day of oral thalidomide once daily until disease progression.
Period Title: Overall Study
STARTED	45
COMPLETED	45
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Stem Cell Transplant, Maintenance Treatment)
Arm/Group Description	Patients receive high-dose melphalan IV 200mg/m^2 over 30 minutes on days -2 and -1 and undergo autologous peripheral blood stem cell transplantation (Minimum dose of 2 X 10(6) CD34 + cells/kg ) on day 0. Patients receive filgrastim 5ug/kg IV or SQ beginning on day 5 and continuing until blood counts recover. Beginning 4 to 8 weeks after transplantation, patients receive maintenance therapy comprising 1.3 mg/m^2 of bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive 40mg of oral dexamethasone on days 1 to 4. Treatment with dexamethasone repeats every month for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after completion of bortezomib, patients receive 50mg/day of oral thalidomide once daily until disease progression.
Overall Participants	45
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55
Sex: Female, Male (Count of Participants)
Female	20 44.4%
Male	25 55.6%
Region of Enrollment (participants) [Number]
United States	45 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events
Description	All grade 3 and above treatment-related adverse events (AEs) during bortezomib/dexamethasone treatment cycles.
Time Frame	After 4 months of maintenance therapy

Outcome Measure Data

Analysis Population Description

Five patients did not start the maintenance phase of the study because of neurotoxicity (n=3), thrombocytopenia (n=1), or withdrawal of consent (n=1).

Arm/Group Title	Treatment (Stem Cell Transplant, Maintenance Treatment)
Arm/Group Description	Patients receive high-dose melphalan IV 200mg/m^2 over 30 minutes on days -2 and -1 and undergo autologous peripheral blood stem cell transplantation (Minimum dose of 2 X 10(6) CD34 + cells/kg ) on day 0. Patients receive filgrastim 5ug/kg IV or SQ beginning on day 5 and continuing until blood counts recover. Beginning 4 to 8 weeks after transplantation, patients receive maintenance therapy comprising 1.3 mg/m^2 of bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive 40mg of oral dexamethasone on days 1 to 4. Treatment with dexamethasone repeats every month for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after completion of bortezomib, patients receive 50mg/day of oral thalidomide once daily until disease progression.
Measure Participants	40
Leukopenia	1 2.2%
Lymphopenia	13 28.9%
Neutropenia	2 4.4%
Thrombocytopenia	1 2.2%
Cataract	1 2.2%
Fatigue	2 4.4%
Upper respiratory infection	1 2.2%
Anxiety	1 2.2%
Pain in extremity	1 2.2%
Sinus bradycardia	1 2.2%
Hyperglycemia	4 8.9%
Hypophosphatemia	3 6.7%

2. Primary Outcome

Title	One Year Overall Survival
Description	One year overall survival estimated using the product-limit method of Kaplan and Meier. Defined as the percentage of patients alive at year one after starting treatment.
Time Frame	From date of treatment initiation until death from any cause, assessed up to one year.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Stem Cell Transplant, Maintenance Treatment)
Arm/Group Description	Patients receive high-dose melphalan IV 200mg/m^2 over 30 minutes on days -2 and -1 and undergo autologous peripheral blood stem cell transplantation (Minimum dose of 2 X 10(6) CD34 + cells/kg ) on day 0. Patients receive filgrastim 5ug/kg IV or SQ beginning on day 5 and continuing until blood counts recover. Beginning 4 to 8 weeks after transplantation, patients receive maintenance therapy comprising 1.3 mg/m^2 of bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive 40mg of oral dexamethasone on days 1 to 4. Treatment with dexamethasone repeats every month for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after completion of bortezomib, patients receive 50mg/day of oral thalidomide once daily until disease progression.
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	95 211.1%

3. Secondary Outcome

Title	Count of Response in Patients Started on Maintenance Therapy
Description	Complete Response (CR): Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow. Very Good Partial Response (VGPR): Serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level < 100mg per 24-h. Partial Response (PR): > 50% reduction of serum M-protein and reduction in 24-h urinary M-protein by > 90% or to < 200mg per 24-h In addition to the above listed criteria, if present at baseline, a . 50% reduction in the size of soft tissue plasmacytomas is also required. Stable Disease (SD): Not meeting criteria for CR, VGPR, PR or progressive disease. Relapse: Any of the following: Reappearance of serum or urine M-protein by immunofixation or electrophoresis Development of > 5% plasma cells in the bone marrow. Appearance of any other sign of progression (i.e., new plasmacytoma, lytic bone lesion)
Time Frame	Post-Thalidomide at 1 year.

Outcome Measure Data

Analysis Population Description

Five patients did not start the maintenance phase of the study because of neurotoxicity (n=3), thrombocytopenia (n=1), or withdrawal of consent (n=1).

Arm/Group Title	Treatment (Stem Cell Transplant, Maintenance Treatment)
Arm/Group Description	Patients receive high-dose melphalan IV 200mg/m^2 over 30 minutes on days -2 and -1 and undergo autologous peripheral blood stem cell transplantation (Minimum dose of 2 X 10(6) CD34 + cells/kg ) on day 0. Patients receive filgrastim 5ug/kg IV or SQ beginning on day 5 and continuing until blood counts recover. Beginning 4 to 8 weeks after transplantation, patients receive maintenance therapy comprising 1.3 mg/m^2 of bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive 40mg of oral dexamethasone on days 1 to 4. Treatment with dexamethasone repeats every month for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after completion of bortezomib, patients receive 50mg/day of oral thalidomide once daily until disease progression.
Measure Participants	40
CR	20 44.4%
VPR	2 4.4%
PR	3 6.7%
Relapsed	6 13.3%
Not Assessed	9 20%

4. Secondary Outcome

Title	One Year Progression-free Survival (PFS)
Description	PFS estimated using the product-limit method of Kaplan and Meier. Defined as the percentage of patients progression-free at year one after starting treatment. International Myeloma Working Group uniform response criteria for disease progression: Increase of > 25% from baseline in Serum M-component and/or (the absolute increase must be > 0.5 g/dl); Urine M-component and/or (the absolute increase must be > 200 mg/24 h; Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved FLC levels. The absolute increase must be >l0mg/dl. Bone marrow plasma cell percentage: the absolute % must be > 10%C; Definite development of new bone lesions or soft tissue plasmacytomas. or definite increase in the size of existing bone lesions or soft tissue plasmacytomas Development of hypercalcemia (corrected serum calcium >11.5 mg/dl or 2.65 mmol/l) that can be attributed solely to the plasma cell proliferative disorder.
Time Frame	From start of treatment initiation until disease progression, relapse or death from any cause, assessed up to 1 year.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Stem Cell Transplant, Maintenance Treatment)
Arm/Group Description	Patients receive high-dose melphalan IV 200mg/m^2 over 30 minutes on days -2 and -1 and undergo autologous peripheral blood stem cell transplantation (Minimum dose of 2 X 10(6) CD34 + cells/kg ) on day 0. Patients receive filgrastim 5ug/kg IV or SQ beginning on day 5 and continuing until blood counts recover. Beginning 4 to 8 weeks after transplantation, patients receive maintenance therapy comprising 1.3 mg/m^2 of bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive 40mg of oral dexamethasone on days 1 to 4. Treatment with dexamethasone repeats every month for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after completion of bortezomib, patients receive 50mg/day of oral thalidomide once daily until disease progression.
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	88 195.6%

Adverse Events

Time Frame	Adverse events were collected over a period of 3 years and 11 months.
Adverse Event Reporting Description	"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Arm/Group Title	Treatment (Stem Cell Transplant, Maintenance Treatment)
Arm/Group Description	Patients receive high-dose melphalan IV 200mg/m^2 over 30 minutes on days -2 and -1 and undergo autologous peripheral blood stem cell transplantation (Minimum dose of 2 X 10(6) CD34 + cells/kg ) on day 0. Patients receive filgrastim 5ug/kg IV or SQ beginning on day 5 and continuing until blood counts recover. Beginning 4 to 8 weeks after transplantation, patients receive maintenance therapy comprising 1.3 mg/m^2 of bortezomib IV on days 1, 8, and 15. Treatment repeats every 28 days for 6 courses in the absence of disease progression or unacceptable toxicity. Patients also receive 40mg of oral dexamethasone on days 1 to 4. Treatment with dexamethasone repeats every month for 12 months in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after completion of bortezomib, patients receive 50mg/day of oral thalidomide once daily until disease progression.
All Cause Mortality
	Treatment (Stem Cell Transplant, Maintenance Treatment)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Stem Cell Transplant, Maintenance Treatment)
	Affected / at Risk (%)	# Events
Total	9/45 (20%)
Cardiac disorders
Myocardial ischemia	1/45 (2.2%)	1
Sinus bradycardia	1/45 (2.2%)	1
Gastrointestinal disorders
Gastrointestinal disorder	1/45 (2.2%)	1
General disorders
Disease progression	1/45 (2.2%)	1
Infections and infestations
Bronchitis	1/45 (2.2%)	1
Peripheral nerve infection	1/45 (2.2%)	1
Metabolism and nutrition disorders
Serum phosphate decreased	1/45 (2.2%)	1
Musculoskeletal and connective tissue disorders
Chest wall pain	1/45 (2.2%)	1
Nervous system disorders
Headache	1/45 (2.2%)	1
Vascular disorders
Vascular disorder	1/45 (2.2%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Stem Cell Transplant, Maintenance Treatment)
	Affected / at Risk (%)	# Events
Total	40/45 (88.9%)
Blood and lymphatic system disorders
Hemoglobin decreased	31/45 (68.9%)	143
Hemolysis	1/45 (2.2%)	1
Lymphatic disorder	1/45 (2.2%)	2
Cardiac disorders
Palpitations	1/45 (2.2%)	1
Sinus bradycardia	3/45 (6.7%)	4
Ear and labyrinth disorders
Ear disorder	1/45 (2.2%)	1
Ear pain	1/45 (2.2%)	1
External ear pain	1/45 (2.2%)	1
Hearing loss	3/45 (6.7%)	10
Tinnitus	2/45 (4.4%)	2
Eye disorders
Cataract	1/45 (2.2%)	3
Dry eye syndrome	1/45 (2.2%)	2
Eye disorder	1/45 (2.2%)	1
Eye pain	1/45 (2.2%)	1
Vision blurred	3/45 (6.7%)	3
Watering eyes	1/45 (2.2%)	1
Gastrointestinal disorders
Abdominal pain	2/45 (4.4%)	2
Constipation	5/45 (11.1%)	6
Diarrhea	7/45 (15.6%)	8
Dyspepsia	3/45 (6.7%)	6
Dysphagia	1/45 (2.2%)	1
Flatulence	1/45 (2.2%)	1
Gastritis	1/45 (2.2%)	2
Gastrointestinal disorder	2/45 (4.4%)	2
Lip pain	1/45 (2.2%)	1
Nausea	6/45 (13.3%)	7
Tooth disorder	1/45 (2.2%)	2
Toothache	1/45 (2.2%)	1
Vomiting	6/45 (13.3%)	6
General disorders
Chest pain	2/45 (4.4%)	3
Chills	1/45 (2.2%)	1
Disease progression	1/45 (2.2%)	1
Edema limbs	11/45 (24.4%)	12
Fatigue	15/45 (33.3%)	29
Fever	8/45 (17.8%)	9
General symptom	2/45 (4.4%)	2
Injection site reaction	1/45 (2.2%)	1
Localized edema	3/45 (6.7%)	3
Pain	3/45 (6.7%)	3
Infections and infestations
Bladder infection	1/45 (2.2%)	1
Bone infection	1/45 (2.2%)	1
Bronchitis	1/45 (2.2%)	1
Eye infection	2/45 (4.4%)	4
Gastric infection	1/45 (2.2%)	1
Infection	2/45 (4.4%)	2
Mucosal infection	1/45 (2.2%)	1
Opportunistic infection	1/45 (2.2%)	1
Peripheral nerve infection	1/45 (2.2%)	1
Pharyngitis	1/45 (2.2%)	1
Pneumonia	1/45 (2.2%)	1
Sepsis	1/45 (2.2%)	1
Upper respiratory infection	11/45 (24.4%)	16
Injury, poisoning and procedural complications
Bruising	1/45 (2.2%)	1
Investigations
Alanine aminotransferase increased	15/45 (33.3%)	32
Alkaline phosphatase increased	8/45 (17.8%)	26
Aspartate aminotransferase increased	19/45 (42.2%)	38
Bilirubin increased	4/45 (8.9%)	4
Carbon monoxide diffusing capacity decreased	1/45 (2.2%)	1
Creatinine increased	14/45 (31.1%)	41
INR increased	1/45 (2.2%)	1
Leukocyte count decreased	26/45 (57.8%)	103
Lymphocyte count decreased	22/45 (48.9%)	81
Neutrophil count decreased	22/45 (48.9%)	64
Platelet count decreased	20/45 (44.4%)	66
Serum cholesterol increased	6/45 (13.3%)	12
Weight gain	3/45 (6.7%)	8
Weight loss	1/45 (2.2%)	1
Metabolism and nutrition disorders
Anorexia	1/45 (2.2%)	1
Blood bicarbonate decreased	4/45 (8.9%)	5
Blood glucose increased	17/45 (37.8%)	44
Blood uric acid increased	4/45 (8.9%)	10
Obesity	1/45 (2.2%)	2
Serum albumin decreased	23/45 (51.1%)	57
Serum calcium decreased	18/45 (40%)	36
Serum calcium increased	6/45 (13.3%)	14
Serum glucose decreased	15/45 (33.3%)	27
Serum magnesium decreased	3/45 (6.7%)	4
Serum magnesium increased	3/45 (6.7%)	6
Serum phosphate decreased	9/45 (20%)	16
Serum potassium decreased	12/45 (26.7%)	20
Serum potassium increased	4/45 (8.9%)	5
Serum sodium decreased	13/45 (28.9%)	28
Serum sodium increased	2/45 (4.4%)	2
Serum triglycerides increased	8/45 (17.8%)	16
Musculoskeletal and connective tissue disorders
Arthritis	2/45 (4.4%)	2
Back pain	12/45 (26.7%)	20
Bone pain	1/45 (2.2%)	1
Buttock pain	2/45 (4.4%)	2
Chest wall pain	2/45 (4.4%)	2
Joint disorder	1/45 (2.2%)	1
Joint pain	7/45 (15.6%)	16
Kyphosis	1/45 (2.2%)	1
Muscle weakness	3/45 (6.7%)	5
Muscle weakness lower limb	3/45 (6.7%)	3
Musculoskeletal disorder	6/45 (13.3%)	12
Myalgia	5/45 (11.1%)	9
Pain in extremity	11/45 (24.4%)	20
Nervous system disorders
Depressed level of consciousness	1/45 (2.2%)	1
Dizziness	8/45 (17.8%)	11
Facial muscle weakness	1/45 (2.2%)	1
Headache	10/45 (22.2%)	13
Neuralgia	1/45 (2.2%)	6
Neurological disorder NOS	1/45 (2.2%)	1
Olfactory nerve disorder	1/45 (2.2%)	1
Peripheral sensory neuropathy	33/45 (73.3%)	160
Tremor	1/45 (2.2%)	1
Psychiatric disorders
Anxiety	7/45 (15.6%)	10
Depression	2/45 (4.4%)	4
Insomnia	12/45 (26.7%)	24
Renal and urinary disorders
Hemoglobin urine positive	2/45 (4.4%)	2
Protein urine positive	4/45 (8.9%)	5
Urinary frequency	1/45 (2.2%)	1
Reproductive system and breast disorders
Pelvic pain	1/45 (2.2%)	1
Vaginal dryness	1/45 (2.2%)	1
Vaginal inflammation	1/45 (2.2%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	5/45 (11.1%)	6
Bronchospasm	1/45 (2.2%)	1
Cough	12/45 (26.7%)	20
Dyspnea	3/45 (6.7%)	4
Hemorrhage nasal	1/45 (2.2%)	1
Hiccough	1/45 (2.2%)	2
Nasal congestion	1/45 (2.2%)	1
Pharyngolaryngeal pain	2/45 (4.4%)	2
Respiratory disorder	6/45 (13.3%)	7
Skin and subcutaneous tissue disorders
Dry skin	2/45 (4.4%)	3
Fat atrophy	1/45 (2.2%)	1
Pruritus	2/45 (4.4%)	2
Rash desquamating	13/45 (28.9%)	17
Skin disorder	1/45 (2.2%)	1
Sweating	3/45 (6.7%)	5
Vascular disorders
Flushing	3/45 (6.7%)	8
Hematoma	1/45 (2.2%)	1
Hemorrhage	1/45 (2.2%)	1
Hot flashes	2/45 (4.4%)	2
Hypertension	1/45 (2.2%)	2
Hypotension	1/45 (2.2%)	1
Thrombosis	1/45 (2.2%)	1

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.