Low-Dose Melphalan and Dexamethasone Compared With High-Dose Melphalan Followed By Autologous Stem Cell Transplant in Treating Patients With Primary Systemic Amyloidosis

• Sponsor: Mayo Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT00477971
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 89
• Location: 1
• Arms: 2
• Duration (Months): 110
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as melphalan and dexamethasone, work in different ways to stop the growth of plasma cells, either by killing the cells or by stopping them from dividing. Having an autologous stem cell transplant to replace the blood-forming cells destroyed by chemotherapy, allows higher doses of chemotherapy to be given so that more plasma cells are killed. By reducing the number of plasma cells, the disease may progress more slowly. It is not yet known whether combination chemotherapy is more effective than chemotherapy followed by an autologous stem cell transplant in treating primary systemic amyloidosis.

PURPOSE: This randomized phase III trial is studying the side effects and how well giving low-dose melphalan together with dexamethasone works compared with high-dose melphalan followed by an autologous stem cell transplant in treating patients with primary systemic amyloidosis.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma and Plasma Cell Neoplasm	Biological: filgrastim; Drug: dexamethasone; Drug: melphalan; Procedure: autologous hematopoietic stem cell transplantation	Phase 3

Detailed Description

OBJECTIVES:

Primary

• Compare hematologic response rate in patients with primary systemic amyloidosis treated with conventional chemotherapy comprising low-dose melphalan and dexamethasone vs high-dose melphalan followed by autologous stem cell transplantation.

• Compare the toxicity of these regimens in these patients.

Secondary

• Compare the overall and progression-free survival of patients treated with these regimens.

• Compare the regression of organ involvement in patients treated with these regimens.

• Compare the duration of response in patients treated with these regimens.

• Correlate clonal burden and time to in vitro amyloid formation with clinical outcomes in patients treated with these regimens.

• Compare quality of life of patients treated with these regimens.

• Compare the information-seeking behavior in patients treated with these regimens.

OUTLINE: This is a comprehensive cohort study comprising a randomized option and a nonrandomized option. Patients consenting to randomization are stratified by risk group (high vs low) and ECOG performance status (0-1 vs 2). They are then randomized to 1 of 2 treatment arms. Patients not consenting to randomization choose their treatment arm.

• Arm I: Patients receive low-dose melphalan IV over 15-30 minutes on day 1 or orally once daily on days 1-7 and oral dexamethasone on days 1-4 and 22-25. Treatment repeats every 6 weeks for 10 courses in the absence of disease progression or unacceptable toxicity.

• Arm II: Patients receive filgrastim (G-CSF) on days -7 to -3 and undergo autologous hematopoietic stem cell (HSC) collection. Patients receive high-dose melphalan IV over 1 hour on days -2 and -1 and undergo autologous HSC transplantation on day 0.

Blood and bone marrow samples are collected at baseline. Samples are examined by PCR, cDNA, and nucleotide sequence analysis to determine VH and VL gene families and carrier status. Urine is collected at baseline and analyzed for light-chain protein levels by exclusion chromatography.

Quality of life is assessed at baseline, at months 3, 9, and 12, at completion of study treatment, and then every 6 months for up to 5 years.

After completion of study treatment, patients are followed every 6 months for up to 10 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 89 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase III Trial of Stem Cell Transplantation Compared to Parenteral Melphalan and Oral Dexamethasone in the Treatment of Primary Systemic Amyloidosis (AL)
• Study Start Date: Oct 1, 2005
• Actual Primary Completion Date: Jul 1, 2012
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A Patients receive low-dose melphalan IV over 15-30 minutes on day 1 or orally once daily on days 1-7 and oral dexamethasone on days 1-4 and 22-25. Treatment repeats every 6 weeks for 10 courses. Study treatment beyond one year is not allowed.	Drug: dexamethasone; Given orally; Drug: melphalan; Given IV or orally
Experimental: Arm B Patients receive filgrastim (G-CSF) on days -7 to -3 and undergo autologous hematopoietic stem cell (HSC) collection. Patients receive high-dose melphalan IV over 1 hour on days -2 and -1 and undergo autologous HSC transplantation on day 0.	Biological: filgrastim; No administration information given; Drug: melphalan; Given IV or orally; Procedure: autologous hematopoietic stem cell transplantation; Given on day 0

Outcome Measures

Primary Outcome Measures

1. Hematologic Response Rate [10 years]

   Response that was confirmed on 2 consecutive evaluations during treatment. A hematologic response consisted of a Complete response, Very Good Partial Response or Partial Response. Complete Response (CR): Complete disappearance of M-protein from serum and urine on immunofixation, normalization of Free Light Chain (FLC) ratio and <5% plasma cells in bone marrow. Very Good Partial Response (VGPR): >=90% reduction in serum M-component; Urine M-Component <=100 mg per 24 hours. Partial Response (PR): >=50% reduction in serum M-component and/or Urine M-Component >=90% reduction or <200 mg per 24 hours; or >=50% decrease in difference between involved and uninvolved FLC levels.

Secondary Outcome Measures

1. 3 Year Overall Survival [3 years]

   Percentage of patients who were alive at 3 years. The 3-year survival rate was estimated using the Kaplan Meier method.

2. Organ Response to Treatment [10 years]

   Organ response was evaluated on the basis of improvement of one or more affected organ; only one parameter was required to satisfy the criteria. Response needed to be maintained for a minimum of 3 months to be considered valid. Renal response required a 50% reduction in 24-hour urine protein excretion (at least 0.5 g/d) with stable creatinine. Cardiac response required one of >= 2-mm reduction in the interventricular septal (IVS) thickness by echocardiogram, or improvement of ejection fraction by >= 20%, or improvement by 2 NYHA classes without an increase in diuretic use. Hepatic response required either >= 50% decrease in (or normalization of) an initially elevated alkaline phosphatase level or reduction in the size of the liver by at least 2 cm by radiographic determination. Gastrointestinal tract improvement was defined as normalization of a low serum carotene level, or reduction of diarrhea to < 50% of previous movements/day, or decrease in fecal fat excretion by 50%.

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Histologically confirmed primary systemic amyloidosis

• Amyloid light-chain (AL) disease

• Monoclonal protein by immunoelectrophoresis or immunofixation of the serum or urine OR abnormal free light-chain ratio

• The following amyloid syndromes* are allowed:

• Amyloid hepatomegaly

• Cardiomyopathy

• Proteinuria

• Peripheral or autonomic neuropathy

• Soft tissue involvement including the tongue, submandibular tissues, and vascular claudication

• Diffuse interstitial pulmonary AL disease allowed if pulmonary function is adequate to allow safe transplantation NOTE: *Presence of amyloid deposits in a plasmacytoma or in bone marrow vessels in an asymptomatic patient does not constitute an amyloid syndrome

• No secondary or familial amyloidosis

• No multiple myeloma with lytic or destructive bone lesions or myeloma cast nephropathy

• No multiple myeloma with > 30% plasma cells in the bone marrow

• No amyloidosis manifested only by carpal tunnel syndrome or purpura

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2

• Platelet count ≥ 100,000/mm³

• Bilirubin ≤ 2.0 times upper limit of normal (ULN)

• Alkaline phosphatase ≤ 6 times ULN

• Creatinine ≤ 3.0 mg/dL

• No NYHA class IV heart disease

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No uncontrolled infection

• No HIV positivity

PRIOR CONCURRENT THERAPY:

• Prior alkylating agents, immunosuppressive drugs, or steroids allowed provided they were given for < 1 month

• Therapeutic steroid doses of ≤ 15 mg per day (or equivalent) allowed at discretion of physician

• No concurrent participation in another clinical trial involving a pharmacologic agent

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Study Chair: Morie A. Gertz, MD, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT00477971
• Other Study ID Numbers: CDR0000546745; P30CA015083; MC0482; 1691-05; NCI-2009-01329
• First Posted: May 24, 2007
• Last Update Posted: May 17, 2016
• Last Verified: Jun 1, 2015

• Keywords provided by Mayo Clinic: primary systemic amyloidosis
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Plasmacytoma; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Dexamethasone; Melphalan

Study Results

Participant Flow

Recruitment Details	From October 2005 to August 2012, 89 participants were recruited.
Pre-assignment Detail	This study was originally designed as a randomized Phase III clinical trial; however the unwillingness of participants to be randomized to treatment led to changes. The protocol was amended to allow participants to choose between the two regimens.

Arm/Group Title	Low-Dose Melphalan	High-Dose Melphalan + Autologous HSC
Arm/Group Description	Patients receive low-dose melphalan 20 mg/m^2 IV over 15-30 minutes on day 1 or 0.12 mg/kg tablet orally once daily on days 1-7 and dexamethasone 40 mg orally on days 1-4 and 22-25. Treatment repeats every 6 weeks for 10 courses. (Study treatment beyond one year is not allowed.)	Patients receive filgrastim (G-CSF) 10 mg/kg/day on days -7 to -3 and undergo autologous hematopoietic stem cell (HSC) collection. Patients receive high-dose melphalan 140 mg/m^2 IV for low risk or 200 mg/m^2 IV for high risk patients over 1 hour on days -2 and -1 and undergo autologous HSC transplantation on day 0.
Period Title: Overall Study
STARTED	34	55
COMPLETED	17	49
NOT COMPLETED	17	6

Baseline Characteristics

Arm/Group Title	Low-Dose Melphalan	High-Dose Melphalan + Autologous HSC	Total
Arm/Group Description	Patients receive low-dose melphalan 20 mg/m^2 IV over 15-30 minutes on day 1 or 0.12 mg/kg tablet orally once daily on days 1-7 and dexamethasone 40 mg orally on days 1-4 and 22-25. Treatment repeats every 6 weeks for 10 courses. (Study treatment beyond one year is not allowed.)	Patients receive filgrastim (G-CSF) 10 mg/kg/day on days -7 to -3 and undergo autologous hematopoietic stem cell (HSC) collection. Patients receive high-dose melphalan 140 mg/m^2 IV for low risk or 200 mg/m^2 IV for high risk patients over 1 hour on days -2 and -1 and undergo autologous HSC transplantation on day 0.	Total of all reporting groups
Overall Participants	34	55	89
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62	57	59
Sex: Female, Male (Count of Participants)
Female	17 50%	16 29.1%	33 37.1%
Male	17 50%	39 70.9%	56 62.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 1.8%	1 1.1%
Native Hawaiian or Other Pacific Islander	0 0%	1 1.8%	1 1.1%
Black or African American	1 2.9%	1 1.8%	2 2.2%
White	32 94.1%	51 92.7%	83 93.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 2.9%	1 1.8%	2 2.2%
Region of Enrollment (participants) [Number]
United States	34 100%	55 100%	89 100%
ECOG Performance Score (participants) [Number]
0-1	25 73.5%	50 90.9%	75 84.3%
2	9 26.5%	5 9.1%	14 15.7%
Risk Group (participants) [Number]
Low	20 58.8%	38 69.1%	58 65.2%
High	14 41.2%	17 30.9%	31 34.8%

Outcome Measures

1. Primary Outcome

Title	Hematologic Response Rate
Description	Response that was confirmed on 2 consecutive evaluations during treatment. A hematologic response consisted of a Complete response, Very Good Partial Response or Partial Response. Complete Response (CR): Complete disappearance of M-protein from serum and urine on immunofixation, normalization of Free Light Chain (FLC) ratio and <5% plasma cells in bone marrow. Very Good Partial Response (VGPR): >=90% reduction in serum M-component; Urine M-Component <=100 mg per 24 hours. Partial Response (PR): >=50% reduction in serum M-component and/or Urine M-Component >=90% reduction or <200 mg per 24 hours; or >=50% decrease in difference between involved and uninvolved FLC levels.
Time Frame	10 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low-Dose Melphalan	High-Dose Melphalan + Autologous HSC
Arm/Group Description	Patients receive low-dose melphalan 20 mg/m^2 IV over 15-30 minutes on day 1 or 0.12 mg/kg tablet orally once daily on days 1-7 and dexamethasone 40 mg orally on days 1-4 and 22-25. Treatment repeats every 6 weeks for 10 courses. (Study treatment beyond one year is not allowed.)	Patients receive filgrastim (G-CSF) 10 mg/kg/day on days -7 to -3 and undergo autologous hematopoietic stem cell (HSC) collection. Patients receive high-dose melphalan 140 mg/m^2 IV for low risk or 200 mg/m^2 IV for high risk patients over 1 hour on days -2 and -1 and undergo autologous HSC transplantation on day 0.
Measure Participants	34	55
Number (95% Confidence Interval) [percentage of participants]	55.9 164.4%	69.1 125.6%

2. Secondary Outcome

Title	3 Year Overall Survival
Description	Percentage of patients who were alive at 3 years. The 3-year survival rate was estimated using the Kaplan Meier method.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low-Dose Melphalan	High-Dose Melphalan + Autologous HSC
Arm/Group Description	Patients receive low-dose melphalan 20 mg/m^2 IV over 15-30 minutes on day 1 or 0.12 mg/kg tablet orally once daily on days 1-7 and dexamethasone 40 mg orally on days 1-4 and 22-25. Treatment repeats every 6 weeks for 10 courses. (Study treatment beyond one year is not allowed.)	Patients receive filgrastim (G-CSF) 10 mg/kg/day on days -7 to -3 and undergo autologous hematopoietic stem cell (HSC) collection. Patients receive high-dose melphalan 140 mg/m^2 IV for low risk or 200 mg/m^2 IV for high risk patients over 1 hour on days -2 and -1 and undergo autologous HSC transplantation on day 0.
Measure Participants	34	55
Number (95% Confidence Interval) [percentage of participants]	58.8 172.9%	83.6 152%

3. Secondary Outcome

Title	Organ Response to Treatment
Description	Organ response was evaluated on the basis of improvement of one or more affected organ; only one parameter was required to satisfy the criteria. Response needed to be maintained for a minimum of 3 months to be considered valid. Renal response required a 50% reduction in 24-hour urine protein excretion (at least 0.5 g/d) with stable creatinine. Cardiac response required one of >= 2-mm reduction in the interventricular septal (IVS) thickness by echocardiogram, or improvement of ejection fraction by >= 20%, or improvement by 2 NYHA classes without an increase in diuretic use. Hepatic response required either >= 50% decrease in (or normalization of) an initially elevated alkaline phosphatase level or reduction in the size of the liver by at least 2 cm by radiographic determination. Gastrointestinal tract improvement was defined as normalization of a low serum carotene level, or reduction of diarrhea to < 50% of previous movements/day, or decrease in fecal fat excretion by 50%.
Time Frame	10 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low-Dose Melphalan	High-Dose Melphalan + Autologous HSC
Arm/Group Description	Patients receive low-dose melphalan 20 mg/m^2 IV over 15-30 minutes on day 1 or 0.12 mg/kg tablet orally once daily on days 1-7 and dexamethasone 40 mg orally on days 1-4 and 22-25. Treatment repeats every 6 weeks for 10 courses. (Study treatment beyond one year is not allowed.)	Patients receive filgrastim (G-CSF) 10 mg/kg/day on days -7 to -3 and undergo autologous hematopoietic stem cell (HSC) collection. Patients receive high-dose melphalan 140 mg/m^2 IV for low risk or 200 mg/m^2 IV for high risk patients over 1 hour on days -2 and -1 and undergo autologous HSC transplantation on day 0.
Measure Participants	34	55
Number (95% Confidence Interval) [percentage of participants]	26.5 77.9%	29.1 52.9%

4. Post-Hoc Outcome

Title	3-Year Progression Free Survival
Description	Percentage of patients who were progression free at 3 years. The 3-year progression free rate was estimated using the Kaplan Meier method. Progression is assessed when one of the following occur: reappearance of monoclonal protein by immunofixation, Increase in serum monoclonal paraprotein to >25% above the lowest response level, Increase in urine M-protein to > 25% above the lowest remission value for 24-hour excretion.
Time Frame	3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Low-Dose Melphalan	High-Dose Melphalan + Autologous HSC
Arm/Group Description	Patients receive low-dose melphalan 20 mg/m^2 IV over 15-30 minutes on day 1 or 0.12 mg/kg tablet orally once daily on days 1-7 and dexamethasone 40 mg orally on days 1-4 and 22-25. Treatment repeats every 6 weeks for 10 courses. (Study treatment beyond one year is not allowed.)	Patients receive filgrastim (G-CSF) 10 mg/kg/day on days -7 to -3 and undergo autologous hematopoietic stem cell (HSC) collection. Patients receive high-dose melphalan 140 mg/m^2 IV for low risk or 200 mg/m^2 IV for high risk patients over 1 hour on days -2 and -1 and undergo autologous HSC transplantation on day 0.
Measure Participants	34	55
Number (95% Confidence Interval) [percentage of participants]	29.1 85.6%	51.7 94%

Adverse Events

Arm/Group Title	Low-Dose Melphalan		High-Dose Melphalan + Autologous HSC
Arm/Group Description	Patients receive low-dose melphalan 20 mg/m^2 IV over 15-30 minutes on day 1 or 0.12 mg/kg tablet orally once daily on days 1-7 and dexamethasone 40 mg orally on days 1-4 and 22-25. Treatment repeats every 6 weeks for 10 courses. (Study treatment beyond one year is not allowed.)		Patients receive filgrastim (G-CSF) 10 mg/kg/day on days -7 to -3 and undergo autologous hematopoietic stem cell (HSC) collection. Patients receive high-dose melphalan 140 mg/m^2 IV for low risk or 200 mg/m^2 IV for high risk patients over 1 hour on days -2 and -1 and undergo autologous HSC transplantation on day 0.
All Cause Mortality
	Low-Dose Melphalan		High-Dose Melphalan + Autologous HSC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Low-Dose Melphalan		High-Dose Melphalan + Autologous HSC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/34 (17.6%)		3/55 (5.5%)
Cardiac disorders
Atrial fibrillation	1/34 (2.9%)	1	0/55 (0%)	0
Cardiac disorder	0/34 (0%)	0	1/55 (1.8%)	1
Myocardial ischemia	1/34 (2.9%)	1	0/55 (0%)	0
Pericardial effusion	0/34 (0%)	0	1/55 (1.8%)	1
Ventricular fibrillation	1/34 (2.9%)	1	0/55 (0%)	0
Gastrointestinal disorders
Nausea	0/34 (0%)	0	1/55 (1.8%)	1
Upper gastrointestinal hemorrhage	0/34 (0%)	0	1/55 (1.8%)	1
General disorders
Disease progression	0/34 (0%)	0	1/55 (1.8%)	1
Sudden death	1/34 (2.9%)	1	0/55 (0%)	0
Hepatobiliary disorders
Hepatic failure	0/34 (0%)	0	1/55 (1.8%)	1
Infections and infestations
Pneumonia	1/34 (2.9%)	1	1/55 (1.8%)	1
Sepsis	1/34 (2.9%)	1	1/55 (1.8%)	1
Investigations
Blood bilirubin increased	0/34 (0%)	0	1/55 (1.8%)	1
Creatinine increased	0/34 (0%)	0	1/55 (1.8%)	1
Metabolism and nutrition disorders
Dehydration	0/34 (0%)	0	1/55 (1.8%)	1
Nervous system disorders
Ischemia cerebrovascular	1/34 (2.9%)	1	0/55 (0%)	0
Syncope	1/34 (2.9%)	1	0/55 (0%)	0
Renal and urinary disorders
Renal failure	0/34 (0%)	0	1/55 (1.8%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/34 (2.9%)	1	0/55 (0%)	0
Pleural effusion	0/34 (0%)	0	1/55 (1.8%)	1
Pneumonitis	0/34 (0%)	0	2/55 (3.6%)	2
Skin and subcutaneous tissue disorders
Rash desquamating	0/34 (0%)	0	1/55 (1.8%)	1
Vascular disorders
Hypotension	0/34 (0%)	0	2/55 (3.6%)	2
Thrombosis	2/34 (5.9%)	2	1/55 (1.8%)	1
Other (Not Including Serious) Adverse Events
	Low-Dose Melphalan		High-Dose Melphalan + Autologous HSC
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/34 (100%)		55/55 (100%)
Blood and lymphatic system disorders
Blood disorder	0/34 (0%)	0	1/55 (1.8%)	1
Febrile neutropenia	0/34 (0%)	0	32/55 (58.2%)	33
Hemoglobin decreased	17/34 (50%)	41	49/55 (89.1%)	63
Hemolysis	0/34 (0%)	0	1/55 (1.8%)	1
Cardiac disorders
Arrhythmia	0/34 (0%)	0	2/55 (3.6%)	2
Arrhythmia supraventricular	0/34 (0%)	0	1/55 (1.8%)	1
Atrial fibrillation	0/34 (0%)	0	5/55 (9.1%)	7
Left ventricular dysfunction	0/34 (0%)	0	1/55 (1.8%)	1
Left ventricular failure	0/34 (0%)	0	1/55 (1.8%)	1
Myocarditis	0/34 (0%)	0	1/55 (1.8%)	1
Restrictive cardiomyopathy	1/34 (2.9%)	1	2/55 (3.6%)	3
Sinus tachycardia	0/34 (0%)	0	2/55 (3.6%)	2
Supraventricular tachycardia	0/34 (0%)	0	1/55 (1.8%)	2
Ventricular tachycardia	0/34 (0%)	0	3/55 (5.5%)	3
Eye disorders
Cataract	1/34 (2.9%)	2	0/55 (0%)	0
Dry eye syndrome	0/34 (0%)	0	1/55 (1.8%)	2
Gastrointestinal disorders
Abdominal pain	0/34 (0%)	0	1/55 (1.8%)	1
Colitis	0/34 (0%)	0	1/55 (1.8%)	1
Constipation	0/34 (0%)	0	2/55 (3.6%)	2
Diarrhea	6/34 (17.6%)	6	25/55 (45.5%)	27
Dysphagia	0/34 (0%)	0	12/55 (21.8%)	12
Enteritis	0/34 (0%)	0	1/55 (1.8%)	1
Esophageal pain	1/34 (2.9%)	1	0/55 (0%)	0
Esophagitis	0/34 (0%)	0	1/55 (1.8%)	1
Gastritis	0/34 (0%)	0	2/55 (3.6%)	2
Hemorrhoids	1/34 (2.9%)	1	0/55 (0%)	0
Mucositis oral	0/34 (0%)	0	4/55 (7.3%)	4
Nausea	3/34 (8.8%)	3	32/55 (58.2%)	35
Oesophagoscopy abnormal	0/34 (0%)	0	3/55 (5.5%)	3
Rectal hemorrhage	0/34 (0%)	0	1/55 (1.8%)	1
Rectal pain	0/34 (0%)	0	1/55 (1.8%)	1
Stomach pain	1/34 (2.9%)	1	0/55 (0%)	0
Upper gastrointestinal hemorrhage	1/34 (2.9%)	1	0/55 (0%)	0
Vomiting	2/34 (5.9%)	2	17/55 (30.9%)	19
General disorders
Chest pain	1/34 (2.9%)	1	0/55 (0%)	0
Disease progression	1/34 (2.9%)	1	0/55 (0%)	0
Edema limbs	32/34 (94.1%)	140	48/55 (87.3%)	140
Fatigue	33/34 (97.1%)	178	55/55 (100%)	197
Fever	1/34 (2.9%)	1	8/55 (14.5%)	8
General symptom	0/34 (0%)	0	1/55 (1.8%)	1
Ill-defined disorder	0/34 (0%)	0	1/55 (1.8%)	1
Localized edema	0/34 (0%)	0	1/55 (1.8%)	1
Pain	0/34 (0%)	0	1/55 (1.8%)	1
Infections and infestations
Abdominal infection	1/34 (2.9%)	1	0/55 (0%)	0
Anorectal infection	0/34 (0%)	0	1/55 (1.8%)	1
Bronchitis	2/34 (5.9%)	4	0/55 (0%)	0
Esophageal infection	1/34 (2.9%)	1	0/55 (0%)	0
Gingival infection	1/34 (2.9%)	2	0/55 (0%)	0
Infection	3/34 (8.8%)	5	1/55 (1.8%)	1
Infectious colitis	0/34 (0%)	0	1/55 (1.8%)	1
Infectious meningitis	0/34 (0%)	0	1/55 (1.8%)	1
Joint infection	1/34 (2.9%)	1	0/55 (0%)	0
Lip infection	0/34 (0%)	0	1/55 (1.8%)	1
Lymph gland infection	0/34 (0%)	0	1/55 (1.8%)	1
Nail infection	1/34 (2.9%)	1	0/55 (0%)	0
Pneumonia	5/34 (14.7%)	7	4/55 (7.3%)	5
Sepsis	2/34 (5.9%)	2	10/55 (18.2%)	12
Sinusitis	1/34 (2.9%)	1	1/55 (1.8%)	1
Skin infection	4/34 (11.8%)	4	1/55 (1.8%)	1
Upper aerodigestive tract infection	0/34 (0%)	0	1/55 (1.8%)	1
Upper respiratory infection	5/34 (14.7%)	6	2/55 (3.6%)	2
Urinary tract infection	1/34 (2.9%)	1	0/55 (0%)	0
Vaginal infection	1/34 (2.9%)	2	1/55 (1.8%)	1
Injury, poisoning and procedural complications
Fracture	0/34 (0%)	0	1/55 (1.8%)	1
Intraoperative gastrointestinal injury - Appendix	1/34 (2.9%)	1	0/55 (0%)	0
Intraoperative hepatobiliary injury - Gallbladder	0/34 (0%)	0	1/55 (1.8%)	1
Investigations
Alanine aminotransferase increased	1/34 (2.9%)	1	5/55 (9.1%)	5
Alkaline phosphatase increased	2/34 (5.9%)	2	10/55 (18.2%)	11
Aspartate aminotransferase increased	1/34 (2.9%)	1	5/55 (9.1%)	5
Blood bilirubin increased	0/34 (0%)	0	9/55 (16.4%)	10
Creatine phosphokinase increased	0/34 (0%)	0	1/55 (1.8%)	2
Creatinine increased	6/34 (17.6%)	15	21/55 (38.2%)	33
INR increased	0/34 (0%)	0	1/55 (1.8%)	1
Leukocyte count decreased	9/34 (26.5%)	20	51/55 (92.7%)	56
Lymphocyte count decreased	2/34 (5.9%)	4	3/55 (5.5%)	5
Neutrophil count decreased	8/34 (23.5%)	18	52/55 (94.5%)	60
Platelet count decreased	10/34 (29.4%)	27	52/55 (94.5%)	65
Weight loss	13/34 (38.2%)	24	21/55 (38.2%)	26
Metabolism and nutrition disorders
Anorexia	0/34 (0%)	0	5/55 (9.1%)	5
Blood glucose increased	3/34 (8.8%)	3	3/55 (5.5%)	4
Blood uric acid increased	1/34 (2.9%)	2	1/55 (1.8%)	2
Dehydration	0/34 (0%)	0	31/55 (56.4%)	34
Serum albumin decreased	0/34 (0%)	0	2/55 (3.6%)	2
Serum calcium decreased	0/34 (0%)	0	5/55 (9.1%)	5
Serum magnesium decreased	0/34 (0%)	0	1/55 (1.8%)	1
Serum phosphate decreased	0/34 (0%)	0	1/55 (1.8%)	1
Serum potassium decreased	1/34 (2.9%)	1	9/55 (16.4%)	12
Serum potassium increased	0/34 (0%)	0	1/55 (1.8%)	1
Serum sodium decreased	0/34 (0%)	0	11/55 (20%)	11
Serum sodium increased	0/34 (0%)	0	1/55 (1.8%)	1
Tumor lysis syndrome	0/34 (0%)	0	1/55 (1.8%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	1/34 (2.9%)	1	0/55 (0%)	0
Back pain	2/34 (5.9%)	3	1/55 (1.8%)	1
Bone pain	1/34 (2.9%)	2	2/55 (3.6%)	2
Muscle weakness	1/34 (2.9%)	1	0/55 (0%)	0
Myalgia	1/34 (2.9%)	2	1/55 (1.8%)	1
Neck pain	1/34 (2.9%)	1	0/55 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	1/34 (2.9%)	1	1/55 (1.8%)	1
Nervous system disorders
Dizziness	1/34 (2.9%)	1	1/55 (1.8%)	1
Dysgeusia	0/34 (0%)	0	1/55 (1.8%)	1
Headache	0/34 (0%)	0	1/55 (1.8%)	1
Peripheral sensory neuropathy	19/34 (55.9%)	72	21/55 (38.2%)	60
Syncope	3/34 (8.8%)	6	4/55 (7.3%)	6
Syncope vasovagal	1/34 (2.9%)	1	1/55 (1.8%)	1
Psychiatric disorders
Confusion	0/34 (0%)	0	1/55 (1.8%)	1
Depression	2/34 (5.9%)	3	0/55 (0%)	0
Insomnia	2/34 (5.9%)	3	4/55 (7.3%)	4
Psychosis	0/34 (0%)	0	1/55 (1.8%)	1
Renal and urinary disorders
Proteinuria	0/34 (0%)	0	1/55 (1.8%)	2
Renal failure	4/34 (11.8%)	5	4/55 (7.3%)	5
Urinary retention	0/34 (0%)	0	1/55 (1.8%)	1
Urogenital disorder	0/34 (0%)	0	1/55 (1.8%)	1
Reproductive system and breast disorders
Vaginal inflammation	1/34 (2.9%)	1	0/55 (0%)	0
Respiratory, thoracic and mediastinal disorders
Apnea	0/34 (0%)	0	1/55 (1.8%)	1
Cough	2/34 (5.9%)	2	0/55 (0%)	0
Dyspnea	6/34 (17.6%)	7	11/55 (20%)	14
Epistaxis	0/34 (0%)	0	1/55 (1.8%)	1
Hiccups	0/34 (0%)	0	2/55 (3.6%)	2
Hypoxia	0/34 (0%)	0	8/55 (14.5%)	8
Pharyngolaryngeal pain	1/34 (2.9%)	1	0/55 (0%)	0
Pleural effusion	1/34 (2.9%)	1	7/55 (12.7%)	8
Pneumonitis	1/34 (2.9%)	1	6/55 (10.9%)	6
Pulmonary hemorrhage	0/34 (0%)	0	1/55 (1.8%)	1
Respiratory disorder	0/34 (0%)	0	1/55 (1.8%)	1
Skin and subcutaneous tissue disorders
Petechiae	1/34 (2.9%)	1	2/55 (3.6%)	2
Rash desquamating	1/34 (2.9%)	1	5/55 (9.1%)	6
Skin disorder	0/34 (0%)	0	1/55 (1.8%)	1
Vascular disorders
Hematoma	0/34 (0%)	0	1/55 (1.8%)	1
Hemorrhage	1/34 (2.9%)	1	1/55 (1.8%)	1
Hypotension	4/34 (11.8%)	4	33/55 (60%)	34
Thrombosis	1/34 (2.9%)	1	4/55 (7.3%)	4

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.