Bortezomib After Combination Chemotherapy, Rituximab, and an Autologous Stem Cell Transplant in Treating Patients With Mantle Cell Lymphoma

• Sponsor: Alliance for Clinical Trials in Oncology (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT00310037
• Collaborator: National Cancer Institute (NCI) (NIH), Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 151
• Locations: 48
• Arms: 2
• Patients Per Site: 3.1

Study Details

Study Description

Brief Summary

This randomized phase II trial studies how well bortezomib works when given after combination chemotherapy, rituximab, and an autologous stem cell transplant in treating patients with mantle cell lymphoma. Bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) together with an autologous stem cell transplant may allow more chemotherapy to be given so that more cancer cells are killed. Monoclonal antibodies, such as rituximab, 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. Giving bortezomib after combination chemotherapy, monoclonal antibody therapy, and an autologous stem cell transplant may kill any remaining cancer cells or keep the cancer from coming back.

Condition or Disease	Intervention/Treatment	Phase
Mantle Cell Lymphoma	Drug: bortezomib	Phase 2

Detailed Description

Objectives

Primary Objective:

To determine the 18-month progression-free survival (PFS) in patients with previously untreated mantle cell lymphoma who are treated with aggressive chemo-immunotherapy and autologous stem cell transplant followed by randomization to either maintenance or consolidation bortezomib therapy

Secondary Objectives:

• To determine the toxicity profiles of maintenance and consolidation bortezomib by evaluating the number of patients able to complete all maintenance or consolidation therapy

• To determine the complete response rate to intensive chemo-immunotherapy plus maintenance or consolidation bortezomib

• To determine time to progression and overall survival using these two treatment regimens

Correlative/Other Pre-Specified Objectives:

• To determine the importance of p53 mutation or deletion on patient outcome with respect to CR rate, PFS, and OS

• To determine the importance of Ki67, cyclin D1, phosphohistone 3, p27, p21, p16, and PARP p85 expression in pre-treatment tumor biopsies with respect to CR rate, PFS, and OS

• To determine the relationship between proliferation signature and clinical outcome using quantitative real-time RT-PCR

• To evaluate the importance of quantitative cyclin D1 expression and expression of cyclin D1 isoforms in predicting clinical outcome using quantitative real-time RT-PCR

• To evaluate the prognostic significance of microRNAs in mantle cell lymphoma using microRNA arras

• To explore the correlation of selected microRNA polymorphisms with gene target expression with clinical outcomes such as response, PFS, and OS

• To determine changes in gene expression profile from diagnosis to relapse samples to identify genes differentially silenced or over-expressed with disease recurrence

• To determine the importance of early PCR negativity (following Treatment 2) using bcl-1/IgH junction and/or IgH chain gene rearrangement with respect to maintained PFS and the success of maintenance or consolidation therapy to converting patients to PCR negative status

OUTLINE OF INTERVENTIONS:

CHEMOIMMUNOTHERAPY: Patients receive chemoimmunotherapy comprising rituximab* intravenously (IV) over 4-6 hours on day 1, methotrexate (MTX) IV over 4 hours on day 2, cyclophosphamide IV over 2 hours, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 3, and prednisone orally (PO) on days 3-7. Beginning 24 hours after completion of MTX, patients receive leucovorin calcium IV every 6 hours until blood levels of MTX are in a safe range. Patients also receive filgrastim (G-CSF) subcutaneously (SC) once daily (QD) beginning on day 3 and continuing until blood counts recover. Beginning no sooner than day 22, but no later that day 29 of the first course, patients receive a second course of chemoimmunotherapy as above. Patients with > 15% persistent bone marrow involvement may receive a third course of chemoimmunotherapy. Patients are restaged and those with progressive disease are removed from therapy.

NOTE: *During the first course of chemoimmunotherapy, patients receive rituximab only if the number of circulating mantle cells is =< 10,000/mm^3, otherwise, rituximab is omitted during the first course of chemoimmunotherapy.

HIGH-DOSE CONSOLIDATION CHEMOIMMUNOTHERAPY AND PERIPHERAL BLOOD STEM CELL (PBSC) COLLECTION:

Approximately 4 weeks after completion of chemoimmunotherapy, patients receive high-dose consolidation chemoimmunotherapy comprising cytarabine IV over 2 hours and etoposide phosphate IV continuously on days 1-4, and rituximab IV over 4-6 hours on days 5 and 12 OR 6 and 13. Beginning on day 14 and continuing until completion of PBSC collection, patients receive G-CSF SC QD. Once blood counts recover, patients undergo 1-3 leukapheresis procedures for collection of PBSCs on days 22-25.

HIGH-DOSE CHEMOTHERAPY AND AUTOLOGOUS PBSC TRANSPLANTATION (PBSCT): Beginning 4-6 weeks after completion of leukapheresis, patients receive carmustine IV over 2 hours on day -6, etoposide phosphate IV over 4 hours on day -4, and cyclophosphamide IV over 2 hours on day -2. Patients undergo autologous PBSCT on day 0. Patients also receive G-CSF SC QD beginning on day 4 and continuing until blood counts recover.

POST-TRANSPLANTATION IMMUNOTHERAPY: Approximately 5 weeks after autologous PBSCT, patients receive rituximab IV over 4-6 hours once weekly for 2 weeks. Approximately 4 weeks after completion of post-transplantation immunotherapy, patients proceed to maintenance therapy or consolidation therapy with bortezomib as described in the Arms section.

After completion of study treatment, patients are followed every 2 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 151 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Trial of Maintenance vs Consolidation Bortezomib Therapy Following Aggressive Chemo-Immunotherapy and Autologous Stem Cell Transplant for Previously Untreated Mantle Cell Lymphoma
• Actual Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm A maintenance therapy Patients receive bortezomib 1.6 mg/m^2 IV on days 1, 8, 15, and 22 once daily for 4 weeks. There will be a 4 week rest period. One cycle is a total of 8 weeks. A total of 10 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.	Drug: bortezomib; Given IV
Experimental: Arm B consolidation therapy Patients receive bortezomib 1.3 mg/m^2 IV on days 1, 4, 8, and 11 once daily for 3 weeks. One cycle is a total of 3 weeks. A total of 4 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.	Drug: bortezomib; Given IV

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival Rate at 18 Months [At 18 months]

   Progression free survival (PFS) rate at 18 months was defined as the proportion of patients that were alive and progression-free 18 months after registration into the study. The Kaplan-Meier method of 18 month progression-free survival was calculated..

Secondary Outcome Measures

1. Overall Survival [Up to 10 years]

   Overall Survival (OS) was measured from the date of study entry to date of death due to any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method.

2. Number of Participants With Complete Response Intensive Chemo-immunotherapy Plus Maintenance or Consolidation Bortezomib [Up to 10 years]

   Complete response is: Complete disappearance of all detectable clinical and radiographic evidence of target lesions and disappearance of all disease-related symptoms if present prior to therapy and normalization of biochemical abnormalities definitely assignable to NHL All lymph nodes and nodal masses must have regressed to normal size (<= 1.5 cm in the greatest transverse diameter (GTD) for nodes > 1.5 cm prior to therapy) or <= 1 cm for nodes that were 1.1-1.5 cm in the GTD prior to therapy or by more than 75% in the sum of the products of the GTD The spleen, if enlarged before therapy, must have regressed in size and must not be palpable on physical examination. Any macroscopic nodules in any organs detectable on imaging studies should no longer be present. Other organs enlarged prior to therapy due to involvement of lymphoma must have decreased in size If bone marrow was involved by lymphoma prior to treatment, infiltrate must be cleared on repeat bone marrow aspirate

3. Number of Participants With Grade 3, 4 or 5 Adverse Event at Least Possibly Related to Treatment. [Duration of treatment (up to approximately 2 years)]

   The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life Threatening; Grade 5: Death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 69 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

1. Documentation of Disease

A. Histologic Documentation:

• Histologically documented mantle cell lymphoma with co-expression of CD20 (or CD19) and CD5 and lack of CD23 expression by immunophenotyping AND at least one of the following confirmatory tests:

• positive immunostaining for cyclin D1; OR

• the presence of t(11;14) on cytogenetic analysis; OR

• molecular evidence of bcl-1/IgH rearrangement.

• Cases that are CD5-negative and/or CD23-positive will be eligible provided that the histopathology is consistent with mantle cell lymphoma AND positive for cyclin D1, t(11;14), or bcl-1/IgH rearrangement.A tissue block should be submitted to the CALGB Pathology Coordinating Office for central pathology review.

• A diagnosis based on peripheral blood or bone marrow is allowed. If the diagnosis is based only on blood, in addition to the immunophenotype and molecular confirmation above, a peripheral blood smear must be available for central pathology review. If the diagnosis is based on a bone marrow biopsy, the tissue block should be submitted.

• Note: Failure to submit pathology materials within 60 days of patient registration will be considered a major protocol violation.

B. Extent of Disease:

• Stage I-IV. Patients with nodular histology mantle cell lymphoma must have Ann Arbor stage III or IV disease to be eligible. Patients with mantle zone histology will not be eligible because of their relatively favorable prognosis. Patients with other mantle cell histologies are eligible regardless of stage.

• No active CNS disease defined as symptomatic meningeal lymphoma or known CNS parenchymal lymphoma. A lumbar puncture demonstrating mantle cell lymphoma at the time of registration to this study is not an exclusion for study enrollment.

1. Prior Treatment:

1. Patients must be previously untreated or have received no more than one prior cycle of chemotherapy and/or rituximab treatment.

2. No prior radiation therapy for mantle cell lymphoma.

3. ≥ 2 weeks since major surgery.

4. ≥ 3 weeks since prior chemotherapy.

1. Age Eligibility: Age ≥ 18 years and < 70 years

2. Murine Products Hypersensitivity Eligibility: No known hypersensitivity to murine products.

3. Use of Systemic Corticosteroids Eligibility: No medical condition requiring chronic use of systemic corticosteroids.

4. Eligibility Criteria on HIV Infection: No HIV infection. Patients with a history of intravenous drug abuse or any behavior associated with an increased risk of HIV infection should be tested for exposure to the HIV virus. Patients who test positive or who are known to be infected are not eligible due to an increased risk of infection with this regimen. An HIV test is not required for entry on this protocol, but is required if the patient is perceived to be at risk.

5. Non-pregnant and non-nursing: Non-pregnant and non-nursing. Treatment under this protocol would expose an unborn child to significant risks. Women and men of reproductive potential should agree to use an effective means of birth control.

6. HepBSAg or HepC Ab Eligibility: Patients who test positive for HepBSAg or HepC Ab are eligible provided all of the following criteria are met:

1. bilirubin ≤ 2 x upper limit of normal; AND

2. AST ≤ 3 x upper limit of normal; AND

3. liver biopsy demonstrates ≤ grade 2 fibrosis and no cirrhosis.

Hepatitis B surface Ag(+) patients will be treated with lamivudine (3TC) throughout protocol therapy and for 6-12 months thereafter.

1. Secondary Malignancy Eligibility: Patients with a "currently active" second malignancy, other than non-melanoma skin cancers are not eligible. This includes Waldenstrom's Macroglobulinemia, since such patents have experienced transient increases in IgM following initiation of rituximab, with the potential for hyperviscosity syndrome requiring plasmapheresis. Patients are not considered to have a "currently active" malignancy if they have completed anti-cancer therapy, and are considered by their physician to be at less than 30% risk of relapse.

2. Initial Required Laboratory Values:

• LVEF by MUGA or ECHO ≥ 45%

• Creatinine ≤ 2.0 mg/dL

• Total Bilirubin ≤ 2.0 mg/dL (Unless attributable to Gilbert's Disease)

• u-HCG or serum HCG Negative (If patient of childbearing potential).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
2	Illinois CancerCare - Bloomington	Bloomington	Illinois	United States	61701
3	St. Joseph Medical Center	Bloomington	Illinois	United States	61701
4	Graham Hospital	Canton	Illinois	United States	61520
5	Illinois CancerCare - Canton	Canton	Illinois	United States	61520
6	Illinois CancerCare - Carthage	Carthage	Illinois	United States	62321
7	Memorial Hospital	Carthage	Illinois	United States	62321
8	University of Chicago Cancer Research Center	Chicago	Illinois	United States	60637-1470
9	Eureka Community Hospital	Eureka	Illinois	United States	61530
10	Illinois CancerCare - Eureka	Eureka	Illinois	United States	61530
11	Galesburg Clinic, PC	Galesburg	Illinois	United States	61401
12	Illinois CancerCare - Galesburg	Galesburg	Illinois	United States	61401
13	Illinois CancerCare - Havana	Havana	Illinois	United States	62644
14	Mason District Hospital	Havana	Illinois	United States	62644
15	Illinois CancerCare - Kewanee Clinic	Kewanee	Illinois	United States	61443
16	Illinois CancerCare - Macomb	Macomb	Illinois	United States	61455
17	McDonough District Hospital	Macomb	Illinois	United States	61455
18	Illinois CancerCare - Monmouth	Monmouth	Illinois	United States	61462
19	OSF Holy Family Medical Center	Monmouth	Illinois	United States	61462
20	BroMenn Regional Medical Center	Normal	Illinois	United States	61761
21	Community Cancer Center	Normal	Illinois	United States	61761
22	Illinois CancerCare - Community Cancer Center	Normal	Illinois	United States	61761
23	Community Hospital of Ottawa	Ottawa	Illinois	United States	61350
24	Oncology Hematology Associates of Central Illinois, PC - Ottawa	Ottawa	Illinois	United States	61350
25	Illinois CancerCare - Pekin	Pekin	Illinois	United States	61603
26	Proctor Hospital	Peoria	Illinois	United States	61614
27	CCOP - Illinois Oncology Research Association	Peoria	Illinois	United States	61615
28	Oncology Hematology Associates of Central Illinois, PC - Peoria	Peoria	Illinois	United States	61615
29	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61636
30	OSF St. Francis Medical Center	Peoria	Illinois	United States	61637
31	Illinois CancerCare - Peru	Peru	Illinois	United States	61354
32	Illinois Valley Community Hospital	Peru	Illinois	United States	61354
33	Illinois CancerCare - Princeton	Princeton	Illinois	United States	61356
34	Perry Memorial Hospital	Princeton	Illinois	United States	61356
35	Illinois CancerCare - Spring Valley	Spring Valley	Illinois	United States	61362
36	Dana-Farber/Brigham and Women's Cancer Center	Boston	Massachusetts	United States	02115
37	Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute	Boston	Massachusetts	United States	02115
38	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
39	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756-0002
40	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
41	Monter Cancer Center of the North Shore-LIJ Health System	Lake Success	New York	United States	11042
42	CCOP - North Shore University Hospital	Manhasset	New York	United States	11030
43	Don Monti Comprehensive Cancer Center at North Shore University Hospital	Manhasset	New York	United States	11030
44	Long Island Jewish Medical Center	New Hyde Park	New York	United States	11040
45	SUNY Upstate Medical University Hospital	Syracuse	New York	United States	13210
46	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295
47	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096
48	Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210-1240

Sponsors and Collaborators

• Alliance for Clinical Trials in Oncology
• National Cancer Institute (NCI)
• Millennium Pharmaceuticals, Inc.

Investigators

• Study Chair: Lawrence D. Kaplan, MD, University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alliance for Clinical Trials in Oncology
• ClinicalTrials.gov Identifier: NCT00310037
• Other Study ID Numbers: CALGB-50403; CDR0000466167
• First Posted: Apr 3, 2006
• Last Update Posted: Aug 18, 2021
• Last Verified: Aug 1, 2021

• Additional relevant MeSH terms: Lymphoma; Lymphoma, Mantle-Cell; Bortezomib

Study Results

Participant Flow

Recruitment Details	From June 2006 to June 2010, 151 participants were enrolled at 14 sites and 147 participants received protocol treatment.
Pre-assignment Detail	Of the 147 participants who began treatment, 102 participants were randomized. Participants who were not randomized are excluded from all analyses per study design.

Arm/Group Title	Arm A Maintenance Therapy	Arm B Consolidation Therapy
Arm/Group Description	Patients receive bortezomib 1.6 mg/m^2 IV on days 1, 8, 15, and 22 once daily for 4 weeks. There will be a 4 week rest period. One cycle is a total of 8 weeks. A total of 10 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.	Patients receive bortezomib 1.3 mg/m^2 IV on days 1, 4, 8, and 11 once daily for 3 weeks. One cycle is a total of 3 weeks. A total of 4 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	52	50
COMPLETED	34	33
NOT COMPLETED	18	17

Baseline Characteristics

Arm/Group Title	Arm A Maintenance Therapy	Arm B Consolidation Therapy	Total
Arm/Group Description	Patients receive bortezomib 1.6 mg/m^2 IV on days 1, 8, 15, and 22 once daily for 4 weeks. There will be a 4 week rest period. One cycle is a total of 8 weeks. A total of 10 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.	Patients receive bortezomib 1.3 mg/m^2 IV on days 1, 4, 8, and 11 once daily for 3 weeks. One cycle is a total of 3 weeks. A total of 4 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	52	50	102
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58	59	58.5
Sex: Female, Male (Count of Participants)
Female	10 19.2%	12 24%	22 21.6%
Male	42 80.8%	38 76%	80 78.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 2%	1 1%
Not Hispanic or Latino	46 88.5%	43 86%	89 87.3%
Unknown or Not Reported	6 11.5%	6 12%	12 11.8%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 5.8%	0 0%	3 2.9%
White	46 88.5%	48 96%	94 92.2%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	3 5.8%	2 4%	5 4.9%
Region of Enrollment (participants) [Number]
United States	52 100%	50 100%	102 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival Rate at 18 Months
Description	Progression free survival (PFS) rate at 18 months was defined as the proportion of patients that were alive and progression-free 18 months after registration into the study. The Kaplan-Meier method of 18 month progression-free survival was calculated..
Time Frame	At 18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A Maintenance Therapy	Arm B Consolidation Therapy
Arm/Group Description	Patients receive bortezomib 1.6 mg/m^2 IV on days 1, 8, 15, and 22 once daily for 4 weeks. There will be a 4 week rest period. One cycle is a total of 8 weeks. A total of 10 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.	Patients receive bortezomib 1.3 mg/m^2 IV on days 1, 4, 8, and 11 once daily for 3 weeks. One cycle is a total of 3 weeks. A total of 4 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.
Measure Participants	52	50
Number (95% Confidence Interval) [percentage of participants]	88.5 170.2%	96 192%

2. Secondary Outcome

Title	Overall Survival
Description	Overall Survival (OS) was measured from the date of study entry to date of death due to any cause. The median OS with 95% CI was estimated using the Kaplan-Meier method.
Time Frame	Up to 10 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A Maintenance Therapy	Arm B Consolidation Therapy
Arm/Group Description	Patients receive bortezomib 1.6 mg/m^2 IV on days 1, 8, 15, and 22 once daily for 4 weeks. There will be a 4 week rest period. One cycle is a total of 8 weeks. A total of 10 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.	Patients receive bortezomib 1.3 mg/m^2 IV on days 1, 4, 8, and 11 once daily for 3 weeks. One cycle is a total of 3 weeks. A total of 4 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.
Measure Participants	52	50
Median (95% Confidence Interval) [years]	NA	8.9

3. Secondary Outcome

Title	Number of Participants With Complete Response Intensive Chemo-immunotherapy Plus Maintenance or Consolidation Bortezomib
Description	Complete response is: Complete disappearance of all detectable clinical and radiographic evidence of target lesions and disappearance of all disease-related symptoms if present prior to therapy and normalization of biochemical abnormalities definitely assignable to NHL All lymph nodes and nodal masses must have regressed to normal size (<= 1.5 cm in the greatest transverse diameter (GTD) for nodes > 1.5 cm prior to therapy) or <= 1 cm for nodes that were 1.1-1.5 cm in the GTD prior to therapy or by more than 75% in the sum of the products of the GTD The spleen, if enlarged before therapy, must have regressed in size and must not be palpable on physical examination. Any macroscopic nodules in any organs detectable on imaging studies should no longer be present. Other organs enlarged prior to therapy due to involvement of lymphoma must have decreased in size If bone marrow was involved by lymphoma prior to treatment, infiltrate must be cleared on repeat bone marrow aspirate
Time Frame	Up to 10 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A Maintenance Therapy	Arm B Consolidation Therapy
Arm/Group Description	Patients receive bortezomib 1.6 mg/m^2 IV on days 1, 8, 15, and 22 once daily for 4 weeks. There will be a 4 week rest period. One cycle is a total of 8 weeks. A total of 10 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.	Patients receive bortezomib 1.3 mg/m^2 IV on days 1, 4, 8, and 11 once daily for 3 weeks. One cycle is a total of 3 weeks. A total of 4 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.
Measure Participants	52	80
Number [participants]	31 59.6%	35 70%

4. Secondary Outcome

Title	Number of Participants With Grade 3, 4 or 5 Adverse Event at Least Possibly Related to Treatment.
Description	The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3. Grade 1: Mild; Grade 2: Moderate; Grade 3: Severe; Grade 4: Life Threatening; Grade 5: Death.
Time Frame	Duration of treatment (up to approximately 2 years)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm A Maintenance Therapy	Arm B Consolidation Therapy
Arm/Group Description	Patients receive bortezomib 1.6 mg/m^2 IV on days 1, 8, 15, and 22 once daily for 4 weeks. There will be a 4 week rest period. One cycle is a total of 8 weeks. A total of 10 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.	Patients receive bortezomib 1.3 mg/m^2 IV on days 1, 4, 8, and 11 once daily for 3 weeks. One cycle is a total of 3 weeks. A total of 4 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.
Measure Participants	52	50
Number [participants]	52 100%	50 100%

Adverse Events

Arm/Group Title	Arm A Maintenance Therapy		Arm B Consolidation Therapy
Arm/Group Description	Patients receive bortezomib 1.6 mg/m^2 IV on days 1, 8, 15, and 22 once daily for 4 weeks. There will be a 4 week rest period. One cycle is a total of 8 weeks. A total of 10 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.		Patients receive bortezomib 1.3 mg/m^2 IV on days 1, 4, 8, and 11 once daily for 3 weeks. One cycle is a total of 3 weeks. A total of 4 cycles of bortezomib will be given in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Arm A Maintenance Therapy		Arm B Consolidation Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A Maintenance Therapy		Arm B Consolidation Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/52 (25%)		10/50 (20%)
Blood and lymphatic system disorders
Febrile neutropenia	2/52 (3.8%)	2	4/50 (8%)	4
Hemoglobin decreased	10/52 (19.2%)	15	9/50 (18%)	10
Cardiac disorders
Palpitations	0/52 (0%)	0	1/50 (2%)	1
Sinus bradycardia	0/52 (0%)	0	1/50 (2%)	1
Sinus tachycardia	0/52 (0%)	0	2/50 (4%)	2
Eye disorders
Photophobia	1/52 (1.9%)	1	1/50 (2%)	1
Vision blurred	0/52 (0%)	0	1/50 (2%)	1
Watering eyes	1/52 (1.9%)	1	0/50 (0%)	0
Gastrointestinal disorders
Abdominal distension	0/52 (0%)	0	1/50 (2%)	1
Abdominal pain	5/52 (9.6%)	5	2/50 (4%)	2
Colitis	1/52 (1.9%)	1	1/50 (2%)	1
Constipation	3/52 (5.8%)	3	1/50 (2%)	2
Diarrhea	7/52 (13.5%)	8	4/50 (8%)	5
Dysphagia	0/52 (0%)	0	1/50 (2%)	1
Ear, nose and throat examination abnormal	0/52 (0%)	0	2/50 (4%)	2
Esophagitis	0/52 (0%)	0	1/50 (2%)	1
Gingival pain	1/52 (1.9%)	1	1/50 (2%)	1
Ileus	1/52 (1.9%)	1	0/50 (0%)	0
Mucositis oral	3/52 (5.8%)	4	2/50 (4%)	2
Nausea	7/52 (13.5%)	8	5/50 (10%)	7
Oral pain	0/52 (0%)	0	1/50 (2%)	1
Rectal pain	1/52 (1.9%)	1	0/50 (0%)	0
Toothache	2/52 (3.8%)	2	0/50 (0%)	0
Vomiting	4/52 (7.7%)	5	3/50 (6%)	3
General disorders
Chest pain	0/52 (0%)	0	1/50 (2%)	1
Chills	3/52 (5.8%)	3	3/50 (6%)	3
Edema limbs	3/52 (5.8%)	3	2/50 (4%)	2
Fatigue	8/52 (15.4%)	8	5/50 (10%)	5
Fever	3/52 (5.8%)	3	4/50 (8%)	4
Pain	2/52 (3.8%)	2	1/50 (2%)	1
Immune system disorders
Cytokine release syndrome	2/52 (3.8%)	2	2/50 (4%)	2
Hypersensitivity	1/52 (1.9%)	1	3/50 (6%)	3
Infections and infestations
Catheter related infection	1/52 (1.9%)	1	1/50 (2%)	1
Colitis, infectious (e.g., Clostridium difficile)	1/52 (1.9%)	2	0/50 (0%)	0
Infectious colitis	0/52 (0%)	0	1/50 (2%)	1
Infectious meningitis	1/52 (1.9%)	1	0/50 (0%)	0
Pneumonia	0/52 (0%)	0	1/50 (2%)	1
Sepsis	3/52 (5.8%)	3	2/50 (4%)	2
Skin infection	1/52 (1.9%)	1	0/50 (0%)	0
Ureteritis	0/52 (0%)	0	1/50 (2%)	1
Injury, poisoning and procedural complications
Vascular access complication	1/52 (1.9%)	1	1/50 (2%)	2
Investigations
Activated partial thromboplastin time prolonged	1/52 (1.9%)	1	3/50 (6%)	4
Alanine aminotransferase increased	5/52 (9.6%)	7	3/50 (6%)	3
Alkaline phosphatase increased	3/52 (5.8%)	3	2/50 (4%)	2
Aspartate aminotransferase increased	7/52 (13.5%)	7	3/50 (6%)	3
Blood bilirubin increased	4/52 (7.7%)	4	4/50 (8%)	4
Creatinine increased	4/52 (7.7%)	4	1/50 (2%)	1
Gamma-glutamyltransferase increased	1/52 (1.9%)	1	0/50 (0%)	0
INR increased	0/52 (0%)	0	3/50 (6%)	4
Leukocyte count decreased	8/52 (15.4%)	11	6/50 (12%)	7
Lymphocyte count decreased	8/52 (15.4%)	10	9/50 (18%)	9
Neutrophil count decreased	10/52 (19.2%)	12	7/50 (14%)	9
Platelet count decreased	11/52 (21.2%)	15	9/50 (18%)	11
Weight loss	2/52 (3.8%)	2	1/50 (2%)	1
Metabolism and nutrition disorders
Anorexia	4/52 (7.7%)	5	5/50 (10%)	5
Blood glucose increased	6/52 (11.5%)	7	5/50 (10%)	6
Blood uric acid increased	2/52 (3.8%)	2	1/50 (2%)	1
Dehydration	0/52 (0%)	0	1/50 (2%)	1
Serum albumin decreased	5/52 (9.6%)	5	4/50 (8%)	5
Serum calcium decreased	7/52 (13.5%)	8	5/50 (10%)	6
Serum calcium increased	1/52 (1.9%)	1	2/50 (4%)	2
Serum glucose decreased	0/52 (0%)	0	3/50 (6%)	3
Serum magnesium decreased	1/52 (1.9%)	2	2/50 (4%)	2
Serum phosphate decreased	0/52 (0%)	0	4/50 (8%)	4
Serum potassium decreased	4/52 (7.7%)	5	5/50 (10%)	6
Serum sodium decreased	6/52 (11.5%)	6	3/50 (6%)	3
Serum sodium increased	0/52 (0%)	0	2/50 (4%)	3
Tumor lysis syndrome	1/52 (1.9%)	1	0/50 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	2/52 (3.8%)	3	1/50 (2%)	1
Bone pain	1/52 (1.9%)	1	0/50 (0%)	0
Muscle weakness	0/52 (0%)	0	2/50 (4%)	2
Muscle weakness upper limb	0/52 (0%)	0	1/50 (2%)	1
Myalgia	1/52 (1.9%)	1	0/50 (0%)	0
Pain in extremity	1/52 (1.9%)	2	0/50 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	1/52 (1.9%)	1	0/50 (0%)	0
Nervous system disorders
Ataxia	1/52 (1.9%)	1	0/50 (0%)	0
Dizziness	0/52 (0%)	0	3/50 (6%)	3
Headache	5/52 (9.6%)	5	3/50 (6%)	5
Hydrocephalus	0/52 (0%)	0	1/50 (2%)	1
Peripheral motor neuropathy	1/52 (1.9%)	1	0/50 (0%)	0
Peripheral sensory neuropathy	4/52 (7.7%)	5	2/50 (4%)	2
Syncope	0/52 (0%)	0	1/50 (2%)	1
Psychiatric disorders
Anxiety	3/52 (5.8%)	4	0/50 (0%)	0
Confusion	0/52 (0%)	0	3/50 (6%)	3
Depression	1/52 (1.9%)	1	0/50 (0%)	0
Insomnia	1/52 (1.9%)	2	2/50 (4%)	2
Renal and urinary disorders
Urogenital disorder	0/52 (0%)	0	1/50 (2%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	1/52 (1.9%)	1	1/50 (2%)	1
Cough	3/52 (5.8%)	3	3/50 (6%)	3
Dyspnea	2/52 (3.8%)	2	2/50 (4%)	2
Epistaxis	1/52 (1.9%)	1	0/50 (0%)	0
Hiccups	1/52 (1.9%)	1	1/50 (2%)	1
Hypoxia	2/52 (3.8%)	2	2/50 (4%)	2
Pharyngolaryngeal pain	1/52 (1.9%)	1	0/50 (0%)	0
Pleuritic pain	0/52 (0%)	0	1/50 (2%)	1
Pneumonitis	0/52 (0%)	0	1/50 (2%)	1
Skin and subcutaneous tissue disorders
Alopecia	3/52 (5.8%)	3	0/50 (0%)	0
Hand-and-foot syndrome	0/52 (0%)	0	1/50 (2%)	1
Pruritus	1/52 (1.9%)	1	0/50 (0%)	0
Rash desquamating	4/52 (7.7%)	4	2/50 (4%)	2
Skin ulceration	1/52 (1.9%)	1	0/50 (0%)	0
Sweating	1/52 (1.9%)	1	1/50 (2%)	1
Urticaria	1/52 (1.9%)	1	0/50 (0%)	0
Vascular disorders
Flushing	1/52 (1.9%)	1	0/50 (0%)	0
Hypertension	1/52 (1.9%)	1	0/50 (0%)	0
Hypotension	3/52 (5.8%)	3	2/50 (4%)	2
Other (Not Including Serious) Adverse Events
	Arm A Maintenance Therapy		Arm B Consolidation Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/52 (100%)		50/50 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	32/52 (61.5%)	46	27/50 (54%)	43
Hemoglobin decreased	38/52 (73.1%)	357	44/50 (88%)	307
Hemolysis	3/52 (5.8%)	3	3/50 (6%)	7
Lymph node pain	0/52 (0%)	0	3/50 (6%)	3
Lymphatic disorder	0/52 (0%)	0	1/50 (2%)	1
Transfusion: Platelets	1/52 (1.9%)	2	0/50 (0%)	0
Transfusion: pRBCs	1/52 (1.9%)	2	0/50 (0%)	0
Cardiac disorders
Arrhythmia supraventricular	0/52 (0%)	0	1/50 (2%)	1
Atrial fibrillation	4/52 (7.7%)	4	3/50 (6%)	5
Atrial flutter	1/52 (1.9%)	1	1/50 (2%)	1
Atrial tachycardia	0/52 (0%)	0	1/50 (2%)	1
Atrioventricular block first degree	0/52 (0%)	0	1/50 (2%)	1
Cardiac disorder	1/52 (1.9%)	1	0/50 (0%)	0
Cardiac pain	1/52 (1.9%)	1	0/50 (0%)	0
Cardiac valve disease	1/52 (1.9%)	1	2/50 (4%)	2
Conduction disorder	0/52 (0%)	0	1/50 (2%)	1
Edema	3/52 (5.8%)	5	1/50 (2%)	2
Left ventricular failure	3/52 (5.8%)	3	1/50 (2%)	1
Palpitations	3/52 (5.8%)	4	3/50 (6%)	12
Pericardial effusion	0/52 (0%)	0	2/50 (4%)	2
Pericarditis	1/52 (1.9%)	1	0/50 (0%)	0
Sinus arrhythmia	1/52 (1.9%)	1	0/50 (0%)	0
Sinus bradycardia	3/52 (5.8%)	5	0/50 (0%)	0
Sinus tachycardia	8/52 (15.4%)	9	6/50 (12%)	7
Supraventricular extrasystoles	0/52 (0%)	0	1/50 (2%)	2
Supraventricular tachycardia	2/52 (3.8%)	3	2/50 (4%)	2
Ventricular arrhythmia	0/52 (0%)	0	1/50 (2%)	1
Ventricular tachycardia	1/52 (1.9%)	1	1/50 (2%)	1
Ear and labyrinth disorders
Ear disorder	0/52 (0%)	0	2/50 (4%)	2
Ear pain	1/52 (1.9%)	1	1/50 (2%)	2
External ear pain	1/52 (1.9%)	1	0/50 (0%)	0
Hearing impaired	3/52 (5.8%)	4	0/50 (0%)	0
Tinnitus	1/52 (1.9%)	1	0/50 (0%)	0
Eye disorders
Conjunctivitis	1/52 (1.9%)	1	0/50 (0%)	0
Diplopia	0/52 (0%)	0	1/50 (2%)	1
Dry eye syndrome	4/52 (7.7%)	8	4/50 (8%)	6
Extraocular muscle paresis	0/52 (0%)	0	2/50 (4%)	5
Eye disorder	4/52 (7.7%)	6	2/50 (4%)	2
Eye pain	1/52 (1.9%)	1	2/50 (4%)	2
Photophobia	1/52 (1.9%)	1	0/50 (0%)	0
Vision blurred	7/52 (13.5%)	11	3/50 (6%)	4
Watering eyes	3/52 (5.8%)	3	0/50 (0%)	0
Gastrointestinal disorders
Abdominal distension	6/52 (11.5%)	10	2/50 (4%)	3
Abdominal pain	16/52 (30.8%)	32	18/50 (36%)	29
Anal pain	0/52 (0%)	0	2/50 (4%)	2
Colitis	2/52 (3.8%)	2	0/50 (0%)	0
Colonic hemorrhage	1/52 (1.9%)	1	0/50 (0%)	0
Constipation	28/52 (53.8%)	59	28/50 (56%)	70
Diarrhea	45/52 (86.5%)	144	45/50 (90%)	124
Dry mouth	2/52 (3.8%)	2	1/50 (2%)	1
Dyspepsia	12/52 (23.1%)	14	9/50 (18%)	17
Dysphagia	5/52 (9.6%)	7	8/50 (16%)	9
Ear, nose and throat examination abnormal	5/52 (9.6%)	5	7/50 (14%)	13
Enteritis	3/52 (5.8%)	3	0/50 (0%)	0
Esophageal pain	3/52 (5.8%)	4	5/50 (10%)	5
Esophagitis	1/52 (1.9%)	1	2/50 (4%)	3
Flatulence	5/52 (9.6%)	8	1/50 (2%)	1
Gastritis	0/52 (0%)	0	2/50 (4%)	2
Gastrointestinal disorder	4/52 (7.7%)	6	1/50 (2%)	1
Gingival pain	1/52 (1.9%)	2	1/50 (2%)	1
Hemorrhoids	7/52 (13.5%)	8	6/50 (12%)	7
Lower gastrointestinal hemorrhage	1/52 (1.9%)	1	0/50 (0%)	0
Mucositis oral	35/52 (67.3%)	52	35/50 (70%)	58
Nausea	47/52 (90.4%)	170	48/50 (96%)	170
Oesophagoscopy abnormal	0/52 (0%)	0	1/50 (2%)	2
Oral hemorrhage	2/52 (3.8%)	2	0/50 (0%)	0
Oral pain	1/52 (1.9%)	3	3/50 (6%)	4
Peritoneal pain	1/52 (1.9%)	1	0/50 (0%)	0
Proctitis	1/52 (1.9%)	1	0/50 (0%)	0
Rectal hemorrhage	0/52 (0%)	0	2/50 (4%)	2
Rectal pain	2/52 (3.8%)	2	5/50 (10%)	6
Salivary gland disorder	1/52 (1.9%)	1	1/50 (2%)	1
Stomach pain	2/52 (3.8%)	2	2/50 (4%)	2
Toothache	1/52 (1.9%)	1	2/50 (4%)	2
Typhlitis	2/52 (3.8%)	2	1/50 (2%)	1
Vomiting	45/52 (86.5%)	103	44/50 (88%)	95
General disorders
Chest pain	4/52 (7.7%)	4	6/50 (12%)	7
Chills	24/52 (46.2%)	36	25/50 (50%)	48
Death NOS	0/52 (0%)	0	1/50 (2%)	1
Edema limbs	16/52 (30.8%)	42	18/50 (36%)	36
Facial pain	0/52 (0%)	0	1/50 (2%)	4
Fatigue	44/52 (84.6%)	284	45/50 (90%)	257
Fever	28/52 (53.8%)	47	26/50 (52%)	37
Flu-like symptoms	2/52 (3.8%)	4	0/50 (0%)	0
Gait abnormal	1/52 (1.9%)	1	0/50 (0%)	0
General symptom	1/52 (1.9%)	1	1/50 (2%)	2
Hypothermia	1/52 (1.9%)	1	0/50 (0%)	0
Ill-defined disorder	1/52 (1.9%)	1	1/50 (2%)	1
Localized edema	5/52 (9.6%)	5	5/50 (10%)	6
Pain	14/52 (26.9%)	24	10/50 (20%)	15
Radiation-Other(Specify,_____)	0/52 (0%)	0	1/50 (2%)	1
Hepatobiliary disorders
Hepatobiliary disease	1/52 (1.9%)	1	0/50 (0%)	0
Immune system disorders
Cytokine release syndrome	6/52 (11.5%)	7	10/50 (20%)	13
Hypersensitivity	7/52 (13.5%)	11	11/50 (22%)	15
Serum sickness	1/52 (1.9%)	1	0/50 (0%)	0
Infections and infestations
Abdominal infection	2/52 (3.8%)	2	1/50 (2%)	1
Anal infection	0/52 (0%)	0	1/50 (2%)	1
Anorectal infection	0/52 (0%)	0	1/50 (2%)	1
Arteritis infective	0/52 (0%)	0	1/50 (2%)	1
Bronchitis	4/52 (7.7%)	5	0/50 (0%)	0
Catheter related infection	9/52 (17.3%)	12	12/50 (24%)	15
Colitis, infectious (e.g., Clostridium difficile)	2/52 (3.8%)	3	1/50 (2%)	2
Conjunctivitis infective	0/52 (0%)	0	2/50 (4%)	3
Gingival infection	3/52 (5.8%)	5	2/50 (4%)	2
Infection	4/52 (7.7%)	4	6/50 (12%)	9
Infection with grade 3 or 4 neutropenia	0/52 (0%)	0	2/50 (4%)	3
Infection without neutropenia	0/52 (0%)	0	2/50 (4%)	2
Infectious colitis	4/52 (7.7%)	4	2/50 (4%)	2
Lip infection	2/52 (3.8%)	2	1/50 (2%)	1
Mucosal infection	1/52 (1.9%)	1	0/50 (0%)	0
Nail infection	1/52 (1.9%)	1	0/50 (0%)	0
Opportunistic infection	0/52 (0%)	0	2/50 (4%)	2
Otitis externa	1/52 (1.9%)	2	0/50 (0%)	0
Otitis media	2/52 (3.8%)	2	0/50 (0%)	0
Pharyngitis	1/52 (1.9%)	1	0/50 (0%)	0
Pneumonia	8/52 (15.4%)	12	5/50 (10%)	8
Rhinitis infective	3/52 (5.8%)	3	1/50 (2%)	1
Sepsis	7/52 (13.5%)	7	5/50 (10%)	6
Sinusitis	11/52 (21.2%)	11	6/50 (12%)	8
Skin infection	4/52 (7.7%)	4	7/50 (14%)	12
Tooth infection	1/52 (1.9%)	2	1/50 (2%)	1
Tracheitis	1/52 (1.9%)	1	0/50 (0%)	0
Upper aerodigestive tract infection	1/52 (1.9%)	1	1/50 (2%)	1
Upper respiratory infection	14/52 (26.9%)	19	6/50 (12%)	6
Ureteritis	2/52 (3.8%)	3	2/50 (4%)	2
Urinary tract infection	5/52 (9.6%)	5	3/50 (6%)	6
Vaginal infection	0/52 (0%)	0	1/50 (2%)	1
Wound infection	0/52 (0%)	0	1/50 (2%)	1
Injury, poisoning and procedural complications
Bruising	3/52 (5.8%)	3	3/50 (6%)	3
Fracture	1/52 (1.9%)	1	2/50 (4%)	2
Gastrointestinal anastomotic leak	1/52 (1.9%)	1	0/50 (0%)	0
Intraoperative neurological injury - Spinal cord	0/52 (0%)	0	1/50 (2%)	1
Vascular access complication	3/52 (5.8%)	4	4/50 (8%)	4
Wound dehiscence	0/52 (0%)	0	1/50 (2%)	1
Investigations
Activated partial thromboplastin time prolonged	6/52 (11.5%)	12	7/50 (14%)	9
Alanine aminotransferase increased	26/52 (50%)	99	27/50 (54%)	86
Alkaline phosphatase	1/52 (1.9%)	1	1/50 (2%)	1
Alkaline phosphatase increased	17/52 (32.7%)	32	19/50 (38%)	56
Aspartate aminotransferase increased	29/52 (55.8%)	92	31/50 (62%)	95
Blood bilirubin increased	15/52 (28.8%)	33	16/50 (32%)	54
CD4 lymphocytes decreased	1/52 (1.9%)	1	3/50 (6%)	3
Cardiac troponin T increased	1/52 (1.9%)	1	1/50 (2%)	1
Creatinine increased	11/52 (21.2%)	25	11/50 (22%)	27
Fibrinogen decreased	0/52 (0%)	0	1/50 (2%)	1
Gamma-glutamyltransferase increased	4/52 (7.7%)	11	1/50 (2%)	3
INR increased	7/52 (13.5%)	13	5/50 (10%)	7
Laboratory test abnormal	1/52 (1.9%)	2	2/50 (4%)	2
Leukocyte count decreased	37/52 (71.2%)	261	38/50 (76%)	229
Leukocytes (total WBC) for BMT studies, if specified in the protocol.	0/52 (0%)	0	1/50 (2%)	1
Lymphocyte count decreased	35/52 (67.3%)	285	38/50 (76%)	264
Neutrophil count decreased	52/52 (100%)	283	50/50 (100%)	300
Platelet count decreased	52/52 (100%)	472	50/50 (100%)	399
Serum cholesterol increased	0/52 (0%)	0	1/50 (2%)	1
Weight gain	10/52 (19.2%)	15	9/50 (18%)	10
Weight loss	10/52 (19.2%)	18	12/50 (24%)	15
Metabolism and nutrition disorders
Acidosis	1/52 (1.9%)	1	0/50 (0%)	0
Anorexia	32/52 (61.5%)	55	35/50 (70%)	83
Blood glucose increased	27/52 (51.9%)	217	23/50 (46%)	135
Blood uric acid increased	4/52 (7.7%)	4	3/50 (6%)	4
Dehydration	7/52 (13.5%)	8	8/50 (16%)	13
Glucose intolerance	0/52 (0%)	0	1/50 (2%)	1
Serum albumin decreased	22/52 (42.3%)	57	23/50 (46%)	60
Serum calcium decreased	29/52 (55.8%)	126	25/50 (50%)	85
Serum calcium increased	3/52 (5.8%)	3	4/50 (8%)	8
Serum glucose decreased	9/52 (17.3%)	14	9/50 (18%)	17
Serum magnesium decreased	15/52 (28.8%)	29	13/50 (26%)	28
Serum magnesium increased	6/52 (11.5%)	7	8/50 (16%)	12
Serum phosphate decreased	15/52 (28.8%)	25	11/50 (22%)	20
Serum potassium decreased	28/52 (53.8%)	80	22/50 (44%)	67
Serum potassium increased	4/52 (7.7%)	7	7/50 (14%)	10
Serum sodium decreased	24/52 (46.2%)	73	21/50 (42%)	71
Serum sodium increased	10/52 (19.2%)	17	8/50 (16%)	10
Serum triglycerides increased	0/52 (0%)	0	1/50 (2%)	1
Tumor lysis syndrome	0/52 (0%)	0	2/50 (4%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	16/52 (30.8%)	48	15/50 (30%)	33
Arthritis	3/52 (5.8%)	13	2/50 (4%)	8
Back pain	15/52 (28.8%)	36	13/50 (26%)	20
Bone pain	14/52 (26.9%)	25	8/50 (16%)	12
Chest wall pain	5/52 (9.6%)	6	4/50 (8%)	4
Muscle weakness	5/52 (9.6%)	15	12/50 (24%)	22
Muscle weakness lower limb	0/52 (0%)	0	3/50 (6%)	5
Muscle weakness upper limb	0/52 (0%)	0	1/50 (2%)	2
Musculoskeletal disorder	7/52 (13.5%)	11	3/50 (6%)	8
Myalgia	11/52 (21.2%)	29	12/50 (24%)	28
Neck pain	7/52 (13.5%)	16	6/50 (12%)	6
Osteonecrosis	0/52 (0%)	0	1/50 (2%)	5
Osteoporosis	0/52 (0%)	0	1/50 (2%)	3
Pain in extremity	16/52 (30.8%)	29	12/50 (24%)	19
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/52 (1.9%)	1	0/50 (0%)	0
Nervous system disorders
Acoustic nerve disorder NOS	1/52 (1.9%)	1	0/50 (0%)	0
Ataxia	0/52 (0%)	0	1/50 (2%)	1
Cognitive disturbance	2/52 (3.8%)	2	0/50 (0%)	0
Depressed level of consciousness	0/52 (0%)	0	1/50 (2%)	1
Dizziness	16/52 (30.8%)	24	14/50 (28%)	17
Dysgeusia	8/52 (15.4%)	12	9/50 (18%)	12
Extrapyramidal disorder	3/52 (5.8%)	7	1/50 (2%)	1
Facial muscle weakness	0/52 (0%)	0	2/50 (4%)	2
Headache	32/52 (61.5%)	85	33/50 (66%)	56
Hydrocephalus	0/52 (0%)	0	1/50 (2%)	1
Ischemia cerebrovascular	2/52 (3.8%)	2	1/50 (2%)	1
Memory impairment	7/52 (13.5%)	11	2/50 (4%)	4
Neuralgia	6/52 (11.5%)	27	10/50 (20%)	26
Neurological disorder NOS	4/52 (7.7%)	5	1/50 (2%)	3
Nystagmus	1/52 (1.9%)	1	0/50 (0%)	0
Peripheral motor neuropathy	11/52 (21.2%)	37	4/50 (8%)	11
Peripheral sensory neuropathy	38/52 (73.1%)	243	42/50 (84%)	216
Phrenic nerve paralysis	0/52 (0%)	0	2/50 (4%)	4
Radiculitis brachial	0/52 (0%)	0	2/50 (4%)	4
Seizure	0/52 (0%)	0	1/50 (2%)	1
Sinus pain	0/52 (0%)	0	1/50 (2%)	1
Syncope	6/52 (11.5%)	7	2/50 (4%)	4
Syncope vasovagal	0/52 (0%)	0	2/50 (4%)	2
Tremor	2/52 (3.8%)	2	4/50 (8%)	5
Psychiatric disorders
Agitation	0/52 (0%)	0	1/50 (2%)	3
Anxiety	13/52 (25%)	38	14/50 (28%)	24
Confusion	1/52 (1.9%)	1	4/50 (8%)	7
Depression	3/52 (5.8%)	4	10/50 (20%)	17
Insomnia	19/52 (36.5%)	50	29/50 (58%)	74
Libido decreased	1/52 (1.9%)	1	1/50 (2%)	1
Psychosis	0/52 (0%)	0	1/50 (2%)	1
Renal and urinary disorders
Bladder hemorrhage	1/52 (1.9%)	1	2/50 (4%)	2
Bladder pain	1/52 (1.9%)	1	1/50 (2%)	1
Glomerular filtration rate decreased	2/52 (3.8%)	2	0/50 (0%)	0
Hemoglobin urine positive	1/52 (1.9%)	2	0/50 (0%)	0
Proteinuria	2/52 (3.8%)	3	1/50 (2%)	1
Urethral pain	1/52 (1.9%)	2	1/50 (2%)	1
Urinary frequency	1/52 (1.9%)	1	8/50 (16%)	10
Urinary incontinence	0/52 (0%)	0	2/50 (4%)	3
Urinary retention	0/52 (0%)	0	4/50 (8%)	5
Urine discoloration	1/52 (1.9%)	1	0/50 (0%)	0
Urogenital disorder	3/52 (5.8%)	7	1/50 (2%)	3
Reproductive system and breast disorders
Breast pain	2/52 (3.8%)	2	1/50 (2%)	2
Erectile dysfunction	2/52 (3.8%)	2	1/50 (2%)	1
Gynecomastia	0/52 (0%)	0	2/50 (4%)	2
Pelvic floor muscle weakness	1/52 (1.9%)	1	0/50 (0%)	0
Pelvic pain	1/52 (1.9%)	1	0/50 (0%)	0
Scrotal pain	0/52 (0%)	0	1/50 (2%)	1
Testicular pain	1/52 (1.9%)	1	0/50 (0%)	0
Vaginal hemorrhage	1/52 (1.9%)	1	0/50 (0%)	0
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome	1/52 (1.9%)	1	0/50 (0%)	0
Allergic rhinitis	17/52 (32.7%)	30	10/50 (20%)	15
Atelectasis	0/52 (0%)	0	1/50 (2%)	1
Bronchopulmonary hemorrhage	0/52 (0%)	0	2/50 (4%)	2
Bronchospasm	1/52 (1.9%)	1	1/50 (2%)	1
Cough	30/52 (57.7%)	64	18/50 (36%)	33
Dyspnea	22/52 (42.3%)	53	19/50 (38%)	55
Epistaxis	5/52 (9.6%)	6	11/50 (22%)	14
Hiccups	4/52 (7.7%)	5	3/50 (6%)	5
Hypoxia	2/52 (3.8%)	2	2/50 (4%)	3
Nasal congestion	1/52 (1.9%)	1	1/50 (2%)	1
Pharyngeal mucositis	1/52 (1.9%)	1	0/50 (0%)	0
Pharyngolaryngeal pain	3/52 (5.8%)	3	10/50 (20%)	10
Pleural effusion	2/52 (3.8%)	6	1/50 (2%)	3
Pneumonitis	3/52 (5.8%)	5	12/50 (24%)	22
Pulmonary hypertension	0/52 (0%)	0	1/50 (2%)	1
Respiratory disorder	6/52 (11.5%)	6	1/50 (2%)	1
Voice alteration	2/52 (3.8%)	4	2/50 (4%)	3
Skin and subcutaneous tissue disorders
Alopecia	19/52 (36.5%)	30	5/50 (10%)	10
Dry skin	5/52 (9.6%)	5	4/50 (8%)	5
Erythema multiforme	2/52 (3.8%)	2	2/50 (4%)	2
Hand-and-foot syndrome	0/52 (0%)	0	2/50 (4%)	2
Nail disorder	2/52 (3.8%)	2	1/50 (2%)	2
Pain of skin	4/52 (7.7%)	8	2/50 (4%)	2
Petechiae	3/52 (5.8%)	3	5/50 (10%)	5
Photosensitivity	1/52 (1.9%)	1	0/50 (0%)	0
Pruritus	9/52 (17.3%)	14	9/50 (18%)	12
Rash acneiform	2/52 (3.8%)	3	0/50 (0%)	0
Rash desquamating	34/52 (65.4%)	62	31/50 (62%)	73
Skin disorder	7/52 (13.5%)	10	7/50 (14%)	11
Skin induration	0/52 (0%)	0	1/50 (2%)	2
Sweating	11/52 (21.2%)	23	12/50 (24%)	17
Urticaria	2/52 (3.8%)	3	2/50 (4%)	3
Vascular disorders
Flushing	7/52 (13.5%)	8	7/50 (14%)	8
Hemorrhage	2/52 (3.8%)	2	1/50 (2%)	1
Hot flashes	0/52 (0%)	0	2/50 (4%)	2
Hypertension	5/52 (9.6%)	12	12/50 (24%)	15
Hypotension	13/52 (25%)	18	15/50 (30%)	19
Phlebitis	1/52 (1.9%)	1	0/50 (0%)	0
Thrombosis	5/52 (9.6%)	6	1/50 (2%)	1
Vasculitis	0/52 (0%)	0	1/50 (2%)	1

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.