Phase 2 Study of Carfilzomib in Relapsed Multiple Myeloma

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00530816
• Collaborator: (none)
• Enrollment: 164
• Locations: 30
• Arm: 1
• Duration (Months): 70
• Patients Per Site: 5.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To evaluate the best overall response rate, safety and tolerability of carfilzomib in patients with relapsed or refractory multiple myeloma.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: carfilzomib	Phase 2

Detailed Description

Two groups of patients with multiple myeloma were initially studied: bortezomib-naïve and bortezomib-treated. Following Amendment 2, only bortezomib-naïve patients were enrolled. Study results were reported in 2 parts, depending on whether a patient received prior bortezomib.

Study Design

• Study Type: Interventional
• Actual Enrollment: 164 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Single-arm, Phase 2 Study of Carfilzomib in Patients With Relapsed or Refractory Multiple Myeloma
• Study Start Date: Sep 1, 2007
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Carfilzomib Participants received carfilzomib 20 mg/m² intravenous (IV) injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles. Starting with Amendment 3, if all doses in Cycle 1 were well-tolerated the dose was escalated to 27 mg/m² IV for subsequent cycles.	Drug: carfilzomib; Intravenous (IV) injection over 2 to 10 minutes twice weekly for three weeks followed by 12 days of rest.; Other Names: PR-171 PR171 Kyprolis® (carfilzomib) for Injection

Outcome Measures

Primary Outcome Measures

1. Best Overall Response Rate (ORR) in the Response Evaluable Subset Population [Disease response was assessed on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12, and at End of Study, 30 days after last dose. Median duration of treatment was 100 days for Part 1 and 170 days for Part 2 participants.]

   ORR is defined as the percentage of patients who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) determined by Independent Review Committee (IRC). Responses were assessed according to International Uniform Response Criteria for Multiple Myeloma, documented by 2 consecutive assessments made at any time before the start of new therapy. sCR: CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. CR: absence of M-protein in serum and urine by immunofixation, disappearance of any soft tissue plasmacytomas, and ≤5% plasma cells in bone marrow. VGPR: serum and urine M-proteins detectable by immunofixation but not by electrophoresis or a ≥ 90% reduction in serum M-protein with urine M-protein level < 100 mg/24 hours. PR: ≥ 50% reduction of serum M-protein and in urine of ≥ 90% or to < 200 mg per 24 hours.

Secondary Outcome Measures

1. Best Overall Response Rate (ORR) in the Response Evaluable Population [Disease response was assessed on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12, End of Study, 30 days after last dose; median duration of treatment was 100 days for Part 1 and 170 days for Part 2 participants.]

   ORR is defined as the percentage of patients who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) determined by Independent Review Committee (IRC). Responses were assessed according to International Uniform Response Criteria for Multiple Myeloma, documented by 2 consecutive assessments made at any time before the start of new therapy. sCR: CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. CR: absence of M-protein in serum and urine by immunofixation, disappearance of any soft tissue plasmacytomas, and ≤5% plasma cells in bone marrow. VGPR: serum and urine M-proteins detectable by immunofixation but not by electrophoresis or a ≥ 90% reduction in serum M-protein with urine M-protein level < 100 mg/24 hours. PR: ≥ 50% reduction of serum M-protein and in urine of ≥ 90% or to < 200 mg per 24 hours.

2. Clinical Benefit Rate (CBR) [Disease response was assessed on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12, and at End of Study, 30 days after last dose. Median duration of treatment was 100 days for Part 1 and 170 days for Part 2 participants.]

   Clinical Benefit Rate is defined as the percentage of participants with a best overall response of minimal response (MR) or better, i.e., a best overall response of sCR, CR, VGPR, PR, or MR. MR was defined as outlined by European Group for Blood and Marrow Transplantation (EBMT) criteria, defined as reduction of M-protein in serum of 25% to 49% and in urine of 50% to 89%, maintained for 6 weeks.

3. Duration of Response (DOR) [Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 30 November 2010 for Part 1 and 22 April 2011 for Part 2.]

   DOR is defined as the time from first evidence of PR or better to disease progression assessed by the IRC or death due to any cause. Patients lost to follow-up prior to disease progression or who were alive without disease progression before the analysis cutoff date were censored at the last disease assessment. Progressive disease was defined as any of the following: An increase of M-protein in serum (absolute increase ≥ 0.5 g/dL) or urine (absolute increase ≥ 200 mg/24 hours) of > 25% from the nadir (if not zero). Percentage of plasma cells in bone marrow ≥ 10%. New or increased size of bone lesions or new plasmacytomas. Patients without measurable serum and urine M-protein: 25% increase from nadir in the difference between involved and uninvolved FLC levels and absolute increase >10 mg/dL. Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) attributed solely to the proliferative disorder. Median DOR was estimated using Kaplan-Meier methods.

4. Time to Progression (TTP) [Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 30 November 2010 for Part 1 and 22 April 2011 for Part 2. Median follow-up time was 13.4 months for Part 1 and 11.5 months in Part 2.]

   Time to Progression is defined as the time from the start of treatment to IRC-determined disease progression. Patients who were lost to follow-up prior to documentation of disease progression, or who died before documentation of disease progression or who were alive and did not have documentation of disease progression before the data analysis cut-off date were censored at the last disease assessment. Median TTP was estimated using the Kaplan-Meier method.

5. Progression-free Survival (PFS) [Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 30 November 2010 for Part 1 and 22 April 2011 for Part 2. Median follow-up time was 13.4 months for Part 1 and 11.5 months in Part 2.]

   Progression-free Survival (PFS) is defined as the time from start of treatment to IRC determined disease progression or death due to any cause. Patients who were lost to follow-up prior to documentation of disease progression and patients who were alive without disease progression before a data analysis cut-off date were censored at the last disease assessment. Median PFS was estimated using the Kaplan-Meier method.

6. Overall Survival (OS) [Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 19 November 2012 for Part 1 and 07 January 2013 for Part 2. Median follow-up time was 19.1 months for Part 1 and 35.9 months in Part 2.]

   Overall Survival is defined as the time from the start of study treatment to date of death due to any cause. Patients who were alive or lost to follow-up as of the data analysis cut-off date for the final OS analysis were censored at the date the patient was last known to be alive. Median OS was estimated using the Kaplan-Meier method.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Disease Related

• Multiple myeloma

• Subjects must have measurable disease, defined as one or more of the following:

• Serum M-protein ≥ 1 g/dL

• Urine M-protein ≥ 200 mg/24 hours

• Subjects must have been responsive (i.e., achieve a minimal response [MR] or better) to standard, first line therapy

• Relapsed and/or refractory or progressive disease after at least one, but no more than three, prior therapeutic treatments or regimens for multiple myeloma. Refractory disease is defined as ≤ 25% response or progression during therapy or within 60 days after completion of therapy. Induction therapy and stem cell transplant will be considered as one regimen

Demographic

• Males and females ≥18 years of age

• Life expectancy of more than three months

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2

Laboratory

• Adequate hepatic function, with bilirubin < 2.0 times the upper limit of normal, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of < 3.0 times the upper limit of normal

• Uric acid, if elevated, must be corrected to within laboratory normal range prior to dosing

• Total white blood cell (WBC) count ≥ 2,000/mm³, absolute neutrophil count > 1,000/mm³, hemoglobin ≥ 8.0 g/dL, and platelet count > 50,000/mm³

• Subjects should be platelet transfusion independent

• Screening absolute neutrophil count (ANC) should be independent of granulocyte colony stimulating factor (G-CSF) or granulocyte macrophage colony stimulating factor (GM-CSF) support for ≥ 1 week and of pegylated G-CSF for ≥ 2 weeks

• Subjects may receive red blood cell (RBC) transfusion or receive supportive care such as erythropoietin and darbepoetin in accordance with institutional guidelines

• Calculated or measured creatinine clearance of ≥ 30 mL/minute, calculated using the formula of Cockcroft and Gault [(140 - Age) X Mass (kg) / (72 X Creatinine mg/dL)]. Multiply result by 0.85 if female.

• Serum creatinine ≤ 2 mg/dL

Ethical / Other

• Written informed consent in accordance with federal, local, and institutional guidelines

• Female subjects of child-bearing potential must have a negative serum pregnancy test within seven days of the first dose and agree to use dual methods of contraception during and for 3 months following last dose of drug. Post menopausal females (> 45 years old and without menses for > 1 year) and surgically sterilized females are exempt from a pregnancy test. Male subjects must use an effective barrier method of contraception during study and for 3 months following the last dose if sexually active with a female of child-bearing potential.

• Subjects must be able to receive outpatient treatment and laboratory monitoring at the institute that administers agent.

Exclusion Criteria:

Disease Related

• Multiple Myeloma Immunoglobulin M (IgM)

• Subjects previously treated with any proteasome inhibitor (for Part 2 Proteasome Inhibitor - Naïve only, criteria added at Amendment 2)

• Subjects must not be primary refractory to standard first-line therapy

• Subjects with non-secretory multiple myeloma, defined as < 1 g/dL M-protein in serum, < 200 mg/24 hour M-protein in urine

• Subjects with disease measurable only by serum free light chain (SFLC) analysis

• Glucocorticoid therapy (prednisone >10 mg/day orally or equivalent) within the last three weeks

• POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes)

• Plasma cell leukemia

• Chemotherapy with approved or investigative anticancer therapeutics, including steroid therapy, within the three weeks prior to first dose

• Radiation therapy or immunotherapy in the previous four weeks; localized radiation therapy within 1 week prior to first dose

• Participation in an investigational therapeutic study within three weeks or within five drug half-lives (t1/2) prior to first dose, whichever time is greater

• Prior treatment with carfilzomib

Concurrent Conditions

• Major surgery within three weeks before Day 1

• Congestive heart failure (New York Heart Association class III to IV), symptomatic ischemia, conduction abnormalities uncontrolled by conventional intervention, or myocardial infarction in the previous six months

• Acute active infection requiring systemic antibiotics, antivirals or antifungals within 2 weeks prior to first dose

• Known or suspected human immunodeficiency (HIV) infection or subjects who are HIV seropositive

• Active hepatitis A, B, or C infection

• Non-hematologic malignancy within the past three years except a) adequately treated basal cell or squamous cell skin cancer, b) carcinoma in situ of the cervix, or c) prostate cancer < Gleason Grade 6 with stable prostate-specific antigen (PSA)

• Subjects with treatment related myelodysplastic syndrome

• Significant neuropathy (Grade 3, 4 or Grade 2 with pain) at the time of study initiation

• Subjects with known contraindication to receiving allopurinol

• Subjects in whom the required program of oral and intravenous fluid hydration is contraindicated, e.g., due to pre-existing pulmonary, cardiac, or renal impairment

• Subjects with known or suspected amyloidosis Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis

• Any clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent

Ethical / Other

• Female subjects who are pregnant or lactating

• Serious psychiatric or medical conditions that could interfere with treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic Scottsdale	Scottsdale	Arizona	United States	85259
2	Tower Cancer Research Foundation	Beverly Hills	California	United States	90211
3	Therapeutic Research Institute of Orange County	Laguna Hills	California	United States	92653
4	Rocky Mountain Blood and Marrow Transplant Program	Denver	Colorado	United States	80218
5	Oncology & Hematology Assoc. of W. Broward	Tamarac	Florida	United States	33321
6	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida	United States	33612
7	Emory University Winship Cancer Institute	Atlanta	Georgia	United States	404-778-5747
8	Northwestern University	Chicago	Illinois	United States	60605
9	Orchard Research	Skokie	Illinois	United States	60076
10	University of Kentucky College of Medicine	Lexington	Kentucky	United States	40536-0093
11	Montgomery Cancer Center	Mount Sterling	Kentucky	United States	40353
12	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109-0936
13	Mayo Clinic Rochester	Rochester	Minnesota	United States	55905
14	Hattiesburg Clinic	Hattiesburg	Mississippi	United States	39401
15	Jackson Oncology Associates	Jackson	Mississippi	United States	39202
16	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
17	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
18	St. Vincent's Comprehensive Cancer Center	New York	New York	United States	10011
19	Summa Health System	Akron	Ohio	United States	44304
20	Gabrail Cancer Center	Canton	Ohio	United States	44718
21	Cleveland Clinic	Cleveland	Ohio	United States	44195
22	Dayton Clinical Oncology Program	Dayton	Ohio	United States	45429
23	Signal Point Clinical Research Center, LLC	Middletown	Ohio	United States	45042
24	Harrington Cancer Center	Amarillo	Texas	United States	79106
25	Texas Oncology Cancer Center	Austin	Texas	United States	78731
26	MD Anderson Cancer Center	Houston	Texas	United States	77030
27	University of Calgary	Calgary	Alberta	Canada	T2N 4N2
28	University of Alberta Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
29	University of Toronto Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
30	Royal Victoria Hospital	Montreal	Quebec	Canada	H3A 1A1

Sponsors and Collaborators

• Amgen

Investigators

• Study Director: MD, Amgen

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Amgen
• ClinicalTrials.gov Identifier: NCT00530816
• Other Study ID Numbers: PX-171-004
• First Posted: Sep 18, 2007
• Last Update Posted: May 2, 2017
• Last Verified: Apr 1, 2017

• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell

Study Results

Participant Flow

Recruitment Details	This study enrolled patients with multiple myeloma (MM) who had relapsed or refractory disease after at least 1 but no more than 3 prior therapeutic treatments or regimens. The first patient enrolled on 24 September 2007; the last patient was enrolled and received carfilzomib on 28 May 2009.
Pre-assignment Detail	Two groups of patients with MM were initially studied: bortezomib-treated (Part 1) and bortezomib-naïve (Part 2). Following Amendment 2, only bortezomib-naïve patients were enrolled. With Amendment 3, a new cohort of "stepped up" dosing was added to the trial. Study results were analyzed in 2 parts, based on previous bortezomib treatment.

Arm/Group Title	Part 1: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20/27 mg/m²
Arm/Group Description	Participants previously treated with bortezomib received carfilzomib 20 mg/m² intravenous (IV) injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 of Cycle 1. If all doses were well-tolerated the dose was escalated to 27 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 of subsequent cycles, for up to 12 cycles.
Period Title: Overall Study
STARTED	35	59	70
COMPLETED	9	17	29
NOT COMPLETED	26	42	41

Baseline Characteristics

Arm/Group Title	Part 1: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20/27 mg/m²	Total
Arm/Group Description	Participants previously treated with bortezomib received carfilzomib 20 mg/m² intravenous (IV) injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 of Cycle 1. If all doses were well-tolerated the dose was escalated to 27 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 of subsequent cycles, for up to 12 cycles.	Total of all reporting groups
Overall Participants	35	59	70	164
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	21 60%	29 49.2%	31 44.3%	81 49.4%
>=65 years	14 40%	30 50.8%	39 55.7%	83 50.6%
Sex: Female, Male (Count of Participants)
Female	17 48.6%	27 45.8%	26 37.1%	70 42.7%
Male	18 51.4%	32 54.2%	44 62.9%	94 57.3%
Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number]
0 (Fully Active)	15 42.9%	29 49.2%	23 32.9%	67 40.9%
1 (Restrictive but ambulatory)	18 51.4%	27 45.8%	42 60%	87 53%
2 (Ambulatory but unable to work)	1 2.9%	3 5.1%	5 7.1%	9 5.5%
Missing	1 2.9%	0 0%	0 0%	1 0.6%
Measurable Disease Category (participants) [Number]
SPEP and UPEP	3 8.6%	6 10.2%	11 15.7%	20 12.2%
SPEP	22 62.9%	39 66.1%	47 67.1%	108 65.9%
UPEP	6 17.1%	6 10.2%	10 14.3%	22 13.4%
SFLC Only	4 11.4%	6 10.2%	1 1.4%	11 6.7%
IgA, by Immunoglobulin Assay Only	0 0%	2 3.4%	0 0%	2 1.2%
Missing	0 0%	0 0%	1 1.4%	1 0.6%

Outcome Measures

1. Primary Outcome

Title	Best Overall Response Rate (ORR) in the Response Evaluable Subset Population
Description	ORR is defined as the percentage of patients who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) determined by Independent Review Committee (IRC). Responses were assessed according to International Uniform Response Criteria for Multiple Myeloma, documented by 2 consecutive assessments made at any time before the start of new therapy. sCR: CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. CR: absence of M-protein in serum and urine by immunofixation, disappearance of any soft tissue plasmacytomas, and ≤5% plasma cells in bone marrow. VGPR: serum and urine M-proteins detectable by immunofixation but not by electrophoresis or a ≥ 90% reduction in serum M-protein with urine M-protein level < 100 mg/24 hours. PR: ≥ 50% reduction of serum M-protein and in urine of ≥ 90% or to < 200 mg per 24 hours.
Time Frame	Disease response was assessed on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12, and at End of Study, 30 days after last dose. Median duration of treatment was 100 days for Part 1 and 170 days for Part 2 participants.

Outcome Measure Data

Analysis Population Description

The Response Evaluable Subset population consists of all treated patients with measurable disease at Baseline as assessed by M-protein or by quantitative serum Ig for certain patients with IgA myeloma, and with a baseline and at least 1 post-baseline disease assessment. Patients whose disease was only measurable by SFLC were excluded.

Arm/Group Title	Part 1: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20/27 mg/m²
Arm/Group Description	Participants previously treated with bortezomib received carfilzomib 20 mg/m² intravenous (IV) injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 of Cycle 1. If all doses were well-tolerated the dose was escalated to 27 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 for subsequent cycles, for up to 12 cycles.
Measure Participants	31	53	66
Number (95% Confidence Interval) [percentage of participants]	16.1 46%	39.6 67.1%	53.0 75.7%

2. Secondary Outcome

Title	Best Overall Response Rate (ORR) in the Response Evaluable Population
Description	ORR is defined as the percentage of patients who achieved a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR) determined by Independent Review Committee (IRC). Responses were assessed according to International Uniform Response Criteria for Multiple Myeloma, documented by 2 consecutive assessments made at any time before the start of new therapy. sCR: CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. CR: absence of M-protein in serum and urine by immunofixation, disappearance of any soft tissue plasmacytomas, and ≤5% plasma cells in bone marrow. VGPR: serum and urine M-proteins detectable by immunofixation but not by electrophoresis or a ≥ 90% reduction in serum M-protein with urine M-protein level < 100 mg/24 hours. PR: ≥ 50% reduction of serum M-protein and in urine of ≥ 90% or to < 200 mg per 24 hours.
Time Frame	Disease response was assessed on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12, End of Study, 30 days after last dose; median duration of treatment was 100 days for Part 1 and 170 days for Part 2 participants.

Outcome Measure Data

Analysis Population Description

The Response Evaluable population consists of all treated patients with measurable disease at Baseline as assessed by M-protein, SFLC or by quantitative serum Ig for certain patients with IgA myeloma, and with a baseline and at least 1 post-baseline disease assessment.

Arm/Group Title	Part 1: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20/27 mg/m²
Arm/Group Description	Participants previously treated with bortezomib received carfilzomib 20 mg/m² intravenous (IV) injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 of Cycle 1. If all doses were well-tolerated the dose was escalated to 27 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 for subsequent cycles, for up to 12 cycles.
Measure Participants	35	59	67
Number (95% Confidence Interval) [percentage of participants]	17.1 48.9%	42.4 71.9%	52.2 74.6%

3. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	Clinical Benefit Rate is defined as the percentage of participants with a best overall response of minimal response (MR) or better, i.e., a best overall response of sCR, CR, VGPR, PR, or MR. MR was defined as outlined by European Group for Blood and Marrow Transplantation (EBMT) criteria, defined as reduction of M-protein in serum of 25% to 49% and in urine of 50% to 89%, maintained for 6 weeks.
Time Frame	Disease response was assessed on Day 15 of Cycle 1, Day 1 of Cycles 2 through 12, and at End of Study, 30 days after last dose. Median duration of treatment was 100 days for Part 1 and 170 days for Part 2 participants.

Outcome Measure Data

Analysis Population Description

Response Evaluable Population

Arm/Group Title	Part 1: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20/27 mg/m²
Arm/Group Description	Participants previously treated with bortezomib received carfilzomib 20 mg/m² intravenous (IV) injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 of Cycle 1. If all doses were well-tolerated the dose was escalated to 27 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 for subsequent cycles, for up to 12 cycles.
Measure Participants	35	59	67
Median (95% Confidence Interval) [percentage of participants]	31.4 89.7%	59.3 100.5%	64.2 91.7%

4. Secondary Outcome

Title	Duration of Response (DOR)
Description	DOR is defined as the time from first evidence of PR or better to disease progression assessed by the IRC or death due to any cause. Patients lost to follow-up prior to disease progression or who were alive without disease progression before the analysis cutoff date were censored at the last disease assessment. Progressive disease was defined as any of the following: An increase of M-protein in serum (absolute increase ≥ 0.5 g/dL) or urine (absolute increase ≥ 200 mg/24 hours) of > 25% from the nadir (if not zero). Percentage of plasma cells in bone marrow ≥ 10%. New or increased size of bone lesions or new plasmacytomas. Patients without measurable serum and urine M-protein: 25% increase from nadir in the difference between involved and uninvolved FLC levels and absolute increase >10 mg/dL. Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) attributed solely to the proliferative disorder. Median DOR was estimated using Kaplan-Meier methods.
Time Frame	Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 30 November 2010 for Part 1 and 22 April 2011 for Part 2.

Outcome Measure Data

Analysis Population Description

Response Evaluable Population with a response of PR or better.

Arm/Group Title	Part 1: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20/27 mg/m²
Arm/Group Description	Participants previously treated with bortezomib received carfilzomib 20 mg/m² intravenous (IV) injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 of Cycle 1. If all doses were well-tolerated the dose was escalated to 27 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 for subsequent cycles, for up to 12 cycles.
Measure Participants	6	25	35
Median (95% Confidence Interval) [months]	NA	13.1	NA

5. Secondary Outcome

Title	Time to Progression (TTP)
Description	Time to Progression is defined as the time from the start of treatment to IRC-determined disease progression. Patients who were lost to follow-up prior to documentation of disease progression, or who died before documentation of disease progression or who were alive and did not have documentation of disease progression before the data analysis cut-off date were censored at the last disease assessment. Median TTP was estimated using the Kaplan-Meier method.
Time Frame	Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 30 November 2010 for Part 1 and 22 April 2011 for Part 2. Median follow-up time was 13.4 months for Part 1 and 11.5 months in Part 2.

Outcome Measure Data

Analysis Population Description

Response Evaluable Population

Arm/Group Title	Part 1: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20/27 mg/m²
Arm/Group Description	Participants previously treated with bortezomib received carfilzomib 20 mg/m² intravenous (IV) injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 of Cycle 1. If all doses were well-tolerated the dose was escalated to 27 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 for subsequent cycles, for up to 12 cycles.
Measure Participants	35	59	67
Median (95% Confidence Interval) [months]	4.6	8.3	NA

6. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free Survival (PFS) is defined as the time from start of treatment to IRC determined disease progression or death due to any cause. Patients who were lost to follow-up prior to documentation of disease progression and patients who were alive without disease progression before a data analysis cut-off date were censored at the last disease assessment. Median PFS was estimated using the Kaplan-Meier method.
Time Frame	Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 30 November 2010 for Part 1 and 22 April 2011 for Part 2. Median follow-up time was 13.4 months for Part 1 and 11.5 months in Part 2.

Outcome Measure Data

Analysis Population Description

Response Evaluable Population

Arm/Group Title	Part 1: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20/27 mg/m²
Arm/Group Description	Participants previously treated with bortezomib received carfilzomib 20 mg/m² intravenous (IV) injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 of Cycle 1. If all doses were well-tolerated the dose was escalated to 27 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 for subsequent cycles, for up to 12 cycles.
Measure Participants	35	59	67
Median (95% Confidence Interval) [months]	4.6	8.2	NA

7. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall Survival is defined as the time from the start of study treatment to date of death due to any cause. Patients who were alive or lost to follow-up as of the data analysis cut-off date for the final OS analysis were censored at the date the patient was last known to be alive. Median OS was estimated using the Kaplan-Meier method.
Time Frame	Patients were followed for up to 2 years after study discontinuation. The data cutoff for the analysis is 19 November 2012 for Part 1 and 07 January 2013 for Part 2. Median follow-up time was 19.1 months for Part 1 and 35.9 months in Part 2.

Outcome Measure Data

Analysis Population Description

Safety Population includes all patients enrolled on study and who received at least 1 dose of carfilzomib.

Arm/Group Title	Part 1: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20 mg/m²	Part 2: Carfilzomib 20/27 mg/m²
Arm/Group Description	Participants previously treated with bortezomib received carfilzomib 20 mg/m² intravenous (IV) injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.	Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 of Cycle 1. If all doses were well-tolerated the dose was escalated to 27 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 for subsequent cycles, for up to 12 cycles.
Measure Participants	35	59	70
Median (95% Confidence Interval) [months]	45.6	NA	37.3

Adverse Events

Time Frame	From the first dose of study medication until 30 days after the last dose or initiation of new, non-protocol therapy for MM, whichever was first; median duration of treatment was 100 days for Part 1 and 170 days for Part 2 participants.
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	Part 1: Carfilzomib 20 mg/m²		Part 2: Carfilzomib 20 mg/m²		Part 2: Carfilzomib 20/27 mg/m²
Arm/Group Description	Participants previously treated with bortezomib received carfilzomib 20 mg/m² intravenous (IV) injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.		Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV injection on Days 1, 2, 8, 9, 15, and 16, in 28-day treatment cycles for a maximum of 12 cycles.		Participants not previously treated with bortezomib received carfilzomib 20 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 of Cycle 1. If all doses were well-tolerated the dose was escalated to 27 mg/m² IV on Days 1, 2, 8, 9, 15, and 16 for subsequent cycles, for up to 12 cycles.
All Cause Mortality
	Part 1: Carfilzomib 20 mg/m²		Part 2: Carfilzomib 20 mg/m²		Part 2: Carfilzomib 20/27 mg/m²
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Part 1: Carfilzomib 20 mg/m²		Part 2: Carfilzomib 20 mg/m²		Part 2: Carfilzomib 20/27 mg/m²
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/35 (34.3%)		18/59 (30.5%)		27/70 (38.6%)
Blood and lymphatic system disorders
Anaemia	0/35 (0%)		0/59 (0%)		2/70 (2.9%)
Febrile neutropenia	0/35 (0%)		1/59 (1.7%)		1/70 (1.4%)
Neutropenia	0/35 (0%)		0/59 (0%)		2/70 (2.9%)
Thrombocytopenia	1/35 (2.9%)		0/59 (0%)		0/70 (0%)
Cardiac disorders
Atrial fibrillation	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Cardiac arrest	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Cardiac disorder	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Cardiac failure	1/35 (2.9%)		0/59 (0%)		0/70 (0%)
Cardiac failure congestive	1/35 (2.9%)		2/59 (3.4%)		2/70 (2.9%)
Mitral valve incompetence	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Endocrine disorders
Hyperthyroidism	1/35 (2.9%)		0/59 (0%)		0/70 (0%)
Gastrointestinal disorders
Abdominal pain	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Colitis	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Diarrhoea	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Pancreatitis acute	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Upper gastrointestinal haemorrhage	1/35 (2.9%)		0/59 (0%)		0/70 (0%)
Vomiting	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
General disorders
Disease progression	1/35 (2.9%)		1/59 (1.7%)		1/70 (1.4%)
Face oedema	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Generalised oedema	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Multi-organ failure	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Non-cardiac chest pain	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Pain	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Pyrexia	2/35 (5.7%)		1/59 (1.7%)		3/70 (4.3%)
Infections and infestations
Clostridium colitis	1/35 (2.9%)		1/59 (1.7%)		0/70 (0%)
Enterococcal infection	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Epiglottitis	1/35 (2.9%)		0/59 (0%)		0/70 (0%)
Pneumonia	3/35 (8.6%)		6/59 (10.2%)		6/70 (8.6%)
Pneumonia bacterial	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Pneumonia haemophilus	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Pseudomonas infection	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Respiratory syncytial virus infection	1/35 (2.9%)		0/59 (0%)		0/70 (0%)
Respiratory tract infection	1/35 (2.9%)		0/59 (0%)		0/70 (0%)
Sepsis	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Sinusitis	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Sinusitis bacterial	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Staphylococcal bacteraemia	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Tooth abscess	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Upper respiratory tract infection	1/35 (2.9%)		1/59 (1.7%)		0/70 (0%)
Urinary tract infection	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Viral upper respiratory tract infection	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Injury, poisoning and procedural complications
Sternal fracture	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Investigations
Blood creatinine increased	1/35 (2.9%)		0/59 (0%)		0/70 (0%)
Metabolism and nutrition disorders
Hypercalcaemia	2/35 (5.7%)		0/59 (0%)		0/70 (0%)
Hyperglycaemia	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Hypokalaemia	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Musculoskeletal and connective tissue disorders
Bone lesion	1/35 (2.9%)		0/59 (0%)		1/70 (1.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumour lysis syndrome	0/35 (0%)		2/59 (3.4%)		0/70 (0%)
Nervous system disorders
Cerebral haemorrhage	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Spinal cord compression	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Syncope	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Transient ischaemic attack	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Psychiatric disorders
Agitation	0/35 (0%)		1/59 (1.7%)		0/70 (0%)
Mental status changes	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Renal and urinary disorders
Renal failure	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Renal failure acute	1/35 (2.9%)		2/59 (3.4%)		3/70 (4.3%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Dyspnoea	1/35 (2.9%)		1/59 (1.7%)		2/70 (2.9%)
Haemoptysis	1/35 (2.9%)		0/59 (0%)		0/70 (0%)
Pulmonary embolism	0/35 (0%)		2/59 (3.4%)		1/70 (1.4%)
Pulmonary oedema	0/35 (0%)		1/59 (1.7%)		1/70 (1.4%)
Vascular disorders
Haematoma	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Hypertension	0/35 (0%)		0/59 (0%)		1/70 (1.4%)
Hypotension	1/35 (2.9%)		0/59 (0%)		0/70 (0%)
Other (Not Including Serious) Adverse Events
	Part 1: Carfilzomib 20 mg/m²		Part 2: Carfilzomib 20 mg/m²		Part 2: Carfilzomib 20/27 mg/m²
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/35 (100%)		59/59 (100%)		70/70 (100%)
Blood and lymphatic system disorders
Anaemia	12/35 (34.3%)		27/59 (45.8%)		25/70 (35.7%)
Leukopenia	6/35 (17.1%)		12/59 (20.3%)		4/70 (5.7%)
Lymphopenia	6/35 (17.1%)		20/59 (33.9%)		13/70 (18.6%)
Neutropenia	9/35 (25.7%)		18/59 (30.5%)		20/70 (28.6%)
Thrombocytopenia	11/35 (31.4%)		20/59 (33.9%)		19/70 (27.1%)
Cardiac disorders
Bradycardia	1/35 (2.9%)		3/59 (5.1%)		0/70 (0%)
Tachycardia	2/35 (5.7%)		1/59 (1.7%)		3/70 (4.3%)
Ear and labyrinth disorders
Tinnitus	2/35 (5.7%)		0/59 (0%)		1/70 (1.4%)
Eye disorders
Diplopia	2/35 (5.7%)		1/59 (1.7%)		1/70 (1.4%)
Eye irritation	3/35 (8.6%)		1/59 (1.7%)		3/70 (4.3%)
Lacrimation increased	1/35 (2.9%)		4/59 (6.8%)		1/70 (1.4%)
Vision blurred	3/35 (8.6%)		6/59 (10.2%)		4/70 (5.7%)
Gastrointestinal disorders
Abdominal discomfort	0/35 (0%)		0/59 (0%)		5/70 (7.1%)
Abdominal distension	3/35 (8.6%)		4/59 (6.8%)		3/70 (4.3%)
Abdominal pain	5/35 (14.3%)		6/59 (10.2%)		6/70 (8.6%)
Bowel sounds abnormal	2/35 (5.7%)		1/59 (1.7%)		0/70 (0%)
Constipation	8/35 (22.9%)		15/59 (25.4%)		10/70 (14.3%)
Diarrhoea	13/35 (37.1%)		21/59 (35.6%)		18/70 (25.7%)
Dyspepsia	3/35 (8.6%)		4/59 (6.8%)		5/70 (7.1%)
Gastrooesophageal reflux disease	0/35 (0%)		3/59 (5.1%)		1/70 (1.4%)
Mouth ulceration	1/35 (2.9%)		4/59 (6.8%)		2/70 (2.9%)
Nausea	21/35 (60%)		32/59 (54.2%)		31/70 (44.3%)
Vomiting	15/35 (42.9%)		14/59 (23.7%)		14/70 (20%)
General disorders
Asthenia	8/35 (22.9%)		6/59 (10.2%)		8/70 (11.4%)
Chills	6/35 (17.1%)		15/59 (25.4%)		14/70 (20%)
Fatigue	22/35 (62.9%)		42/59 (71.2%)		38/70 (54.3%)
Gait disturbance	4/35 (11.4%)		2/59 (3.4%)		1/70 (1.4%)
Infusion site pain	2/35 (5.7%)		8/59 (13.6%)		8/70 (11.4%)
Injection site irritation	2/35 (5.7%)		4/59 (6.8%)		3/70 (4.3%)
Non-cardiac chest pain	1/35 (2.9%)		1/59 (1.7%)		4/70 (5.7%)
Oedema	0/35 (0%)		3/59 (5.1%)		1/70 (1.4%)
Oedema peripheral	5/35 (14.3%)		17/59 (28.8%)		18/70 (25.7%)
Pain	7/35 (20%)		11/59 (18.6%)		9/70 (12.9%)
Pitting oedema	2/35 (5.7%)		1/59 (1.7%)		2/70 (2.9%)
Pyrexia	8/35 (22.9%)		21/59 (35.6%)		22/70 (31.4%)
Infections and infestations
Bronchitis	2/35 (5.7%)		0/59 (0%)		0/70 (0%)
Cellulitis	2/35 (5.7%)		2/59 (3.4%)		1/70 (1.4%)
Herpes zoster	3/35 (8.6%)		1/59 (1.7%)		2/70 (2.9%)
Influenza	2/35 (5.7%)		4/59 (6.8%)		2/70 (2.9%)
Nasopharyngitis	2/35 (5.7%)		9/59 (15.3%)		11/70 (15.7%)
Oral candidiasis	2/35 (5.7%)		1/59 (1.7%)		2/70 (2.9%)
Respiratory tract infection	2/35 (5.7%)		0/59 (0%)		2/70 (2.9%)
Sinusitis	3/35 (8.6%)		2/59 (3.4%)		4/70 (5.7%)
Upper respiratory tract infection	11/35 (31.4%)		20/59 (33.9%)		20/70 (28.6%)
Urinary tract infection	3/35 (8.6%)		9/59 (15.3%)		3/70 (4.3%)
Investigations
Alanine aminotransferase increased	10/35 (28.6%)		7/59 (11.9%)		2/70 (2.9%)
Aspartate aminotransferase increased	7/35 (20%)		10/59 (16.9%)		11/70 (15.7%)
Blood albumin decreased	3/35 (8.6%)		1/59 (1.7%)		0/70 (0%)
Blood alkaline phosphatase increased	2/35 (5.7%)		3/59 (5.1%)		1/70 (1.4%)
Blood bicarbonate decreased	3/35 (8.6%)		1/59 (1.7%)		3/70 (4.3%)
Blood calcium decreased	2/35 (5.7%)		0/59 (0%)		0/70 (0%)
Blood calcium increased	3/35 (8.6%)		2/59 (3.4%)		2/70 (2.9%)
Blood creatinine increased	12/35 (34.3%)		14/59 (23.7%)		10/70 (14.3%)
Blood glucose increased	4/35 (11.4%)		1/59 (1.7%)		1/70 (1.4%)
Blood magnesium decreased	3/35 (8.6%)		2/59 (3.4%)		1/70 (1.4%)
Blood magnesium increased	3/35 (8.6%)		2/59 (3.4%)		0/70 (0%)
Blood phosphorus decreased	6/35 (17.1%)		7/59 (11.9%)		5/70 (7.1%)
Blood potassium decreased	2/35 (5.7%)		3/59 (5.1%)		0/70 (0%)
Blood potassium increased	2/35 (5.7%)		3/59 (5.1%)		1/70 (1.4%)
Blood sodium decreased	3/35 (8.6%)		5/59 (8.5%)		0/70 (0%)
Blood uric acid increased	4/35 (11.4%)		7/59 (11.9%)		3/70 (4.3%)
Breath sounds abnormal	4/35 (11.4%)		4/59 (6.8%)		0/70 (0%)
Carbon dioxide decreased	0/35 (0%)		3/59 (5.1%)		0/70 (0%)
Vibration test abnormal	0/35 (0%)		3/59 (5.1%)		0/70 (0%)
Weight decreased	3/35 (8.6%)		2/59 (3.4%)		1/70 (1.4%)
Weight increased	2/35 (5.7%)		1/59 (1.7%)		4/70 (5.7%)
Metabolism and nutrition disorders
Anorexia	3/35 (8.6%)		8/59 (13.6%)		5/70 (7.1%)
Decreased appetite	3/35 (8.6%)		3/59 (5.1%)		5/70 (7.1%)
Dehydration	1/35 (2.9%)		4/59 (6.8%)		3/70 (4.3%)
Fluid overload	3/35 (8.6%)		1/59 (1.7%)		1/70 (1.4%)
Fluid retention	2/35 (5.7%)		1/59 (1.7%)		2/70 (2.9%)
Hypercalcaemia	3/35 (8.6%)		6/59 (10.2%)		2/70 (2.9%)
Hyperglycaemia	6/35 (17.1%)		7/59 (11.9%)		7/70 (10%)
Hyperkalaemia	4/35 (11.4%)		5/59 (8.5%)		8/70 (11.4%)
Hypermagnesaemia	0/35 (0%)		3/59 (5.1%)		1/70 (1.4%)
Hyperphosphataemia	2/35 (5.7%)		1/59 (1.7%)		4/70 (5.7%)
Hyperuricaemia	1/35 (2.9%)		6/59 (10.2%)		8/70 (11.4%)
Hypoalbuminaemia	2/35 (5.7%)		2/59 (3.4%)		0/70 (0%)
Hypocalcaemia	3/35 (8.6%)		3/59 (5.1%)		3/70 (4.3%)
Hypoglycaemia	0/35 (0%)		3/59 (5.1%)		4/70 (5.7%)
Hypokalaemia	3/35 (8.6%)		6/59 (10.2%)		10/70 (14.3%)
Hypomagnesaemia	6/35 (17.1%)		7/59 (11.9%)		6/70 (8.6%)
Hyponatraemia	3/35 (8.6%)		3/59 (5.1%)		7/70 (10%)
Hypophosphataemia	4/35 (11.4%)		2/59 (3.4%)		8/70 (11.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/35 (8.6%)		15/59 (25.4%)		7/70 (10%)
Back pain	5/35 (14.3%)		8/59 (13.6%)		14/70 (20%)
Bone pain	1/35 (2.9%)		5/59 (8.5%)		5/70 (7.1%)
Chest wall pain	4/35 (11.4%)		5/59 (8.5%)		5/70 (7.1%)
Groin pain	0/35 (0%)		0/59 (0%)		4/70 (5.7%)
Muscle spasms	5/35 (14.3%)		6/59 (10.2%)		18/70 (25.7%)
Musculoskeletal discomfort	1/35 (2.9%)		5/59 (8.5%)		1/70 (1.4%)
Musculoskeletal stiffness	1/35 (2.9%)		3/59 (5.1%)		0/70 (0%)
Myalgia	4/35 (11.4%)		8/59 (13.6%)		4/70 (5.7%)
Pain in extremity	3/35 (8.6%)		9/59 (15.3%)		13/70 (18.6%)
Pain in jaw	1/35 (2.9%)		3/59 (5.1%)		1/70 (1.4%)
Pathological fracture	2/35 (5.7%)		1/59 (1.7%)		1/70 (1.4%)
Shoulder pain	5/35 (14.3%)		4/59 (6.8%)		1/70 (1.4%)
Nervous system disorders
Areflexia	0/35 (0%)		3/59 (5.1%)		0/70 (0%)
Dizziness	7/35 (20%)		12/59 (20.3%)		10/70 (14.3%)
Headache	9/35 (25.7%)		19/59 (32.2%)		23/70 (32.9%)
Hypoaesthesia	9/35 (25.7%)		10/59 (16.9%)		8/70 (11.4%)
Hyporeflexia	2/35 (5.7%)		4/59 (6.8%)		1/70 (1.4%)
Memory impairment	2/35 (5.7%)		3/59 (5.1%)		3/70 (4.3%)
Neuropathy	2/35 (5.7%)		3/59 (5.1%)		2/70 (2.9%)
Neuropathy peripheral	2/35 (5.7%)		4/59 (6.8%)		5/70 (7.1%)
Paraesthesia	4/35 (11.4%)		7/59 (11.9%)		1/70 (1.4%)
Peripheral sensory neuropathy	1/35 (2.9%)		2/59 (3.4%)		6/70 (8.6%)
Sinus headache	2/35 (5.7%)		2/59 (3.4%)		0/70 (0%)
Psychiatric disorders
Anxiety	2/35 (5.7%)		5/59 (8.5%)		3/70 (4.3%)
Confusional state	2/35 (5.7%)		2/59 (3.4%)		2/70 (2.9%)
Depression	3/35 (8.6%)		2/59 (3.4%)		2/70 (2.9%)
Insomnia	7/35 (20%)		11/59 (18.6%)		18/70 (25.7%)
Mental status changes	2/35 (5.7%)		2/59 (3.4%)		0/70 (0%)
Renal and urinary disorders
Dysuria	4/35 (11.4%)		2/59 (3.4%)		4/70 (5.7%)
Pollakiuria	0/35 (0%)		4/59 (6.8%)		2/70 (2.9%)
Respiratory, thoracic and mediastinal disorders
Cough	8/35 (22.9%)		23/59 (39%)		21/70 (30%)
Crackles lung	3/35 (8.6%)		3/59 (5.1%)		1/70 (1.4%)
Dysphonia	2/35 (5.7%)		1/59 (1.7%)		1/70 (1.4%)
Dyspnoea	13/35 (37.1%)		29/59 (49.2%)		19/70 (27.1%)
Dyspnoea exertional	5/35 (14.3%)		1/59 (1.7%)		9/70 (12.9%)
Epistaxis	2/35 (5.7%)		3/59 (5.1%)		7/70 (10%)
Nasal congestion	1/35 (2.9%)		4/59 (6.8%)		4/70 (5.7%)
Pharyngolaryngeal pain	4/35 (11.4%)		7/59 (11.9%)		7/70 (10%)
Pleural effusion	3/35 (8.6%)		2/59 (3.4%)		1/70 (1.4%)
Productive cough	2/35 (5.7%)		3/59 (5.1%)		3/70 (4.3%)
Pulmonary congestion	3/35 (8.6%)		2/59 (3.4%)		4/70 (5.7%)
Rhinorrhoea	5/35 (14.3%)		6/59 (10.2%)		3/70 (4.3%)
Sinus congestion	2/35 (5.7%)		3/59 (5.1%)		6/70 (8.6%)
Wheezing	3/35 (8.6%)		5/59 (8.5%)		3/70 (4.3%)
Skin and subcutaneous tissue disorders
Ecchymosis	0/35 (0%)		3/59 (5.1%)		1/70 (1.4%)
Erythema	4/35 (11.4%)		5/59 (8.5%)		3/70 (4.3%)
Hyperhidrosis	2/35 (5.7%)		6/59 (10.2%)		4/70 (5.7%)
Night sweats	1/35 (2.9%)		3/59 (5.1%)		1/70 (1.4%)
Periorbital oedema	0/35 (0%)		3/59 (5.1%)		1/70 (1.4%)
Pruritus	3/35 (8.6%)		7/59 (11.9%)		5/70 (7.1%)
Rash	3/35 (8.6%)		7/59 (11.9%)		5/70 (7.1%)
Surgical and medical procedures
Nasal sinus drainage	2/35 (5.7%)		4/59 (6.8%)		1/70 (1.4%)
Vascular disorders
Deep vein thrombosis	0/35 (0%)		3/59 (5.1%)		1/70 (1.4%)
Flushing	3/35 (8.6%)		1/59 (1.7%)		4/70 (5.7%)
Hot flush	1/35 (2.9%)		4/59 (6.8%)		1/70 (1.4%)
Hypertension	6/35 (17.1%)		8/59 (13.6%)		13/70 (18.6%)
Hypotension	2/35 (5.7%)		1/59 (1.7%)		1/70 (1.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

After the study is completed and all case report forms have been sent to Sponsor, Institution shall have the right to publish or otherwise make public any data resulting from the study under this agreement after publication of a multi-center publication coordinated by Sponsor with respect to the data resulting from the study, or 12 months after the Study is completed at all participating sites if a multi-center publication is not submitted by Sponsor for publication within such 12 month period.