Phase 1b Multicenter Study of Carfilzomib With Lenalidomide and Dexamethasone in Relapsed Multiple Myeloma

• Sponsor: Amgen (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00603447
• Collaborator: (none)
• Enrollment: 84
• Locations: 12
• Arm: 1
• Duration (Months): 92
• Patients Per Site: 7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

To evaluate the safety and maximum tolerated dose (MTD) of carfilzomib in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma

Condition or Disease	Intervention/Treatment	Phase
Relapsed Multiple Myeloma	Drug: Carfilzomib; Drug: Lenalidomide; Drug: Dexamethasone	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 84 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1b Multicenter Dose Escalation Study of Carfilzomib With Lenalidomide and Dexamethasone for Safety and Activity in Relapsed Multiple Myeloma
• Study Start Date: May 1, 2008
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Carfilzomib + Lenalidomide + Dexamethasone Treatment during Cycles 1 through 12 consisted of carfilzomib (15, 20, or 20/27 mg/m²) on Days 1, 2, 8, 9, 15, and 16; lenalidomide (10, 15, 20, or 25 mg) on Days 1 to 21; and low-dose dexamethasone (40 mg) given 30 minutes to 4 hours before the carfilzomib dose on Days 1, 8, and 15, as well as on Day 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.

Drug: Carfilzomib; Carfilzomib for Injection was administered intravenously over 10 minutes on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for the first 12 cycles. Each dose of Carfilzomib for Injection was normalized to body surface area.; Other Names: Kyprolis® ; Drug: Lenalidomide; Lenalidomide was administered orally on Days 1 to 21 of each 28-day cycle.; Other Names: REVLIMID® ; Drug: Dexamethasone; Dexamethasone 40 mg orally or intravenous equivalent was administered 30 minutes to 4 hours before carfilzomib on Days 1, 8, and 15, as well as on Day 22 of each 28-day cycle.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events (AEs) [From the first dose of study drug until 30 days after the last dose; 1 to 52 months, with an average of 12 months.]

   Treatment-related are those AEs with possible or probable relationship to carfilzomib, lenalidomide or dexamethasone as assessed by the Investigator. The severity of each adverse event was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0, per the following: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death. Serious adverse events were defined as AEs meeting one of the following: death, life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect in the offspring of an exposed participant, important medical events that may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed above, or pregnancy or suspected pregnancy.

2. Number of Participants With Dose-limiting Toxicities [Cycle 1, 28 days]

   Dose-limiting toxicity was defined as any of the following events assessed as related to carfilzomib, lenalidomide, or dexamethasone: Nonhematologic ≥ Grade 2 neuropathy with pain ≥ Grade 3 nonhematologic toxicity (excluding nausea, vomiting, diarrhea, hyperglycemia due to dexamethasone, and rash due to lenalidomide) ≥ Grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal supportive therapy ≥ Grade 4 fatigue persisting > 7 days Treatment delay for toxicity > 21 days Hematologic Grade 4 neutropenia (absolute neutrophil count [ANC] < 500/mm³) > 7 days Febrile neutropenia (ANC < 1,000/mm³ with fever ≥ 38.3ºC) Grade 4 thrombocytopenia (platelets < 25,000/mm³) for > 7 days despite holding treatment, or Grade 3 or 4 thrombocytopenia associated with bleeding Treatment delay for toxicity > 21 days. The maximum-tolerated dose was defined as the dose level below which a drug-related DLT was observed in ≥ 33% of participants in a cohort.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Disease related:

1. Symptomatic multiple myeloma

2. Relapsed or progressive disease after at least one but no more than three prior therapeutic treatments or regimens for multiple myeloma

3. Prior therapeutic treatment regimens may have included bortezomib, lenalidomide, and/or thalidomide, among other agents.

4. If previously treated with lenalidomide or bortezomib, the subject must not have progressed during the first 3 months of treatment with the drug and must not have discontinued treatment due to lenalidomide intolerance (bortezomib intolerant subjects may enroll).

5. Measurable disease, as indicated by one or more of the following:

• Serum M-protein ≥ 0.5 g/dL

• Urine Bence-Jones protein ≥ 200 mg/24 h

• If Serum Protein Electrophoresis is felt to be unreliable for routine M-protein measurement (particularly for patients with Immunoglobulin (Ig)A multiple myeloma), then quantitative immunoglobulin levels can be accepted.

1. Prior to enrollment, sites must provide evidence of myeloma progression/relapse, with start and stop dates of the most recent treatment regimen, as well as best tumor response to all prior treatment regimens.

Demographic

1. Males and females ≥ 18 years of age

2. Life expectancy of more than three months

3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

Laboratory

1. Adequate hepatic function, with bilirubin < 2 times the upper limit of normal (ULN) and alanine aminotransferase (ALT) < 3 times ULN

2. Absolute neutrophil count (ANC) ≥ 1,000/mm³, hemoglobin ≥ 8 gm/dL, platelet count ≥ 50,000/ mm³ (≥ 30 × 10^9/L if myeloma involvement in the bone marrow is > 50%)

• Screening ANC should be independent of granulocyte- and granulocyte/macrophage colony stimulating factor (G-CSF and GM-CSF) support for at least 1 week and of pegylated G-CSF for at least 2 weeks.

• Subjects may receive red blood cell (RBC) or platelet transfusions, if clinically indicated, in accordance with institutional guidelines

• Screening platelet count should be independent of platelet transfusions for at least 2 weeks

1. Calculated or measured creatinine clearance of ≥ 50 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). Other generally accepted calculation methods can be substituted.

Ethical/Other

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

2. Females of childbearing potential (FCBP) must agree to ongoing pregnancy testing

3. FCBP* must have a negative serum or urine pregnancy test, with a sensitivity of at least 50 mIU/mL within 10-14 days (US/RevAssist®) or 25 mIU/mL within 7-14 days (Canada/RevAidSM), prior to and again within 24 hours of starting lenalidomide and must either commit to continued abstinence from heterosexual intercourse or to use two methods of reliable birth control, including at least one highly effective method AND one additional effective method of birth control (contraception) AT THE SAME TIME, beginning 4 weeks prior to initiating treatment with lenalidomide, during therapy, during therapy delay, and continuing for 4 weeks following discontinuation of lenalidomide therapy. If a hormonal method (birth control pills, injections, patch or implants) or intrauterine device (IUD) is not medically possible for the subject, the subject may use another highly effective method or two barrier methods AT THE SAME TIME.

4. Male subjects must agree to NEVER have unprotected sexual contact with a female who can become pregnant and must agree to either completely abstain from sexual contact with females who are pregnant or are able to become pregnant, or he must use a latex condom EVERY TIME he engages in any sexual contact with females who are pregnant or may become pregnant while he is taking lenalidomide and for 4 weeks after he stops taking the drug, even if he has had a successful vasectomy. The subject must agree to inform his physician if he has had unprotected sexual contact with a female who can become pregnant or if he thinks FOR ANY REASON, that his sexual partner may be pregnant.

5. Male subjects cannot donate semen or sperm while taking lenalidomide.

6. All study participants must be registered into the mandatory RevAssist (US) or RevAid (Canada) programs and be willing and able to comply with the requirements of Rev Assist/RevAid

7. Subjects must adhere to the study visit schedule and other protocol requirements and receive outpatient treatment and laboratory monitoring at the institute that administers the drug

8. Subjects must agree to take enteric-coated aspirin 81-325 mg orally daily, or if history of prior thrombotic disease or allergy to aspirin, must be fully anticoagulated with warfarin (INR 2-3) or be treated with full-dose, low molecular weight heparin, as if to treat deep venous thrombosis (DVT)/pulmonary embolism.

Exclusion Criteria:

Disease related

1. Subjects with non-secretory or hyposecretory multiple myeloma, defined as < 0.5 g/dL M-protein in serum, < 200 mg/24 hr Bence Jones protein in urine, or disease only measured by serum free light chain (FLC)

2. Subjects who never achieved at least a durable minimal response (MR, ≥ 25% reduction in M-protein for at least 6 weeks) on any prior therapy

3. Corticosteroid therapy in a dose equivalent to dexamethasone ≥ 4 mg/day or prednisone ≥ 20 mg/day within 3 weeks prior to first dose

4. Use of any other experimental drug or therapy within 28 days of baseline

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

6. Plasma cell leukemia

7. Waldenström's macroglobulinemia

8. Chemotherapy with approved or investigative anticancer therapeutics, including steroid therapy dose as defined above, within 3 weeks prior to first dose

9. Radiation therapy or immunotherapy within 4 weeks prior to first dose; localized radiation therapy within 1 week prior to first dose

10. Planned radiation therapy that occurs after the start of treatment

11. Participation in an investigational therapeutic study within 3 weeks or within 5 drug half-lives (t1/2) prior to first dose, whichever time is greater.

Concurrent conditions

1. Pregnant or lactating females

2. History of allergy to boron or mannitol

3. Major surgery within 3 weeks prior to first dose

4. 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

5. Uncontrolled hypertension

6. Acute active infection requiring systemic antibiotics, antivirals, or antifungals within two weeks prior to first dose

7. Known or suspected human immunodeficiency virus (HIV) infection, known HIV seropositivity, or active hepatitis A, B, or C infection

8. Non-hematologic malignancy within the past three years except

9. adequately treated basal cell or squamous cell skin cancer,

10. carcinoma in situ of the cervix, or

11. prostate cancer < Gleason Grade 6 with stable prostate specific antigen (PSA) levels

12. Serious psychiatric or medical conditions that could interfere with treatment

13. Significant neuropathy (Grade 3, Grade 4, or Grade 2 with pain) at the time of the first dose and/or within 14 days before enrollment

14. Contraindication to any of the required concomitant drugs, including proton-pump inhibitor (e.g., lansoprazole), enteric-coated aspirin or other anticoagulant, or if a history of prior thrombotic disease, warfarin or low molecular weight heparin

15. 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

16. Subjects with known or suspected amyloidosis

17. Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis

18. Prior carfilzomib treatment

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pacific Shores Medical Group	Long Beach	California	United States	90813
2	Cedars Sinai Medical Center	Los Angeles	California	United States	90048
3	University of California San Francisco	San Francisco	California	United States	94143
4	H. Lee Moffitt Cancer Center & Research Institute	Tampa	Florida	United States	33612
5	Northwestern University	Chicago	Illinois	United States	60611
6	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
7	Cornell University	New York	New York	United States	10021
8	Gabrail Cancer Center	Canton	Ohio	United States	44718
9	MD Anderson Cancer Center	Houston	Texas	United States	77030
10	Fred Hutch Cancer Research Center	Seattle	Washington	United States	98103-1204
11	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
12	Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2

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: NCT00603447
• Other Study ID Numbers: PX-171-006
• First Posted: Jan 29, 2008
• Last Update Posted: May 30, 2017
• Last Verified: Apr 1, 2017

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

Study Results

Participant Flow

Recruitment Details	This was an open-label study of carfilzomib (CFZ) given in combination with lenalidomide (LEN) and low-dose dexamethasone (DEX) in patients with relapsed multiple myeloma. The study consisted of a dose-escalation portion and an expansion portion. Participants were treated until disease progression (PD) or unacceptable toxicity.
Pre-assignment Detail	In the dose-escalation portion, participants were enrolled in sequential cohorts to determine the maximum tolerated doses (MTD) of carfilzomib and lenalidomide. In the expansion portion either the MTD or the maximum planned dose (MPD) from Cohort 6 (if no MTD was determined) was administered to gain additional safety and efficacy information.

Arm/Group Title	1: CFZ 15 mg/m² + LEN 10 mg	2: CFZ 15 mg/m² + LEN 15 mg	3: CFZ 15 mg/m² + LEN 20 mg	4: CFZ 20 mg/m² + LEN 20 mg	5: CFZ 20 mg/m² + LEN 25 mg	6: CFZ 20/27 mg/m² + LEN 25 mg	7: CFZ 20/27 mg/m² + LEN 25 mg
Arm/Group Description	Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 10 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 15 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 20 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 20 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 20 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 20 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment consisted of carfilzomib 20 mg/m² on Days 1 and 2 of Cycle 1, followed by 27 mg/m² for the remainder of treatment (Days 8, 9, 15, and 16 of Cycle 1 and Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles); lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	In the Expansion portion, treatment consisted of carfilzomib 20 mg/m² on Days 1 and 2 of Cycle 1, followed by 27 mg/m² for the remainder of treatment (Days 8, 9, 15, and 16 of Cycle 1 and Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles); lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.
Period Title: Overall Study
STARTED	6	6	8	6	6	8	44
COMPLETED	6	3	6	4	1	6	20
NOT COMPLETED	0	3	2	2	5	2	24

Baseline Characteristics

Arm/Group Title	1: CFZ 15 mg/m² + LEN 10 mg	2: CFZ 15 mg/m² + LEN 15 mg	3: CFZ 15 mg/m² + LEN 20 mg	4: CFZ 20 mg/m² + LEN 20 mg	5: CFZ 20 mg/m² + LEN 25 mg	6: CFZ 20/27 mg/m² + LEN 25 mg	7: CFZ 20/27 mg/m² + LEN 25 mg	Total
Arm/Group Description	Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 10 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 15 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 20 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 20 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 20 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 20 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment consisted of carfilzomib 20 mg/m² on Days 1 and 2 of Cycle 1, followed by 27 mg/m² for the remainder of treatment (Days 8, 9, 15, and 16 of Cycle 1 and Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles); lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	In the Expansion portion, treatment consisted of carfilzomib 20 mg/m² on Days 1 and 2 of Cycle 1, followed by 27 mg/m² for the remainder of treatment (Days 8, 9, 15, and 16 of Cycle 1 and Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles); lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Total of all reporting groups
Overall Participants	6	6	8	6	6	8	44	84
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.7 (6.65)	64.2 (12.11)	55.4 (7.74)	61.7 (6.68)	57.7 (9.31)	65.4 (7.85)	62.4 (10.75)	61.9 (9.86)
Sex: Female, Male (Count of Participants)
Female	1 16.7%	4 66.7%	3 37.5%	4 66.7%	3 50%	3 37.5%	18 40.9%	36 42.9%
Male	5 83.3%	2 33.3%	5 62.5%	2 33.3%	3 50%	5 62.5%	26 59.1%	48 57.1%
Race/Ethnicity, Customized (participants) [Number]
African American	0 0%	2 33.3%	1 12.5%	2 33.3%	1 16.7%	0 0%	3 6.8%	9 10.7%
Asian/Pacific Islander	0 0%	1 16.7%	0 0%	0 0%	0 0%	0 0%	2 4.5%	3 3.6%
Caucasian	6 100%	3 50%	7 87.5%	2 33.3%	5 83.3%	7 87.5%	34 77.3%	64 76.2%
Hispanic	0 0%	0 0%	0 0%	2 33.3%	0 0%	1 12.5%	4 9.1%	7 8.3%
Other	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	1 2.3%	1 1.2%
Eastern Cooperative Oncology Group (ECOG) Performance Status (participants) [Number]
0 (Fully active)	2 33.3%	0 0%	3 37.5%	1 16.7%	2 33.3%	2 25%	23 52.3%	33 39.3%
1 (Restrictive but ambulatory)	4 66.7%	5 83.3%	5 62.5%	5 83.3%	4 66.7%	6 75%	17 38.6%	46 54.8%
2 (Ambulatory but unable to work)	0 0%	1 16.7%	0 0%	0 0%	0 0%	0 0%	4 9.1%	5 6%
Time Since Diagnosis (years) [Median (Full Range) ]
Median (Full Range) [years]	3.3	2.4	3.9	2.8	3.5	4.3	2.8	3.1

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	Treatment-related are those AEs with possible or probable relationship to carfilzomib, lenalidomide or dexamethasone as assessed by the Investigator. The severity of each adverse event was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0, per the following: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life-threatening and Grade 5 = Death. Serious adverse events were defined as AEs meeting one of the following: death, life-threatening, required or prolonged in-patient hospitalization, resulted in persistent or significant disability/incapacity, a congenital anomaly/birth defect in the offspring of an exposed participant, important medical events that may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed above, or pregnancy or suspected pregnancy.
Time Frame	From the first dose of study drug until 30 days after the last dose; 1 to 52 months, with an average of 12 months.

Outcome Measure Data

Analysis Population Description

Safety population consisting of all treated participants

Arm/Group Title	1: CFZ 15 mg/m² + LEN 10 mg	2: CFZ 15 mg/m² + LEN 15 mg	3: CFZ 15 mg/m² + LEN 20 mg	4: CFZ 20 mg/m² + LEN 20 mg	5: CFZ 20 mg/m² + LEN 25 mg	6: CFZ 20/27 mg/m² + LEN 25 mg	7: CFZ 20/27 mg/m² + LEN 25 mg
Arm/Group Description	Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 10 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 15 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 20 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 20 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 20 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 20 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment consisted of carfilzomib 20 mg/m² on Days 1 and 2 of Cycle 1, followed by 27 mg/m² for the remainder of treatment (Days 8, 9, 15, and 16 of Cycle 1 and Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles); lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	In the Expansion portion, treatment consisted of carfilzomib 20 mg/m² on Days 1 and 2 of Cycle 1, followed by 27 mg/m² for the remainder of treatment (Days 8, 9, 15, and 16 of Cycle 1 and Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles); lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.
Measure Participants	6	6	8	6	6	8	44
Any adverse event	6 100%	6 100%	8 100%	6 100%	6 100%	8 100%	44 100%
Treatment-related adverse event	4 66.7%	5 83.3%	8 100%	4 66.7%	6 100%	8 100%	43 97.7%
Grade 3 or higher adverse event	5 83.3%	6 100%	8 100%	6 100%	6 100%	8 100%	41 93.2%
Treatment-related Grade 3 or higher adverse event	1 16.7%	4 66.7%	7 87.5%	4 66.7%	6 100%	8 100%	38 86.4%
Serious adverse event	3 50%	3 50%	4 50%	4 66.7%	3 50%	6 75%	22 50%
AE leading to discontinuation of any study drug	1 16.7%	1 16.7%	3 37.5%	4 66.7%	2 33.3%	3 37.5%	18 40.9%
AE leading to discontinuation of carfilzomib	0 0%	0 0%	1 12.5%	2 33.3%	1 16.7%	1 12.5%	9 20.5%
Deaths within 30 days of last dose of study drug	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	3 6.8%

2. Primary Outcome

Title	Number of Participants With Dose-limiting Toxicities
Description	Dose-limiting toxicity was defined as any of the following events assessed as related to carfilzomib, lenalidomide, or dexamethasone: Nonhematologic ≥ Grade 2 neuropathy with pain ≥ Grade 3 nonhematologic toxicity (excluding nausea, vomiting, diarrhea, hyperglycemia due to dexamethasone, and rash due to lenalidomide) ≥ Grade 3 nausea, vomiting, or diarrhea uncontrolled by maximal supportive therapy ≥ Grade 4 fatigue persisting > 7 days Treatment delay for toxicity > 21 days Hematologic Grade 4 neutropenia (absolute neutrophil count [ANC] < 500/mm³) > 7 days Febrile neutropenia (ANC < 1,000/mm³ with fever ≥ 38.3ºC) Grade 4 thrombocytopenia (platelets < 25,000/mm³) for > 7 days despite holding treatment, or Grade 3 or 4 thrombocytopenia associated with bleeding Treatment delay for toxicity > 21 days. The maximum-tolerated dose was defined as the dose level below which a drug-related DLT was observed in ≥ 33% of participants in a cohort.
Time Frame	Cycle 1, 28 days

Outcome Measure Data

Analysis Population Description

Safety population for the dose escalation portion of the study

Arm/Group Title	1: CFZ 15 mg/m² + LEN 10 mg	2: CFZ 15 mg/m² + LEN 15 mg	3: CFZ 15 mg/m² + LEN 20 mg	4: CFZ 20 mg/m² + LEN 20 mg	5: CFZ 20 mg/m² + LEN 25 mg	6: CFZ 20/27 mg/m² + LEN 25 mg
Arm/Group Description	Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 10 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 15 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 20 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 20 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 20 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment during Cycles 1 through 12 consisted of carfilzomib 20 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.	Treatment consisted of carfilzomib 20 mg/m² on Days 1 and 2 of Cycle 1, followed by 27 mg/m² for the remainder of treatment (Days 8, 9, 15, and 16 of Cycle 1 and Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles); lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.
Measure Participants	6	6	8	6	6	8
Number [participants]	0 0%	0 0%	0 0%	0 0%	0 0%	1 12.5%

Adverse Events

Time Frame	From the first dose of study drug until 30 days after the last dose; 1 to 52 months, with an average of 12 months.
Adverse Event Reporting Description	Other Adverse Events summarizes the non-serious occurrences of adverse events that exceed the indicated frequency threshold.
Arm/Group Title	1: CFZ 15 mg/m² + LEN 10 mg		2: CFZ 15 mg/m² + LEN 15 mg		3: CFZ 15 mg/m² + LEN 20 mg		4: CFZ 20 mg/m² + LEN 20 mg		5: CFZ 20 mg/m² + LEN 25 mg		6: CFZ 20/27 mg/m² + LEN 25 mg		7: CFZ 20/27 mg/m² + LEN 25 mg
Arm/Group Description	Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 10 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.		Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 15 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.		Treatment during Cycles 1 through 12 consisted of carfilzomib 15 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 20 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.		Treatment during Cycles 1 through 12 consisted of carfilzomib 20 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 20 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15, and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.		Treatment during Cycles 1 through 12 consisted of carfilzomib 20 mg/m² on Days 1, 2, 8, 9, 15, and 16; lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.		Treatment consisted of carfilzomib 20 mg/m² on Days 1 and 2 of Cycle 1, followed by 27 mg/m² for the remainder of treatment (Days 8, 9, 15, and 16 of Cycle 1 and Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles); lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.		In the Expansion portion, treatment consisted of carfilzomib 20 mg/m² on Days 1 and 2 of Cycle 1, followed by 27 mg/m² for the remainder of treatment (Days 8, 9, 15, and 16 of Cycle 1 and Days 1, 2, 8, 9, 15, and 16 for all subsequent cycles); lenalidomide 25 mg on Days 1 to 21; and 40 mg dexamethasone on Days 1, 8, and 15 and 22. For Cycles 13 and higher, carfilzomib could be omitted on Days 8 and 9 at the investigator's discretion.
All Cause Mortality
	1: CFZ 15 mg/m² + LEN 10 mg		2: CFZ 15 mg/m² + LEN 15 mg		3: CFZ 15 mg/m² + LEN 20 mg		4: CFZ 20 mg/m² + LEN 20 mg		5: CFZ 20 mg/m² + LEN 25 mg		6: CFZ 20/27 mg/m² + LEN 25 mg		7: CFZ 20/27 mg/m² + LEN 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	1: CFZ 15 mg/m² + LEN 10 mg		2: CFZ 15 mg/m² + LEN 15 mg		3: CFZ 15 mg/m² + LEN 20 mg		4: CFZ 20 mg/m² + LEN 20 mg		5: CFZ 20 mg/m² + LEN 25 mg		6: CFZ 20/27 mg/m² + LEN 25 mg		7: CFZ 20/27 mg/m² + LEN 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/6 (50%)		3/6 (50%)		4/8 (50%)		4/6 (66.7%)		3/6 (50%)		6/8 (75%)		22/44 (50%)
Blood and lymphatic system disorders
Anaemia	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		1/44 (2.3%)
Febrile neutropenia	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Neutropenia	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Thrombocytopenia	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Cardiac disorders
Acute myocardial infarction	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Atrial fibrillation	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Bradycardia	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Coronary artery disease	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Myocardial infarction	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Sick sinus syndrome	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Gastrointestinal disorders
Colonic stenosis	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Diarrhoea	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Gastrointestinal haemorrhage	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Small intestinal obstruction	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
General disorders
Death	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Disease progression	2/6 (33.3%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Face oedema	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Pain	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Pyrexia	0/6 (0%)		0/6 (0%)		2/8 (25%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Infections and infestations
Abscess jaw	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Bronchitis	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Bronchitis viral	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Cellulitis	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Infection	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Influenza	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		2/8 (25%)		0/44 (0%)
Osteomyelitis	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Pneumonia	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		2/8 (25%)		3/44 (6.8%)
Pneumonia pneumococcal	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Pneumonia respiratory syncytial viral	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Sepsis	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Upper respiratory tract infection	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Urinary tract infection	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Viral infection	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Injury, poisoning and procedural complications
Fall	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Multiple fractures	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Subdural haematoma	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Tendon rupture	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Metabolism and nutrition disorders
Dehydration	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Hypercalcaemia	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Musculoskeletal and connective tissue disorders
Bone pain	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Pathological fracture	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer stage IV	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Nervous system disorders
Cerebrovascular accident	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Renal and urinary disorders
Haematuria	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Renal failure acute	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Epistaxis	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Hypoxia	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Laryngeal mass	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Pulmonary embolism	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Skin and subcutaneous tissue disorders
Rash	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Vascular disorders
Embolism	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Thrombosis	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Other (Not Including Serious) Adverse Events
	1: CFZ 15 mg/m² + LEN 10 mg		2: CFZ 15 mg/m² + LEN 15 mg		3: CFZ 15 mg/m² + LEN 20 mg		4: CFZ 20 mg/m² + LEN 20 mg		5: CFZ 20 mg/m² + LEN 25 mg		6: CFZ 20/27 mg/m² + LEN 25 mg		7: CFZ 20/27 mg/m² + LEN 25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/6 (100%)		6/6 (100%)		8/8 (100%)		6/6 (100%)		6/6 (100%)		8/8 (100%)		42/44 (95.5%)
Blood and lymphatic system disorders
Anaemia	2/6 (33.3%)		2/6 (33.3%)		6/8 (75%)		2/6 (33.3%)		3/6 (50%)		3/8 (37.5%)		14/44 (31.8%)
Leukocytosis	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		2/44 (4.5%)
Leukopenia	0/6 (0%)		3/6 (50%)		1/8 (12.5%)		1/6 (16.7%)		1/6 (16.7%)		2/8 (25%)		9/44 (20.5%)
Lymphadenopathy	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Lymphopenia	1/6 (16.7%)		3/6 (50%)		2/8 (25%)		1/6 (16.7%)		0/6 (0%)		5/8 (62.5%)		22/44 (50%)
Neutropenia	4/6 (66.7%)		4/6 (66.7%)		4/8 (50%)		2/6 (33.3%)		5/6 (83.3%)		3/8 (37.5%)		16/44 (36.4%)
Thrombocytopenia	3/6 (50%)		3/6 (50%)		2/8 (25%)		2/6 (33.3%)		3/6 (50%)		3/8 (37.5%)		13/44 (29.5%)
Cardiac disorders
Atrial fibrillation	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Bradycardia	0/6 (0%)		0/6 (0%)		0/8 (0%)		2/6 (33.3%)		1/6 (16.7%)		0/8 (0%)		1/44 (2.3%)
Extrasystoles	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		1/44 (2.3%)
Palpitations	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		2/44 (4.5%)
Tachycardia	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		4/44 (9.1%)
Ventricular hypertrophy	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Ear and labyrinth disorders
Cerumen impaction	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Eye disorders
Cataract	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Conjunctivitis	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Corneal lesion	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Dry eye	0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		2/44 (4.5%)
Eye haemorrhage	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Eye irritation	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Eye pain	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Eye swelling	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Lacrimation increased	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Ocular hyperaemia	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Vision blurred	1/6 (16.7%)		1/6 (16.7%)		3/8 (37.5%)		1/6 (16.7%)		1/6 (16.7%)		1/8 (12.5%)		6/44 (13.6%)
Gastrointestinal disorders
Abdominal discomfort	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		2/44 (4.5%)
Abdominal distension	1/6 (16.7%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		4/44 (9.1%)
Abdominal pain	0/6 (0%)		2/6 (33.3%)		1/8 (12.5%)		1/6 (16.7%)		1/6 (16.7%)		1/8 (12.5%)		3/44 (6.8%)
Abdominal pain upper	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Constipation	1/6 (16.7%)		2/6 (33.3%)		2/8 (25%)		2/6 (33.3%)		1/6 (16.7%)		3/8 (37.5%)		11/44 (25%)
Diarrhoea	3/6 (50%)		3/6 (50%)		3/8 (37.5%)		3/6 (50%)		4/6 (66.7%)		4/8 (50%)		26/44 (59.1%)
Dyspepsia	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Epigastric discomfort	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Faecal incontinence	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Flatulence	1/6 (16.7%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Frequent bowel movements	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Gastrooesophageal reflux disease	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		1/44 (2.3%)
Gingival bleeding	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Gingival swelling	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Gingivitis	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Haematochezia	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Mouth haemorrhage	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Nausea	1/6 (16.7%)		3/6 (50%)		1/8 (12.5%)		2/6 (33.3%)		1/6 (16.7%)		2/8 (25%)		16/44 (36.4%)
Oesophageal discomfort	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Oral pain	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		2/44 (4.5%)
Oral soft tissue disorder	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Palatal disorder	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Stomach discomfort	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Stomatitis	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Toothache	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		1/8 (12.5%)		4/44 (9.1%)
Vomiting	0/6 (0%)		2/6 (33.3%)		2/8 (25%)		2/6 (33.3%)		0/6 (0%)		1/8 (12.5%)		11/44 (25%)
General disorders
Asthenia	2/6 (33.3%)		0/6 (0%)		3/8 (37.5%)		0/6 (0%)		1/6 (16.7%)		2/8 (25%)		5/44 (11.4%)
Axillary pain	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Catheter site haematoma	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Catheter site haemorrhage	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Catheter site pain	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Chest discomfort	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Chest pain	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		2/44 (4.5%)
Chills	0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		2/6 (33.3%)		0/6 (0%)		0/8 (0%)		5/44 (11.4%)
Cyst	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Disease progression	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		1/44 (2.3%)
Face oedema	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Fatigue	3/6 (50%)		4/6 (66.7%)		5/8 (62.5%)		3/6 (50%)		4/6 (66.7%)		6/8 (75%)		30/44 (68.2%)
Feeling hot and cold	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Feeling jittery	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Feeling of body temperature change	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Gait disturbance	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		2/44 (4.5%)
Influenza like illness	0/6 (0%)		0/6 (0%)		2/8 (25%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Infusion site bruising	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Infusion site reaction	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Injection site haemorrhage	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Injection site irritation	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Irritability	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		4/44 (9.1%)
Malaise	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		2/44 (4.5%)
Non-cardiac chest pain	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Oedema	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Oedema peripheral	0/6 (0%)		4/6 (66.7%)		2/8 (25%)		0/6 (0%)		3/6 (50%)		2/8 (25%)		17/44 (38.6%)
Pain	1/6 (16.7%)		0/6 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/6 (0%)		2/8 (25%)		4/44 (9.1%)
Pitting oedema	0/6 (0%)		0/6 (0%)		2/8 (25%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		3/44 (6.8%)
Pyrexia	0/6 (0%)		1/6 (16.7%)		5/8 (62.5%)		3/6 (50%)		1/6 (16.7%)		4/8 (50%)		19/44 (43.2%)
Temperature intolerance	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Vessel puncture site haemorrhage	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	0/6 (0%)		0/6 (0%)		3/8 (37.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Immune system disorders
Drug hypersensitivity	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		1/44 (2.3%)
Seasonal allergy	0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Infections and infestations
Bronchitis	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		1/44 (2.3%)
Candidiasis	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Catheter site cellulitis	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Cellulitis	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		3/44 (6.8%)
Eye infection	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Folliculitis	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Fungal infection	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Gastroenteritis viral	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Herpes simplex	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Influenza	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Lobar pneumonia	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Nasopharyngitis	1/6 (16.7%)		2/6 (33.3%)		1/8 (12.5%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		8/44 (18.2%)
Oral candidiasis	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Pneumonia	0/6 (0%)		0/6 (0%)		2/8 (25%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		4/44 (9.1%)
Rhinitis	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Sinusitis	0/6 (0%)		0/6 (0%)		4/8 (50%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		4/44 (9.1%)
Upper respiratory tract infection	2/6 (33.3%)		3/6 (50%)		4/8 (50%)		1/6 (16.7%)		0/6 (0%)		4/8 (50%)		19/44 (43.2%)
Urinary tract infection	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		1/8 (12.5%)		3/44 (6.8%)
Viral infection	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Injury, poisoning and procedural complications
Contusion	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		2/6 (33.3%)		0/8 (0%)		5/44 (11.4%)
Fall	0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Humerus fracture	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Incision site complication	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		1/44 (2.3%)
Scratch	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Skin laceration	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Transfusion reaction	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Investigations
Alanine aminotransferase increased	1/6 (16.7%)		1/6 (16.7%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		7/44 (15.9%)
Aspartate aminotransferase increased	1/6 (16.7%)		1/6 (16.7%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		6/44 (13.6%)
Blood alkaline phosphatase increased	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Blood bicarbonate decreased	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		3/44 (6.8%)
Blood bilirubin increased	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		3/44 (6.8%)
Blood calcium decreased	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Blood creatinine increased	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		2/8 (25%)		4/44 (9.1%)
Blood magnesium decreased	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Cardiac murmur	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		1/8 (12.5%)		1/44 (2.3%)
Ejection fraction decreased	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Haemoglobin decreased	0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		3/44 (6.8%)
Heart rate irregular	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
International normalised ratio increased	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Platelet count decreased	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Weight decreased	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		2/6 (33.3%)		0/8 (0%)		3/44 (6.8%)
Weight increased	0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Metabolism and nutrition disorders
Anorexia	0/6 (0%)		2/6 (33.3%)		1/8 (12.5%)		1/6 (16.7%)		1/6 (16.7%)		0/8 (0%)		7/44 (15.9%)
Decreased appetite	1/6 (16.7%)		3/6 (50%)		1/8 (12.5%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		4/44 (9.1%)
Dehydration	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/8 (0%)		5/44 (11.4%)
Hypercalcaemia	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		3/44 (6.8%)
Hyperglycaemia	1/6 (16.7%)		2/6 (33.3%)		1/8 (12.5%)		3/6 (50%)		2/6 (33.3%)		3/8 (37.5%)		11/44 (25%)
Hyperkalaemia	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Hypermagnesaemia	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		1/6 (16.7%)		2/8 (25%)		2/44 (4.5%)
Hyperphosphataemia	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Hyperphosphatasaemia	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Hyperuricaemia	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		3/44 (6.8%)
Hypoalbuminaemia	1/6 (16.7%)		1/6 (16.7%)		1/8 (12.5%)		0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		3/44 (6.8%)
Hypocalcaemia	0/6 (0%)		2/6 (33.3%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		2/8 (25%)		5/44 (11.4%)
Hypoglycaemia	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		2/8 (25%)		3/44 (6.8%)
Hypokalaemia	0/6 (0%)		3/6 (50%)		3/8 (37.5%)		2/6 (33.3%)		1/6 (16.7%)		1/8 (12.5%)		12/44 (27.3%)
Hypomagnesaemia	0/6 (0%)		2/6 (33.3%)		1/8 (12.5%)		2/6 (33.3%)		1/6 (16.7%)		2/8 (25%)		9/44 (20.5%)
Hyponatraemia	0/6 (0%)		2/6 (33.3%)		2/8 (25%)		1/6 (16.7%)		1/6 (16.7%)		3/8 (37.5%)		5/44 (11.4%)
Hypophosphataemia	0/6 (0%)		1/6 (16.7%)		3/8 (37.5%)		0/6 (0%)		1/6 (16.7%)		4/8 (50%)		16/44 (36.4%)
Iron deficiency	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Lactose intolerance	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/6 (33.3%)		2/6 (33.3%)		3/8 (37.5%)		1/6 (16.7%)		0/6 (0%)		1/8 (12.5%)		12/44 (27.3%)
Back pain	2/6 (33.3%)		3/6 (50%)		3/8 (37.5%)		1/6 (16.7%)		2/6 (33.3%)		1/8 (12.5%)		15/44 (34.1%)
Bone pain	0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Chest wall pain	0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		2/6 (33.3%)		1/6 (16.7%)		0/8 (0%)		6/44 (13.6%)
Groin pain	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Joint range of motion decreased	0/6 (0%)		1/6 (16.7%)		2/8 (25%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Joint swelling	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Muscle spasms	1/6 (16.7%)		4/6 (66.7%)		4/8 (50%)		1/6 (16.7%)		1/6 (16.7%)		3/8 (37.5%)		17/44 (38.6%)
Muscle twitching	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Muscular weakness	1/6 (16.7%)		1/6 (16.7%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		2/8 (25%)		2/44 (4.5%)
Musculoskeletal discomfort	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		3/44 (6.8%)
Musculoskeletal stiffness	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		2/44 (4.5%)
Myalgia	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		2/6 (33.3%)		0/8 (0%)		5/44 (11.4%)
Neck pain	0/6 (0%)		1/6 (16.7%)		2/8 (25%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Pain in extremity	1/6 (16.7%)		1/6 (16.7%)		4/8 (50%)		1/6 (16.7%)		1/6 (16.7%)		2/8 (25%)		11/44 (25%)
Pain in jaw	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		5/44 (11.4%)
Pathological fracture	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		4/44 (9.1%)
Sacral pain	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Shoulder pain	0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		3/6 (50%)		1/6 (16.7%)		2/8 (25%)		3/44 (6.8%)
Tendonitis	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign neoplasm of skin	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Lung neoplasm	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		1/44 (2.3%)
Malignant melanoma	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Plasmacytoma	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Nervous system disorders
Aphasia	1/6 (16.7%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Areflexia	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Balance disorder	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Convulsion	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Dizziness	0/6 (0%)		2/6 (33.3%)		2/8 (25%)		1/6 (16.7%)		2/6 (33.3%)		1/8 (12.5%)		6/44 (13.6%)
Dysgeusia	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		5/44 (11.4%)
Dysstasia	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Headache	0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		3/6 (50%)		2/6 (33.3%)		0/8 (0%)		11/44 (25%)
Hyperaesthesia	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Hypoaesthesia	1/6 (16.7%)		2/6 (33.3%)		2/8 (25%)		1/6 (16.7%)		0/6 (0%)		1/8 (12.5%)		8/44 (18.2%)
Hyporeflexia	2/6 (33.3%)		2/6 (33.3%)		1/8 (12.5%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Memory impairment	0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		1/44 (2.3%)
Nerve compression	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Neuropathic pain	1/6 (16.7%)		0/6 (0%)		1/8 (12.5%)		1/6 (16.7%)		0/6 (0%)		2/8 (25%)		5/44 (11.4%)
Neuropathy peripheral	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		2/6 (33.3%)		0/6 (0%)		0/8 (0%)		12/44 (27.3%)
Paraesthesia	2/6 (33.3%)		3/6 (50%)		2/8 (25%)		0/6 (0%)		0/6 (0%)		3/8 (37.5%)		9/44 (20.5%)
Peripheral sensory neuropathy	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Sciatica	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Somnolence	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		4/44 (9.1%)
Tremor	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/8 (0%)		4/44 (9.1%)
Psychiatric disorders
Affect lability	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Agitation	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		3/44 (6.8%)
Anxiety	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		2/6 (33.3%)		1/8 (12.5%)		7/44 (15.9%)
Anxiety disorder	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Confusional state	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		2/44 (4.5%)
Depression	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		4/44 (9.1%)
Insomnia	1/6 (16.7%)		3/6 (50%)		3/8 (37.5%)		0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		17/44 (38.6%)
Mood altered	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		3/44 (6.8%)
Mood swings	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Stress	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Renal and urinary disorders
Dysuria	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Haematuria	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Incontinence	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Micturition urgency	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Nocturia	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		2/44 (4.5%)
Proteinuria	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Renal failure	0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		1/44 (2.3%)
Urinary hesitation	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Urinary retention	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Reproductive system and breast disorders
Atrophic vulvovaginitis	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Pelvic pain	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Postmenopausal haemorrhage	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Vaginal haemorrhage	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	1/6 (16.7%)		5/6 (83.3%)		3/8 (37.5%)		2/6 (33.3%)		3/6 (50%)		4/8 (50%)		17/44 (38.6%)
Dry throat	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Dysphonia	2/6 (33.3%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		6/44 (13.6%)
Dyspnoea	0/6 (0%)		3/6 (50%)		3/8 (37.5%)		2/6 (33.3%)		3/6 (50%)		3/8 (37.5%)		15/44 (34.1%)
Dyspnoea exertional	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		1/8 (12.5%)		5/44 (11.4%)
Epistaxis	1/6 (16.7%)		1/6 (16.7%)		1/8 (12.5%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		6/44 (13.6%)
Haemoptysis	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		1/44 (2.3%)
Hiccups	2/6 (33.3%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Lung infiltration	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Nasal congestion	0/6 (0%)		0/6 (0%)		2/8 (25%)		1/6 (16.7%)		0/6 (0%)		1/8 (12.5%)		7/44 (15.9%)
Pharyngeal erythema	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		3/44 (6.8%)
Pharyngolaryngeal pain	0/6 (0%)		0/6 (0%)		3/8 (37.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		12/44 (27.3%)
Pleural effusion	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		1/6 (16.7%)		0/8 (0%)		1/44 (2.3%)
Pleuritic pain	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Productive cough	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		7/44 (15.9%)
Pulmonary oedema	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Rales	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Respiratory tract congestion	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Rhinorrhoea	0/6 (0%)		2/6 (33.3%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		6/44 (13.6%)
Sinus congestion	0/6 (0%)		0/6 (0%)		3/8 (37.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Sleep apnoea syndrome	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		1/44 (2.3%)
Throat irritation	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Throat tightness	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Wheezing	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		3/44 (6.8%)
Skin and subcutaneous tissue disorders
Dermatitis contact	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Dry skin	1/6 (16.7%)		2/6 (33.3%)		1/8 (12.5%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		11/44 (25%)
Ecchymosis	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		4/44 (9.1%)
Erythema	0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		3/44 (6.8%)
Hair growth abnormal	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Hyperhidrosis	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		4/44 (9.1%)
Increased tendency to bruise	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Nail discolouration	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Nail disorder	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Night sweats	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		5/44 (11.4%)
Petechiae	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Pruritus	0/6 (0%)		2/6 (33.3%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		1/8 (12.5%)		4/44 (9.1%)
Rash	0/6 (0%)		2/6 (33.3%)		4/8 (50%)		1/6 (16.7%)		2/6 (33.3%)		2/8 (25%)		8/44 (18.2%)
Rash generalised	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		2/44 (4.5%)
Rash macular	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		3/44 (6.8%)
Rash pruritic	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Skin discolouration	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Skin disorder	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Skin exfoliation	1/6 (16.7%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Skin fragility	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Skin haemorrhage	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		1/44 (2.3%)
Skin lesion	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		1/44 (2.3%)
Subcutaneous nodule	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Swelling face	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Surgical and medical procedures
Tooth extraction	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Vascular disorders
Deep vein thrombosis	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		5/44 (11.4%)
Flushing	1/6 (16.7%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Haematoma	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/44 (0%)
Hypertension	0/6 (0%)		2/6 (33.3%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		4/44 (9.1%)
Peripheral coldness	0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Phlebitis	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		1/44 (2.3%)
Post thrombotic syndrome	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)
Thrombophlebitis superficial	0/6 (0%)		0/6 (0%)		0/8 (0%)		1/6 (16.7%)		0/6 (0%)		0/8 (0%)		2/44 (4.5%)
Vascular fragility	0/6 (0%)		0/6 (0%)		1/8 (12.5%)		0/6 (0%)		0/6 (0%)		0/8 (0%)		0/44 (0%)
Vena cava thrombosis	0/6 (0%)		0/6 (0%)		0/8 (0%)		0/6 (0%)		1/6 (16.7%)		0/8 (0%)		0/44 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.