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A Study of Clofarabine in Combination With Etoposide and Cyclophosphamide in Children With Acute Leukemias.

Sponsor
Genzyme, a Sanofi Company (Industry)
Overall Status
Completed
CT.gov ID
NCT00315705
Collaborator
(none)
50
Enrollment
13
Locations
1
Arm
50
Duration (Months)
3.8
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Clofarabine (injection) is approved by the Food and Drug Administration (FDA) for the treatment of pediatric patients 1 to 21 years old with relapsed or refractory acute lymphoblastic leukemia (ALL) who have had at least 2 prior treatment regimens. This use is based on the induction of complete responses. Randomized trials demonstrating increased survival or other clinical benefit have not been conducted.

The purpose of the phase 1 portion of this study was to determine if clofarabine added to a combination of etoposide and cyclophosphamide is safe in children with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). The purpose of the phase 2 portion of the study was to measure the effectiveness of the combination therapy in children with ALL.

Condition or Disease Intervention/Treatment Phase
Phase 1/Phase 2

Study Design

Study Type:
Interventional
Actual Enrollment :
50 participants
Allocation:
Non-Randomized
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 1/2 Dose-Escalation Study of Clofarabine in Combination With Etoposide and Cyclophosphamide in Pediatric Patients With Refractory or Relapsed Acute Leukemias.
Study Start Date :
Mar 1, 2006
Actual Primary Completion Date :
May 1, 2010
Actual Study Completion Date :
May 1, 2010

Arms and Interventions

Arm Intervention/Treatment
Experimental: clofarabine, etoposide, cyclophosphamide

Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m^2, etoposide dosage from 75-100 mg/m^2, cyclophosphamide dosage from 340-440 mg/m^2. Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously

Drug: clofarabine
Clofarabine 20-40 mg/m²/day 2 hour intravenous (IV) infusion daily for 5 days of a 28 day cycle as the first of the three IV interventions administered. Maximum of 8 cycles given in both the phase 1 and phase 2 study periods.
Other Names:
  • Clolar
  • Evoltra

    • Drug: Etoposide
    Etoposide 75-100 mg/m²/day 2 hour intravenous (IV) infusion daily for 5 days of a 28 day cycle following clofarabine therapy. Maximum of 8 cycles given in both the phase 1 and phase 2 study periods.
    Other Names:
  • Eposin

    • Drug: Cyclophosphamide
    Cyclophosphamide 340-440 mg/m²/day as 30-60 minute intravenous (IV) infusion daily for 5 days of a 28 day cycle following the other two interventions. Maximum of 8 cycles given in both the phase 1 and phase 2 study periods.
    Other Names:
  • Endoxan
  • Revimmune
  • Cytoxan

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Maximum Tolerated Dose (MTD) in Phase 1 [Up to Day 42 (Phase 1 portion of study)]

      The MTD was to be the highest dose level of clofarabine in combination with etoposide and cyclophosphamide that caused <= 1 of 6 participants to experience a dose limiting toxicity (DLT) with the next higher dose level having at least 2 of 3 or 2 of 6 participants experiencing a DLT. The MTD would be used as the recommended phase 2 dose (RP2D). If the MTD could not be determined, then the target dose of clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 as taken by Cohort 5 was to become the RP2D. The rating scale used is 0 = not the MTD, 1 = the MTD.

    2. Participants With Dose Limiting Toxicity in Phase 1 [Up to Day 42 (Phase 1 portion of study)]

      The number of participants in each cohort that had dose limiting toxicity is summarized. Toxicities were reviewed by an independent Data Safety Monitoring Board (DSMB) who determined if additional participants should be added to the cohort and the criteria for escalating to the next cohort.

    3. Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2 [Approximately 28-56 days (Phase 2 portion of study)]

      Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with <5% blasts, and platelet (plt)/ANC recovery: ≥75/ ≥0.75 [x 10^9/L] 2) CR in absence of plt recovery (CRp): plt ≥20 to <75 x 10^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with <5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR.

    Secondary Outcome Measures

    1. Summary of Participants With Adverse Events (AEs) in Phase 1 [Up to 9.5 months (Phase 1 portion of study)]

      Number of participants with AEs that occurred during treatment and follow-up period (45 days after last cycle). Drug-related AEs and SAEs were followed until resolved or mutually agreed by the investigator and Genzyme to discontinue reporting. AEs were classified by the investigator according to severity (graded using National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) and relationship to study drug. The severity scale is:> Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death related to AE

    2. Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1 [Approximately 2 months (Phase 1 portion of study)]

      Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with <5% blasts, and platelet (plt)/ANC recovery: ALL ≥75/ ≥0.75 [x 10^9/L]; AML ≥100/ ≥1.0 [x 10^9/L] 2) CR in absence of plt recovery (CRp): ALL plt ≥20 to <75 x 10^9/L; AML plt ≥20 to <100 x 10^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with <5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR.

    3. Time to Remission for Participants Who Had a Response in Phase 1 [up to 8 weeks (Phase 1 portion of study)]

      The weeks between start of intervention and remission as assessed by the investigator in Phase 1. Participants who had a complete remission (CR) or complete remission with the absence of total platelet recovery (CRp) are included.

    4. Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 1 [Up to 2 years (Phase 1 portion of study)]

      Duration of response is the time from the first objective measurement of complete response (CR) or complete response with the absence of total platelet recovery (CRp) to the date of first objective documentation of disease relapse or death due to any cause, plus one day. For summary purposes, results are presented as weeks.

    5. Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 1 [Up to 2 years (Phase 1 portion of study)]

      Event-free survival (EFS) is defined as the time from date of first administration of study interventions until the earliest of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response, plus one day. For summary purposes, results are presented as weeks.

    6. Number of Participants With 4-month Event Free Survival in Phase 1 [4 months (Phase I portion of study)]

      Number of participants with event-free survival at four months post first dose of therapy. A participant is considered event-free if at month 4 they have not died or had a response assessment confirming a relapse.

    7. Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 1 [Up to 2 years (Phase 1 portion of study)]

      Overall survival is defined as the time from date of first administration of study interventions until date of death, plus one day. For summary purposes, results are presented as weeks.

    8. Summary of Participants With Adverse Events (AEs) in Phase 2 [Up to 9.5 months (Phase 2 portion of study)]

      Number of participants with AEs that occurred during treatment and follow-up period (45 days after last cycle). Drug-related AEs and SAEs were followed until resolved or mutually agreed by the investigator and Genzyme to discontinue reporting. AEs were classified by the investigator according to severity (graded using National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) and relationship to study drug. The severity scale is:> Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death related to AE

    9. Time to Remission for Participants Who Had a Response in Phase 2 [up to 8 weeks (Phase 2 portion of study)]

      The weeks between start of intervention and remission as assessed by the investigator in Phase 2. Participants who had a complete remission (CR) or complete remission with the absence of total platelet recovery (CRp) are included.

    10. Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 2 [Up to 2 years (Phase 2 portion of study)]

      Duration of response is the time from the first objective measurement of complete response (CR) or complete response with the absence of total platelet recovery (CRp) to the date of first objective documentation of disease relapse or death due to any cause, plus one day. For summary purposes, results are presented as weeks.

    11. Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 2 [Up to 2 years (Phase 2 portion of study)]

      Event-free survival (EFS) is defined as the time from date of first administration of study interventions until the earliest of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response, plus one day. For summary purposes, results are presented as weeks.

    12. Number of Participants With 4-month Event Free Survival in Phase 2 [4 months (Phase 2 portion of study)]

      Number of participants with event-free survival at four months post first dose of therapy. A participant is considered event-free if at month 4 they have not died or had a response assessment confirming a relapse.

    13. Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 2 [Up to 2 years (Phase 2 portion of study)]

      Overall survival is defined as the time from date of first administration of study interventions until date of death, plus one day. For summary purposes, results are presented as weeks.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    1 Year to 21 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    • NOTE: the following eligibility criteria were applicable to acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) patients for the Phase 1 portion of this study, and to ALL patients for the Phase 2 portion of the study (only ALL patients were allowed in the Phase 2 portion of the study).

    • ALL with > 25% blasts in bone marrow; AML with ≥ 5% blasts in bone marrow; ALL and AML patients may have extramedullary disease

    • Karnofsky Performance Status ≥ 50 for patients > 10 years old; Lansky Performance Status ≥ 50 for patients ≤ 10 years old

    • Prior therapy: AML: 1-2 prior induction regimens and ≤ 1 hematopoietic stem cell transplant (HSCT); ALL: 1-3 prior induction regimens

    • Adequate liver, renal, pancreatic, and cardiac function

    • Have received no prior HSCT (study amended in Phase 2 to exclude patients with prior HSCT)

    Exclusion Criteria:

    • NOTE: the following eligibility criteria were applicable to ALL and AML patients for the Phase 1 portion of this study, and to ALL patients for the Phase 2 portion of the study (only ALL patients were allowed in the Phase 2 portion of the study).

    • Burkitt's leukemia

    • Previous treatment with clofarabine

    • Uncontrolled systemic fungal, bacterial or other infection and 48 hrs negative blood cultures required for patients with a history of fever within 3 days of enrollment

    • Active CNS involvement (i.e., should be CNS1 or CNS2)

    • Inadequate time since last therapy: ≤ 14 days since last cytotoxic chemotherapy; ≤ 7 days since last biologic therapy; ≤ 14 days since last monoclonal antibody therapy

    • Have received prior HSCT (study amended in Phase 2 to exclude patients with prior HSCT)

    • Pregnant or lactating

    • Have tested positive for hepatitis B or hepatitis C infection or history of cirrhosis

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Children's Hospital of Alabama Birmingham Alabama United States
    2 Children's Hospital of Los Angeles Los Angeles California United States
    3 Rady Children's Hospital San Diego California United States
    4 Connecticut Children's Medical Center Hartford Connecticut United States
    5 Children's Memorial Hospital Chicago Illinois United States
    6 St. Vincent Children's Hospital Indianapolis Indiana United States
    7 Dana Farber Cancer Institute Boston Massachusetts United States
    8 Children's Hospital of Michigan Detroit Michigan United States
    9 Memorial Sloan-Kettering Cancer Center New York New York United States
    10 New York School of Medicine New York New York United States
    11 St. Jude Children's Research Hospital Memphis Tennessee United States
    12 University of Texas MD Anderson Cancer Center Houston Texas United States
    13 Seattle Children's Hospital Seattle Washington United States

    Sponsors and Collaborators

    • Genzyme, a Sanofi Company

    Investigators

    • Study Director: Medical Monitor, Genzyme, a Sanofi Company

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Genzyme, a Sanofi Company
    ClinicalTrials.gov Identifier:
    NCT00315705
    Other Study ID Numbers:
    • CLO21800205
    First Posted:
    Apr 19, 2006
    Last Update Posted:
    Apr 14, 2014
    Last Verified:
    Mar 1, 2014
    Keywords provided by Genzyme, a Sanofi Company
    clofarabine
    acute leukemia
    ALL
    AML
    clolar
    CLO218
    Additional relevant MeSH terms:
    Leukemia
    Precursor Cell Lymphoblastic Leukemia-Lymphoma
    Leukemia, Myeloid
    Leukemia, Myeloid, Acute
    Cyclophosphamide
    Etoposide
    Clofarabine

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m^2, etoposide dosage from 75-100 mg/m^2, cyclophosphamide dosage from 340-440 mg/m^2.> Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously
    Period Title: Phase 1
    STARTED 25
    COMPLETED 0
    NOT COMPLETED 25
    Period Title: Phase 1
    STARTED 25
    COMPLETED 0
    NOT COMPLETED 25

    Baseline Characteristics

    Arm/Group Title Phase 1: Clofarabine, Etoposide, Cyclophosphamide Phase 2: Clofarabine, Etoposide, Cyclophosphamide Total
    Arm/Group Description Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m^2, etoposide dosage from 75-100 mg/m^2, cyclophosphamide dosage from 340-440 mg/m^2. Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously Total of all reporting groups
    Overall Participants 25 25 50
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    9.1
    (5.03)
    13.2
    (5.25)
    11.2
    (5.49)
    Sex: Female, Male (Count of Participants)
    Female
    10
    40%
    9
    36%
    19
    38%
    Male
    15
    60%
    16
    64%
    31
    62%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    5
    20%
    10
    40%
    15
    30%
    Not Hispanic or Latino
    20
    80%
    15
    60%
    35
    70%
    Unknown or Not Reported
    0
    0%
    0
    0%
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    1
    4%
    1
    2%
    Asian
    3
    12%
    2
    8%
    5
    10%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    4
    16%
    2
    8%
    6
    12%
    White
    16
    64%
    12
    48%
    28
    56%
    More than one race
    0
    0%
    0
    0%
    0
    0%
    Unknown or Not Reported
    2
    8%
    8
    32%
    10
    20%
    Percent Leukemic Blast Cells (percentage of total blast cells) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [percentage of total blast cells]
    66.8
    (24.85)
    69.52
    (23.566)
    68.16
    (24.008)
    Absolute Neutrophil Counts (10^9/L) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [10^9/L]
    1.93828
    (3.049992)
    1.9280
    (1.708126)
    1.93325
    (2.459536)
    White Blood Cell Counts (10^9/L) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [10^9/L]
    8.323
    (9.1305)
    12.171
    (23.0150)
    10.247
    (17.4370)
    Immunophenotype (participants) [Number]
    B cell
    13
    52%
    21
    84%
    34
    68%
    T cell
    5
    20%
    1
    4%
    6
    12%
    Unknown
    2
    8%
    3
    12%
    5
    10%
    not included (AML participants)
    5
    20%
    0
    0%
    5
    10%
    Count of Previous Anti-Leukemic (non-transplant) Treatment Regimens (participants) [Number]
    1 regimen
    4
    16%
    4
    16%
    8
    16%
    2 regimens
    18
    72%
    14
    56%
    32
    64%
    3 regimens
    3
    12%
    7
    28%
    10
    20%
    Participants with Previous Anti-Leukemic Transplant Regimens (participants) [Number]
    Transplants
    4
    16%
    4
    16%
    8
    16%
    No transplants
    21
    84%
    21
    84%
    42
    84%
    Participants Who Were Refractory to the Most Recent Previous Anti-Leukemic Treatment (participants) [Number]
    Yes
    7
    28%
    15
    60%
    22
    44%
    No
    18
    72%
    10
    40%
    28
    56%
    Participant Rating Using the Karnofsky/Lansky Performance Status Scale (participants) [Number]
    50
    0
    0%
    2
    8%
    2
    4%
    60
    0
    0%
    2
    8%
    2
    4%
    70
    1
    4%
    2
    8%
    3
    6%
    80
    5
    20%
    3
    12%
    8
    16%
    90
    7
    28%
    6
    24%
    13
    26%
    100
    12
    48%
    10
    40%
    22
    44%

    Outcome Measures

    1. Primary Outcome
    Title Maximum Tolerated Dose (MTD) in Phase 1
    Description The MTD was to be the highest dose level of clofarabine in combination with etoposide and cyclophosphamide that caused <= 1 of 6 participants to experience a dose limiting toxicity (DLT) with the next higher dose level having at least 2 of 3 or 2 of 6 participants experiencing a DLT. The MTD would be used as the recommended phase 2 dose (RP2D). If the MTD could not be determined, then the target dose of clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 as taken by Cohort 5 was to become the RP2D. The rating scale used is 0 = not the MTD, 1 = the MTD.
    Time Frame Up to Day 42 (Phase 1 portion of study)

    Outcome Measure Data

    Analysis Population Description
    All phase 1 participants
    Arm/Group Title Phase 1 - Cohort 1 Phase 1 - Cohort 2 Phase 1 - Cohort 3 Phase 1 - Cohort 4 Phase 1 - Cohort 5
    Arm/Group Description Participants were treated with clofarabine 20 mg/m^2, etoposide 75 mg/m^2, and cyclophosphamide 340 mg/m^2. Participants were treated with clofarabine 20 mg/m^2, etoposide 75 mg/m^2, and cyclophosphamide 440 mg/m^2. Participants were treated with clofarabine 20 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2. Participants were treated with clofarabine 30 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2. Participants were treated with clofarabine 40 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2.
    Measure Participants 3 3 3 10 6
    Number [units on a scale]
    0
    0
    0
    0
    0
    2. Primary Outcome
    Title Participants With Dose Limiting Toxicity in Phase 1
    Description The number of participants in each cohort that had dose limiting toxicity is summarized. Toxicities were reviewed by an independent Data Safety Monitoring Board (DSMB) who determined if additional participants should be added to the cohort and the criteria for escalating to the next cohort.
    Time Frame Up to Day 42 (Phase 1 portion of study)

    Outcome Measure Data

    Analysis Population Description
    All phase 1 participants
    Arm/Group Title Phase 1 - Cohort 1 Phase 1 - Cohort 2 Phase 1 - Cohort 3 Phase 1 - Cohort 4 Phase 1 - Cohort 5
    Arm/Group Description Participants were treated with clofarabine 20 mg/m^2, etoposide 75 mg/m^2, and cyclophosphamide 340 mg/m^2. Participants were treated with clofarabine 20 mg/m^2, etoposide 75 mg/m^2, and cyclophosphamide 440 mg/m^2. Participants were treated with clofarabine 20 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2. Participants were treated with clofarabine 30 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2. Participants were treated with clofarabine 40 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2.
    Measure Participants 3 3 3 10 6
    Number [participants]
    0
    0%
    0
    0%
    0
    0%
    1
    NaN
    1
    NaN
    3. Secondary Outcome
    Title Summary of Participants With Adverse Events (AEs) in Phase 1
    Description Number of participants with AEs that occurred during treatment and follow-up period (45 days after last cycle). Drug-related AEs and SAEs were followed until resolved or mutually agreed by the investigator and Genzyme to discontinue reporting. AEs were classified by the investigator according to severity (graded using National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) and relationship to study drug. The severity scale is:> Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death related to AE
    Time Frame Up to 9.5 months (Phase 1 portion of study)

    Outcome Measure Data

    Analysis Population Description
    All phase 1 participants
    Arm/Group Title Phase 1 - Cohort 1 Phase 1 - Cohort 2 Phase 1 - Cohort 3 Phase 1 - Cohort 4 Phase 1 - Cohort 5
    Arm/Group Description Participants were treated with clofarabine 20 mg/m^2, etoposide 75 mg/m^2, and cyclophosphamide 340 mg/m^2. Participants were treated with clofarabine 20 mg/m^2, etoposide 75 mg/m^2, and cyclophosphamide 440 mg/m^2. Participants were treated with clofarabine 20 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2. Participants were treated with clofarabine 30 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2. Participants were treated with clofarabine 40 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2.
    Measure Participants 3 3 3 10 6
    At least one AE
    3
    12%
    3
    12%
    3
    6%
    10
    NaN
    6
    NaN
    At least one AE related to clofarabine
    3
    12%
    3
    12%
    3
    6%
    10
    NaN
    6
    NaN
    At least one serious AE
    3
    12%
    3
    12%
    3
    6%
    9
    NaN
    6
    NaN
    At least one serious AE related to clofarabine
    3
    12%
    2
    8%
    3
    6%
    9
    NaN
    5
    NaN
    Discontinued study due to AE
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    Died
    3
    12%
    1
    4%
    3
    6%
    9
    NaN
    5
    NaN
    AE with the worst grade of: 1
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    AE with the worst grade of: 2
    0
    0%
    0
    0%
    0
    0%
    0
    NaN
    0
    NaN
    AE with the worst grade of: 3
    2
    8%
    1
    4%
    1
    2%
    3
    NaN
    3
    NaN
    AE with the worst grade of: 4
    1
    4%
    1
    4%
    2
    4%
    5
    NaN
    2
    NaN
    AE with the worst grade of: 5
    0
    0%
    1
    4%
    0
    0%
    2
    NaN
    1
    NaN
    4. Secondary Outcome
    Title Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 1
    Description Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with <5% blasts, and platelet (plt)/ANC recovery: ALL ≥75/ ≥0.75 [x 10^9/L]; AML ≥100/ ≥1.0 [x 10^9/L] 2) CR in absence of plt recovery (CRp): ALL plt ≥20 to <75 x 10^9/L; AML plt ≥20 to <100 x 10^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with <5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR.
    Time Frame Approximately 2 months (Phase 1 portion of study)

    Outcome Measure Data

    Analysis Population Description
    All phase 1 participants
    Arm/Group Title Phase 1: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m^2, etoposide dosage from 75-100 mg/m^2, cyclophosphamide dosage from 340-440 mg/m^2.
    Measure Participants 25
    Complete remission (CR)
    40
    160%
    Complete remission/absence total platelet recovery
    24
    96%
    Partial remission (PR)
    0
    0%
    Overall remission (OR)
    64
    256%
    Any response (CR+CRp+PR)
    64
    256%
    5. Secondary Outcome
    Title Time to Remission for Participants Who Had a Response in Phase 1
    Description The weeks between start of intervention and remission as assessed by the investigator in Phase 1. Participants who had a complete remission (CR) or complete remission with the absence of total platelet recovery (CRp) are included.
    Time Frame up to 8 weeks (Phase 1 portion of study)

    Outcome Measure Data

    Analysis Population Description
    Participants in phase 1 who had an overall remission.
    Arm/Group Title Phase 1: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m^2, etoposide dosage from 75-100 mg/m^2, cyclophosphamide dosage from 340-440 mg/m^2.
    Measure Participants 16
    Mean (Standard Deviation) [weeks]
    4.96
    (1.912)
    6. Secondary Outcome
    Title Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 1
    Description Duration of response is the time from the first objective measurement of complete response (CR) or complete response with the absence of total platelet recovery (CRp) to the date of first objective documentation of disease relapse or death due to any cause, plus one day. For summary purposes, results are presented as weeks.
    Time Frame Up to 2 years (Phase 1 portion of study)

    Outcome Measure Data

    Analysis Population Description
    Phase 1 participants who achieved overall remission. Data are censored at date of last known follow-up visit.
    Arm/Group Title Phase 1: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m^2, etoposide dosage from 75-100 mg/m^2, cyclophosphamide dosage from 340-440 mg/m^2.
    Measure Participants 16
    Median (95% Confidence Interval) [weeks]
    18.2
    7. Secondary Outcome
    Title Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 1
    Description Event-free survival (EFS) is defined as the time from date of first administration of study interventions until the earliest of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response, plus one day. For summary purposes, results are presented as weeks.
    Time Frame Up to 2 years (Phase 1 portion of study)

    Outcome Measure Data

    Analysis Population Description
    All phase 1 participants. Data are censored at date of last known follow-up visit.
    Arm/Group Title Phase 1: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m^2, etoposide dosage from 75-100 mg/m^2, cyclophosphamide dosage from 340-440 mg/m^2.
    Measure Participants 25
    Median (95% Confidence Interval) [weeks]
    19.3
    8. Secondary Outcome
    Title Number of Participants With 4-month Event Free Survival in Phase 1
    Description Number of participants with event-free survival at four months post first dose of therapy. A participant is considered event-free if at month 4 they have not died or had a response assessment confirming a relapse.
    Time Frame 4 months (Phase I portion of study)

    Outcome Measure Data

    Analysis Population Description
    All participants
    Arm/Group Title Phase 1: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m^2, etoposide dosage from 75-100 mg/m^2, cyclophosphamide dosage from 340-440 mg/m^2.
    Measure Participants 25
    Number [participants]
    13
    52%
    9. Secondary Outcome
    Title Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 1
    Description Overall survival is defined as the time from date of first administration of study interventions until date of death, plus one day. For summary purposes, results are presented as weeks.
    Time Frame Up to 2 years (Phase 1 portion of study)

    Outcome Measure Data

    Analysis Population Description
    All phase 1 participants
    Arm/Group Title Phase 1: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 1: escalating dosage of the three drugs delivered intravenously. Clofarabine dosage from 20-40 mg/m^2, etoposide dosage from 75-100 mg/m^2, cyclophosphamide dosage from 340-440 mg/m^2.
    Measure Participants 25
    Median (95% Confidence Interval) [weeks]
    27.1
    10. Primary Outcome
    Title Percentage of Participants Achieving A Response Over the First Two Treatment Cycles in Phase 2
    Description Response categories 1) complete remission (CR): without circulating blasts or extramedullary disease, bone marrow (BM) with <5% blasts, and platelet (plt)/ANC recovery: ≥75/ ≥0.75 [x 10^9/L] 2) CR in absence of plt recovery (CRp): plt ≥20 to <75 x 10^9/L 3) partial remission (PR): no circulating blasts, appearance of normal hematopoietic progenitors, and either a BM with ≥5% and ≤25% blasts with recovery of plts/ANC or a BM with <5% blasts not meeting CR/CRp definition 4) Overall remission (OR): CR+CRp 5) Any response: CR+CRp+PR.
    Time Frame Approximately 28-56 days (Phase 2 portion of study)

    Outcome Measure Data

    Analysis Population Description
    All phase 2 participants
    Arm/Group Title Phase 2: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously
    Measure Participants 25
    Complete remission (CR)
    28
    112%
    Complete remission/absence total platelet recovery
    16
    64%
    Partial remission (PR)
    12
    48%
    Overall remission (OR)
    44
    176%
    Any response (CR+CRp+PR)
    56
    224%
    11. Secondary Outcome
    Title Summary of Participants With Adverse Events (AEs) in Phase 2
    Description Number of participants with AEs that occurred during treatment and follow-up period (45 days after last cycle). Drug-related AEs and SAEs were followed until resolved or mutually agreed by the investigator and Genzyme to discontinue reporting. AEs were classified by the investigator according to severity (graded using National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 3.0) and relationship to study drug. The severity scale is:> Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death related to AE
    Time Frame Up to 9.5 months (Phase 2 portion of study)

    Outcome Measure Data

    Analysis Population Description
    All phase 2 participants
    Arm/Group Title Phase 2: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously
    Measure Participants 25
    At least one AE
    25
    100%
    At least one AE related to clofarabine
    25
    100%
    At least one serious AE
    21
    84%
    At least one serious AE related to clofarabine
    20
    80%
    Discontinued study due to AE
    1
    4%
    Died
    16
    64%
    AE with the worst grade of: 1
    0
    0%
    AE with the worst grade of: 2
    0
    0%
    AE with the worst grade of: 3
    1
    4%
    AE with the worst grade of: 4
    16
    64%
    AE with the worst grade of: 5
    8
    32%
    12. Secondary Outcome
    Title Time to Remission for Participants Who Had a Response in Phase 2
    Description The weeks between start of intervention and remission as assessed by the investigator in Phase 2. Participants who had a complete remission (CR) or complete remission with the absence of total platelet recovery (CRp) are included.
    Time Frame up to 8 weeks (Phase 2 portion of study)

    Outcome Measure Data

    Analysis Population Description
    Participants in phase 2 who had an overall remission.
    Arm/Group Title Phase 2: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously.
    Measure Participants 11
    Mean (Standard Deviation) [weeks]
    4.84
    (2.092)
    13. Secondary Outcome
    Title Kaplan Meier Estimate of Duration of Remission (DOR) for Participants Who Achieved Overall Remission (OR) in Phase 2
    Description Duration of response is the time from the first objective measurement of complete response (CR) or complete response with the absence of total platelet recovery (CRp) to the date of first objective documentation of disease relapse or death due to any cause, plus one day. For summary purposes, results are presented as weeks.
    Time Frame Up to 2 years (Phase 2 portion of study)

    Outcome Measure Data

    Analysis Population Description
    Phase 2 participants who achieved overall remission. Data are censored at date of last known follow-up visit.
    Arm/Group Title Phase 2: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously
    Measure Participants 11
    Median (95% Confidence Interval) [weeks]
    67.3
    14. Secondary Outcome
    Title Kaplan Meier Estimates of Event-free Survival (EFS) for Participants in Phase 2
    Description Event-free survival (EFS) is defined as the time from date of first administration of study interventions until the earliest of the following: date of death or date of first response assessment confirming relapse or date of final response assessment which fails to confirm response, plus one day. For summary purposes, results are presented as weeks.
    Time Frame Up to 2 years (Phase 2 portion of study)

    Outcome Measure Data

    Analysis Population Description
    All phase 2 participants. Data are censored at date of last known follow-up visit.
    Arm/Group Title Phase 2: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously
    Measure Participants 25
    Median (95% Confidence Interval) [weeks]
    10.7
    15. Secondary Outcome
    Title Number of Participants With 4-month Event Free Survival in Phase 2
    Description Number of participants with event-free survival at four months post first dose of therapy. A participant is considered event-free if at month 4 they have not died or had a response assessment confirming a relapse.
    Time Frame 4 months (Phase 2 portion of study)

    Outcome Measure Data

    Analysis Population Description
    All participants
    Arm/Group Title Phase 2: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously.
    Measure Participants 25
    Number [participants]
    11
    44%
    16. Secondary Outcome
    Title Kaplan Meier Estimates of Overall Survival (OS) for Participants in Phase 2
    Description Overall survival is defined as the time from date of first administration of study interventions until date of death, plus one day. For summary purposes, results are presented as weeks.
    Time Frame Up to 2 years (Phase 2 portion of study)

    Outcome Measure Data

    Analysis Population Description
    All phase 2 participants. Data are censored at date of last known follow-up visit.
    Arm/Group Title Phase 2: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously
    Measure Participants 25
    Median (95% Confidence Interval) [weeks]
    10.7

    Adverse Events

    Time Frame Treatment emergent adverse experiences collected in Phase 1 from day 1 up to 9.5 months. Phase 2 also lasted up to 9.5 months and started after Phase 1.
    Adverse Event Reporting Description In the event a single participant has experienced both a serious and a non-serious form of the same adverse event term, the individual has been included in the numerator ("number of affected participants") of adverse event tables.
    Arm/Group Title Phase 1 - Cohort 1 Phase 1 - Cohort 2 Phase 1 - Cohort 3 Phase 1 - Cohort 4 Phase 1 - Cohort 5 Phase 1 - Total Phase 2: Clofarabine, Etoposide, Cyclophosphamide
    Arm/Group Description Participants were treated with clofarabine 20 mg/m^2, etoposide 75 mg/m^2, and cyclophosphamide 340 mg/m^2. Participants were treated with clofarabine 20 mg/m^2, etoposide 75 mg/m^2, and cyclophosphamide 440 mg/m^2. Participants were treated with clofarabine 20 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2. Participants were treated with clofarabine 30 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2. Participants were treated with clofarabine 40 mg/m^2, etoposide 100 mg/m^2, and cyclophosphamide 440 mg/m^2. All participants from Cohorts 1-5 in Phase 1 Phase 2: The recommended phase 2 doses (RP2D) were clofarabine 40 mg/m^2, etoposide 100 mg/m^2 and cyclophosphamide 440 mg/m^2 delivered intravenously.
    All Cause Mortality
    Phase 1 - Cohort 1 Phase 1 - Cohort 2 Phase 1 - Cohort 3 Phase 1 - Cohort 4 Phase 1 - Cohort 5 Phase 1 - Total Phase 2: Clofarabine, Etoposide, Cyclophosphamide
    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
    Phase 1 - Cohort 1 Phase 1 - Cohort 2 Phase 1 - Cohort 3 Phase 1 - Cohort 4 Phase 1 - Cohort 5 Phase 1 - Total Phase 2: Clofarabine, Etoposide, Cyclophosphamide
    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 3/3 (100%) 3/3 (100%) 3/3 (100%) 9/10 (90%) 6/6 (100%) 24/25 (96%) 21/25 (84%)
    Blood and lymphatic system disorders
    Anaemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Bone marrow failure 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Disseminated intravascular coagulation 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Febrile neutropenia 3/3 (100%) 1/3 (33.3%) 3/3 (100%) 7/10 (70%) 3/6 (50%) 17/25 (68%) 15/25 (60%)
    Leukocytosis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Lymphopenia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Neutropenia 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 2/6 (33.3%) 5/25 (20%) 0/25 (0%)
    Pancytopenia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Thrombocytopenia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Cardiac disorders
    Intracardiac mass 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Pericardial effusion 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Ventricular tachycardia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Eye disorders
    Trichiasis 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Gastrointestinal disorders
    Abdominal pain 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 1/25 (4%)
    Ascites 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Caecitis 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 3/10 (30%) 0/6 (0%) 4/25 (16%) 3/25 (12%)
    Diarrhoea 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Enteritis 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Gastritis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Gingival bleeding 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Oesophagitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Pancreatitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 2/25 (8%)
    Rectal fissure 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Vomiting 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    General disorders
    Chills 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Generalised oedema 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Mucosal inflammation 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/10 (20%) 0/6 (0%) 2/25 (8%) 0/25 (0%)
    Multi-organ failure 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Pyrexia 1/3 (33.3%) 0/3 (0%) 3/3 (100%) 2/10 (20%) 0/6 (0%) 6/25 (24%) 3/25 (12%)
    Hepatobiliary disorders
    Hyperbilirubinaemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 2/25 (8%)
    Venoocclusive liver disease 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 3/25 (12%)
    Immune system disorders
    Drug hypersensitivity 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Infections and infestations
    Acinetobacter bacteraemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Alpha haemolytic streptococcal infection 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 1/25 (4%)
    Bacteraemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/10 (20%) 0/6 (0%) 2/25 (8%) 0/25 (0%)
    Bacterial sepsis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    BK virus infection 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 3/25 (12%) 0/25 (0%)
    Bronchopulmonary aspergillosis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 2/25 (8%)
    Cellulitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Central nervous system infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Cerebral fungal infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Clostridial infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Clostridium difficile colitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Cystitis 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Cytomegalovirus viraemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Device related infection 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 2/6 (33.3%) 3/25 (12%) 2/25 (8%)
    Ear infection fungal 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Enterobacter bacteraemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Enterobacter infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Enterococcal bacteraemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Enterococcal sepsis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Escherichia bacteraemia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 2/25 (8%)
    Escherichia infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Herpes zoster 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Human herpesvirus 6 infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Klebsiella bacteraemia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Klebsiella infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Lobar pneumonia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Lung infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/10 (20%) 0/6 (0%) 2/25 (8%) 2/25 (8%)
    Meningitis bacterial 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Meningitis streptococcal 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Otitis media bacterial 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Pelvic abscess 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Perirectal abscess 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Pneumonia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 2/25 (8%)
    Pneumonia fungal 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Pulmonary mycosis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Sepsis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 1/25 (4%)
    Septic shock 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 4/25 (16%)
    Sinusitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Sinusitis fungal 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Staphylococcal bacteraemia 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 0/25 (0%)
    Staphylococcal infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 2/6 (33.3%) 3/25 (12%) 1/25 (4%)
    Staphylococcal sepsis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Streptococcal bacteraemia 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Streptococcal sepsis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Upper respiratory tract infection 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Urinary tract infection enterococcal 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 1/25 (4%)
    Viraemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Wound infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Wound infection staphylococcal 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Investigations
    Alanine aminotransferase increased 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 2/25 (8%)
    Aspartate aminotransferase increased 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 2/25 (8%)
    Blood creatine phosphokinase increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Fungal test positive 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Lipase increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/10 (20%) 0/6 (0%) 2/25 (8%) 1/25 (4%)
    Polyomavirus test positive 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Metabolism and nutrition disorders
    Decreased appetite 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Dehydration 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Hyperglycaemia 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Hypernatraemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Hyperuricaemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Hypokalaemia 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 2/25 (8%) 2/25 (8%)
    Hypophosphataemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Metabolic acidosis 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Tumour lysis syndrome 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 0/25 (0%)
    Nervous system disorders
    Cerebral haemorrhage 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Convulsion 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 2/25 (8%) 0/25 (0%)
    Encephalopathy 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Post herpetic neuralgia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Renal and urinary disorders
    Cystitis haemorrhagic 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Haematuria 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Renal failure 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Renal failure acute 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 3/25 (12%)
    Renal impairment 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Reproductive system and breast disorders
    Genital rash 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Hypoxia 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 3/25 (12%) 1/25 (4%)
    Pleural effusion 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 2/25 (8%) 1/25 (4%)
    Pneumothorax 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Pulmonary oedema 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Skin and subcutaneous tissue disorders
    Rash 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Vascular disorders
    Capillary leak syndrome 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 4/25 (16%)
    Hypotension 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 4/25 (16%)
    Venoocclusive disease 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Other (Not Including Serious) Adverse Events
    Phase 1 - Cohort 1 Phase 1 - Cohort 2 Phase 1 - Cohort 3 Phase 1 - Cohort 4 Phase 1 - Cohort 5 Phase 1 - Total Phase 2: Clofarabine, Etoposide, Cyclophosphamide
    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 3/3 (100%) 3/3 (100%) 3/3 (100%) 10/10 (100%) 6/6 (100%) 25/25 (100%) 25/25 (100%)
    Blood and lymphatic system disorders
    Anaemia 1/3 (33.3%) 1/3 (33.3%) 2/3 (66.7%) 1/10 (10%) 2/6 (33.3%) 7/25 (28%) 16/25 (64%)
    Bone marrow failure 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Coagulopathy 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 3/25 (12%)
    Disseminated intravascular coagulation 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Febrile neutropenia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 4/25 (16%)
    Leukopenia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 4/25 (16%)
    Lymphadenopathy 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Lymphopenia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Neutropenia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 2/10 (20%) 0/6 (0%) 3/25 (12%) 13/25 (52%)
    Pancytopenia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 2/25 (8%) 2/25 (8%)
    Splenomegaly 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/10 (30%) 0/6 (0%) 3/25 (12%) 2/25 (8%)
    Thrombocytopenia 1/3 (33.3%) 0/3 (0%) 2/3 (66.7%) 5/10 (50%) 3/6 (50%) 11/25 (44%) 16/25 (64%)
    Cardiac disorders
    Bradycardia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Cardiomyopathy 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Left ventricular dysfunction 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Left ventricular hypertrophy 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Palpitations 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Pericardial effusion 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 3/25 (12%) 3/25 (12%)
    Tachycardia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 3/10 (30%) 2/6 (33.3%) 6/25 (24%) 7/25 (28%)
    Tricuspid valve incompetence 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Ventricular extrasystoles 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Ear and labyrinth disorders
    Deafness 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Deafness neurosensory 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Deafness unilateral 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Ear pain 0/3 (0%) 0/3 (0%) 2/3 (66.7%) 1/10 (10%) 1/6 (16.7%) 4/25 (16%) 0/25 (0%)
    Mixed deafness 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Endocrine disorders
    Cushingoid 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Eye disorders
    Conjunctival hyperaemia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Conjunctivitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Diplopia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Dry eye 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 2/25 (8%) 0/25 (0%)
    Ectropion 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Exophthalmos 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Eye haemorrhage 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Eye pain 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Eye swelling 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Eyelid oedema 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Photophobia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Retinal exudates 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Retinopathy 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Scleral haemorrhage 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 1/25 (4%)
    Vision blurred 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Gastrointestinal disorders
    Abdominal distension 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 1/6 (16.7%) 2/25 (8%) 1/25 (4%)
    Abdominal pain 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 9/10 (90%) 2/6 (33.3%) 13/25 (52%) 7/25 (28%)
    Abdominal pain upper 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 2/10 (20%) 0/6 (0%) 3/25 (12%) 1/25 (4%)
    Anal fissure 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Ascites 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 3/25 (12%)
    Cheilitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Colitis 0/3 (0%) 2/3 (66.7%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 2/25 (8%) 1/25 (4%)
    Constipation 2/3 (66.7%) 1/3 (33.3%) 1/3 (33.3%) 4/10 (40%) 1/6 (16.7%) 9/25 (36%) 5/25 (20%)
    Dental caries 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 2/10 (20%) 2/6 (33.3%) 5/25 (20%) 1/25 (4%)
    Diarrhoea 2/3 (66.7%) 2/3 (66.7%) 1/3 (33.3%) 7/10 (70%) 5/6 (83.3%) 17/25 (68%) 7/25 (28%)
    Dry mouth 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Dyspepsia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Eructation 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Faecal incontinence 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Gastrointestinal haemorrhage 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Gastrooesophageal reflux disease 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 2/25 (8%) 1/25 (4%)
    Gingival bleeding 0/3 (0%) 0/3 (0%) 2/3 (66.7%) 1/10 (10%) 0/6 (0%) 3/25 (12%) 3/25 (12%)
    Gingival pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Haematemesis 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 3/25 (12%)
    Haematochezia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Haemorrhoids 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Intestinal dilatation 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Lip blister 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Lip dry 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Mouth haemorrhage 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 2/25 (8%) 1/25 (4%)
    Mouth ulceration 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/10 (20%) 0/6 (0%) 2/25 (8%) 0/25 (0%)
    Nausea 2/3 (66.7%) 2/3 (66.7%) 3/3 (100%) 9/10 (90%) 5/6 (83.3%) 21/25 (84%) 20/25 (80%)
    Oesophageal ulcer 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Oesophagitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Oral disorder 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 2/25 (8%)
    Oral pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 3/25 (12%)
    Oral pruritus 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Painful defaecation 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Pancreatic atrophy 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Pancreatitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 3/25 (12%)
    Perianal erythema 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Proctalgia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 1/6 (16.7%) 3/25 (12%) 3/25 (12%)
    Proctitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Rectal fissure 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Stomatitis 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 2/10 (20%) 0/6 (0%) 3/25 (12%) 3/25 (12%)
    Tongue discolouration 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Toothache 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Vomiting 2/3 (66.7%) 2/3 (66.7%) 3/3 (100%) 9/10 (90%) 6/6 (100%) 22/25 (88%) 22/25 (88%)
    General disorders
    Application site rash 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Catheter site erythema 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 2/25 (8%) 1/25 (4%)
    Catheter site haematoma 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Catheter site pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/10 (20%) 1/6 (16.7%) 3/25 (12%) 2/25 (8%)
    Catheter site rash 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Catheter site related reaction 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Chest pain 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Chills 1/3 (33.3%) 0/3 (0%) 2/3 (66.7%) 0/10 (0%) 1/6 (16.7%) 4/25 (16%) 4/25 (16%)
    Device occlusion 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Disease progression 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Face oedema 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Fatigue 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 2/10 (20%) 2/6 (33.3%) 6/25 (24%) 2/25 (8%)
    Feeling abnormal 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Generalised oedema 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 1/25 (4%)
    Hypothermia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Infusion site extravasation 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Injection site haemorrhage 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Irritability 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 0/25 (0%)
    Malaise 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Mucosal inflammation 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/10 (20%) 3/6 (50%) 5/25 (20%) 6/25 (24%)
    Non-cardiac chest pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 1/25 (4%)
    Oedema peripheral 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 2/25 (8%) 0/25 (0%)
    Pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 2/25 (8%) 2/25 (8%)
    Pneumatosis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Puncture site pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Pyrexia 2/3 (66.7%) 0/3 (0%) 1/3 (33.3%) 7/10 (70%) 5/6 (83.3%) 15/25 (60%) 13/25 (52%)
    Hepatobiliary disorders
    Cholecystitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Cholelithiasis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Cholestasis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Gallbladder disorder 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Hepatic steatosis 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Hepatomegaly 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 3/10 (30%) 0/6 (0%) 4/25 (16%) 5/25 (20%)
    Hepatosplenomegaly 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Hyperbilirubinaemia 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 0/6 (0%) 3/25 (12%) 6/25 (24%)
    Jaundice 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Immune system disorders
    Drug hypersensitivity 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/10 (20%) 0/6 (0%) 2/25 (8%) 0/25 (0%)
    Infections and infestations
    Acute sinusitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    BK virus infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Brain abscess 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Bronchopulmonary aspergillosis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Candidiasis 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/10 (30%) 0/6 (0%) 3/25 (12%) 0/25 (0%)
    Catheter site cellulitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Cellulitis 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 2/25 (8%) 2/25 (8%)
    Clostridial infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Conjunctivitis bacterial 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Conjunctivitis infective 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Ear infection 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Enterobacter bacteraemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Enterococcal bacteraemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Enterococcal infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Escherichia urinary tract infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Gastrointestinal candidiasis 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Herpes zoster 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Herpes zoster multi-dermatomal 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Keratitis herpetic 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Lung infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Onychomycosis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Oral candidiasis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Otitis media 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 0/25 (0%)
    Otitis media chronic 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Rhinitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 2/25 (8%) 0/25 (0%)
    Sinusitis 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 3/25 (12%)
    Sinusitis fungal 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Staphylococcal bacteraemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Staphylococcal infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Streptococcal sepsis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Tooth abscess 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Upper respiratory tract infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Urinary tract infection staphylococcal 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 0/25 (0%)
    Viral upper respiratory tract infection 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Wound infection staphylococcal 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Injury, poisoning and procedural complications
    Allergic transfusion reaction 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Contusion 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 2/25 (8%)
    Excoriation 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Head injury 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Incision site haemorrhage 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Joint injury 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Joint sprain 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Post lumbar puncture syndrome 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Post procedural haemorrhage 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Postoperative wound complication 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Procedural pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/10 (20%) 2/6 (33.3%) 4/25 (16%) 3/25 (12%)
    Skin laceration 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Transfusion reaction 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 2/25 (8%)
    Wound 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Investigations
    Alanine aminotransferase increased 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 3/25 (12%) 8/25 (32%)
    Antimicrobial susceptibility test sensitive 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Aspartate aminotransferase increased 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 2/25 (8%) 11/25 (44%)
    Bacterial test positive 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Blood albumin decreased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Blood amylase increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Blood bicarbonate decreased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Blood creatinine increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Blood glucose increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Blood lactate dehydrogenase increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Blood phosphorus increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Blood pressure increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Blood urea increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Brain natriuretic peptide increased 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Cardiac murmur 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 2/25 (8%) 0/25 (0%)
    Coagulation test abnormal 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Culture stool positive 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Fibrin d dimer increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Fungal test positive 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Haemoglobin decreased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 1/25 (4%)
    Lipase increased 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 2/25 (8%) 5/25 (20%)
    Occult blood positive 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 1/6 (16.7%) 2/25 (8%) 1/25 (4%)
    Polyomavirus test positive 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Protein total decreased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Prothrombin time prolonged 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 2/25 (8%)
    Serum ferritin increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Specific gravity urine abnormal 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Specific gravity urine increased 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 2/25 (8%) 0/25 (0%)
    Urine ketone body 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Urine output decreased 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 2/25 (8%) 0/25 (0%)
    Weight decreased 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Metabolism and nutrition disorders
    Decreased appetite 1/3 (33.3%) 0/3 (0%) 2/3 (66.7%) 5/10 (50%) 4/6 (66.7%) 12/25 (48%) 15/25 (60%)
    Dehydration 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Fluid imbalance 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 3/25 (12%) 1/25 (4%)
    Fluid overload 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Fluid retention 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Hypercalcaemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Hyperglycaemia 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 0/6 (0%) 3/25 (12%) 4/25 (16%)
    Hyperkalaemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Hypermagnesaemia 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 2/25 (8%) 0/25 (0%)
    Hypernatraemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Hyperphosphataemia 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 2/25 (8%) 4/25 (16%)
    Hypertriglyceridaemia 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 1/25 (4%)
    Hyperuricaemia 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Hypoalbuminaemia 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 2/25 (8%) 3/25 (12%)
    Hypocalcaemia 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 3/25 (12%) 6/25 (24%)
    Hypoglycaemia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Hypokalaemia 1/3 (33.3%) 2/3 (66.7%) 1/3 (33.3%) 6/10 (60%) 1/6 (16.7%) 11/25 (44%) 15/25 (60%)
    Hypomagnesaemia 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 3/10 (30%) 1/6 (16.7%) 5/25 (20%) 5/25 (20%)
    Hyponatraemia 1/3 (33.3%) 1/3 (33.3%) 1/3 (33.3%) 1/10 (10%) 2/6 (33.3%) 6/25 (24%) 7/25 (28%)
    Hypophosphataemia 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 3/25 (12%) 8/25 (32%)
    Metabolic acidosis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Polydipsia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 5/25 (20%)
    Back pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/10 (20%) 1/6 (16.7%) 3/25 (12%) 1/25 (4%)
    Bone pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 1/25 (4%)
    Flank pain 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Muscle fatigue 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Muscle twitching 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Musculoskeletal chest pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Musculoskeletal pain 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 4/25 (16%)
    Myalgia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Neck pain 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 2/10 (20%) 1/6 (16.7%) 4/25 (16%) 0/25 (0%)
    Osteopenia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 3/25 (12%)
    Pain in extremity 1/3 (33.3%) 0/3 (0%) 2/3 (66.7%) 5/10 (50%) 3/6 (50%) 11/25 (44%) 6/25 (24%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Malignant neoplasm progression 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Penile wart 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Nervous system disorders
    Amnesia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Cerebral thrombosis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Depressed level of consciousness 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Dizziness 0/3 (0%) 0/3 (0%) 2/3 (66.7%) 4/10 (40%) 1/6 (16.7%) 7/25 (28%) 2/25 (8%)
    Dysaesthesia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Headache 1/3 (33.3%) 0/3 (0%) 2/3 (66.7%) 7/10 (70%) 4/6 (66.7%) 14/25 (56%) 9/25 (36%)
    Hydrocephalus 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Lethargy 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Paraesthesia 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Peripheral sensory neuropathy 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Somnolence 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Syncope 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Tremor 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Psychiatric disorders
    Agitation 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 2/25 (8%) 2/25 (8%)
    Anxiety 1/3 (33.3%) 1/3 (33.3%) 2/3 (66.7%) 4/10 (40%) 2/6 (33.3%) 10/25 (40%) 3/25 (12%)
    Depression 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Hallucination 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Insomnia 1/3 (33.3%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 1/6 (16.7%) 4/25 (16%) 3/25 (12%)
    Mental status changes 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Panic attack 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Psychotic disorder 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Social avoidant behaviour 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Renal and urinary disorders
    Dysuria 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/10 (20%) 0/6 (0%) 2/25 (8%) 0/25 (0%)
    Haematuria 1/3 (33.3%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 2/6 (33.3%) 4/25 (16%) 6/25 (24%)
    Haemoglobinuria 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Kidney enlargement 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Micturition urgency 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Oliguria 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Proteinuria 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Renal failure acute 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Urinary bladder haemorrhage 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Reproductive system and breast disorders
    Balanitis 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Breast pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Epididymal cyst 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Genital pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Genital rash 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Metrorrhagia 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Pelvic haematoma 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Pelvic pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Vulvovaginal pruritus 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Alveolitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Atelectasis 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Cough 0/3 (0%) 1/3 (33.3%) 1/3 (33.3%) 2/10 (20%) 3/6 (50%) 7/25 (28%) 5/25 (20%)
    Dyspnoea 1/3 (33.3%) 2/3 (66.7%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 4/25 (16%) 4/25 (16%)
    Epistaxis 0/3 (0%) 0/3 (0%) 3/3 (100%) 3/10 (30%) 1/6 (16.7%) 7/25 (28%) 4/25 (16%)
    Haemoptysis 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Hiccups 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Hypoxia 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 1/6 (16.7%) 2/25 (8%) 0/25 (0%)
    Lung infiltration 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Nasal congestion 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 3/6 (50%) 3/25 (12%) 2/25 (8%)
    Oropharyngeal pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/10 (30%) 2/6 (33.3%) 5/25 (20%) 0/25 (0%)
    Painful respiration 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/10 (20%) 1/6 (16.7%) 3/25 (12%) 1/25 (4%)
    Pleural effusion 0/3 (0%) 0/3 (0%) 0/3 (0%) 2/10 (20%) 0/6 (0%) 2/25 (8%) 1/25 (4%)
    Pleuritic pain 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Pneumonitis 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Pneumothorax 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Productive cough 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Pulmonary oedema 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 1/25 (4%)
    Rhinorrhoea 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 1/6 (16.7%) 3/25 (12%) 4/25 (16%)
    Sinus congestion 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Sinus disorder 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Sleep apnoea syndrome 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Tachypnoea 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 2/25 (8%)
    Upper respiratory tract congestion 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Wheezing 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Skin and subcutaneous tissue disorders
    Acanthosis 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Alopecia 0/3 (0%) 0/3 (0%) 2/3 (66.7%) 3/10 (30%) 1/6 (16.7%) 6/25 (24%) 4/25 (16%)
    Blister 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Decubitus ulcer 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 2/25 (8%)
    Dermatitis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Drug eruption 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Dry skin 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 1/25 (4%)
    Ecchymosis 0/3 (0%) 0/3 (0%) 2/3 (66.7%) 1/10 (10%) 1/6 (16.7%) 4/25 (16%) 2/25 (8%)
    Eczema 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Erythema 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 6/25 (24%)
    Exfoliative rash 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Hyperhidrosis 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Palmar-plantar erythrodysaesthesia syndrome 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Periorbital oedema 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Petechiae 0/3 (0%) 0/3 (0%) 0/3 (0%) 3/10 (30%) 0/6 (0%) 3/25 (12%) 3/25 (12%)
    Pruritus 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 5/10 (50%) 2/6 (33.3%) 8/25 (32%) 6/25 (24%)
    Pruritus generalised 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Rash 0/3 (0%) 2/3 (66.7%) 2/3 (66.7%) 6/10 (60%) 4/6 (66.7%) 14/25 (56%) 4/25 (16%)
    Rash macular 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Rash papular 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 1/6 (16.7%) 2/25 (8%) 0/25 (0%)
    Red man syndrome 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Skin discolouration 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 0/25 (0%) 1/25 (4%)
    Skin disorder 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Skin exfoliation 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Skin hyperpigmentation 0/3 (0%) 1/3 (33.3%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 2/25 (8%) 1/25 (4%)
    Skin lesion 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Skin ulcer 1/3 (33.3%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Vascular disorders
    Flushing 0/3 (0%) 0/3 (0%) 0/3 (0%) 1/10 (10%) 0/6 (0%) 1/25 (4%) 0/25 (0%)
    Haematoma 0/3 (0%) 0/3 (0%) 0/3 (0%) 0/10 (0%) 1/6 (16.7%) 1/25 (4%) 0/25 (0%)
    Hypertension 0/3 (0%) 0/3 (0%) 1/3 (33.3%) 1/10 (10%) 0/6 (0%) 2/25 (8%) 2/25 (8%)
    Hypotension 0/3 (0%) 0/3 (0%) 2/3 (66.7%) 5/10 (50%) 2/6 (33.3%) 9/25 (36%) 11/25 (44%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    In multi-site studies, PI can publish after Genzyme publishes or 18 months after study completion. PI gives Genzyme a draft 60 days before publication. Genzyme can ask that confidential information be removed, and can defer publication another 60 days upon notifying PI that it will file a patent application on inventions contained in the draft.

    Results Point of Contact

    Name/Title Genzyme Medical Information
    Organization Genzyme Corporation
    Phone 1-800-745-4447
    Email
    Responsible Party:
    Genzyme, a Sanofi Company
    ClinicalTrials.gov Identifier:
    NCT00315705
    Other Study ID Numbers:
    • CLO21800205
    First Posted:
    Apr 19, 2006
    Last Update Posted:
    Apr 14, 2014
    Last Verified:
    Mar 1, 2014