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Study to Find a Safe Dose and Show Early Clinical Activity of Weekly Nab-paclitaxel in Pediatric Patients With Recurrent/ Refractory Solid Tumors

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ClinicalTrials.gov Identifier: NCT01962103
Recruitment Status : Completed
First Posted : October 14, 2013
Results First Posted : December 27, 2018
Last Update Posted : December 27, 2019
Sponsor:
Information provided by (Responsible Party):
Celgene

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Neuroblastoma
Rhabdomyosarcoma
Ewing's Sarcoma
Ewing's Tumor
Sarcoma, Ewing's
Sarcomas, Epitheliod
Sarcoma, Soft Tissue
Sarcoma, Spindle Cell
Melanoma
Malignant Melanoma
Clinical Oncology
Oncology, Medical
Pediatrics, Osteosarcoma
Osteogenic Sarcoma
Osteosarcoma Tumor
Sarcoma, Osteogenic
Tumors
Cancer
Neoplasia
Neoplasm
Histiocytoma
Fibrosarcoma
Dermatofibrosarcoma
Intervention Drug: nab-paclitaxel
Enrollment 107
Recruitment Details  
Pre-assignment Details Sixty-five participants were included in the Phase 1 enrolled population, and 64 enrolled partcipants received at least 1 dose of study drug and were included in the safety population, noted below. Forty-two participants were included in the Phase 2 enrolled and safety populations.
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2 Phase 2: Ewing's Sarcoma Phase 2: Neuroblastoma Phase 2: Rhabdomyosarcoma
Hide Arm/Group Description nab-paclitaxel 120 mg/m^2 intravenously (IV) on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the recommended phase 2 dose (RP2D). nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. Participants with Ewing's sarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity. Participants with neuroblastoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity. Participants with rhabdomyosarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Period Title: Phase 1
Started 16 8 14 11 8 7 0 0 0
Completed 0 0 0 0 0 0 0 0 0
Not Completed 16 8 14 11 8 7 0 0 0
Reason Not Completed
Adverse Event             4             0             2             1             2             2             0             0             0
Progressive Disease             8             6             8             4             5             4             0             0             0
Withdrawal by Subject             0             0             0             2             0             0             0             0             0
Withdrawal by Parent/Guardian             0             0             2             1             0             0             0             0             0
Physician Decision             0             0             0             1             0             0             0             0             0
Symptomatic Deterioration             3             2             2             2             1             1             0             0             0
Miscellaneous             1             0             0             0             0             0             0             0             0
Period Title: Phase 2
Started 0 0 0 0 0 0 14 14 14
Completed 0 0 0 0 0 0 0 [1] 0 [1] 0 [1]
Not Completed 0 0 0 0 0 0 14 14 14
Reason Not Completed
Adverse Event             0             0             0             0             0             0             1             0             3
Progressive Disease             0             0             0             0             0             0             11             12             11
Symptomatic Deterioration             0             0             0             0             0             0             2             2             0
[1]
completed treatment
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2 Phase 2: Ewing's Sarcoma Phase 2: Neuroblastoma Phase 2: Rhabdomyosarcoma Total
Hide Arm/Group Description nab-paclitaxel 120 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. Participants with Ewing's sarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity. Participants with neuroblastoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity. Participants with rhabdomyosarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity. Total of all reporting groups
Overall Number of Baseline Participants 16 8 14 11 8 7 14 14 14 106
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 16 participants 8 participants 14 participants 11 participants 8 participants 7 participants 14 participants 14 participants 14 participants 106 participants
11.7  (3.32) 12.1  (5.84) 10.2  (4.64) 10.2  (5.36) 11.6  (4.63) 12.1  (2.97) 10.1  (4.63) 7.1  (3.42) 12.4  (6.42) 10.7  (4.81)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 8 participants 14 participants 11 participants 8 participants 7 participants 14 participants 14 participants 14 participants 106 participants
Female
9
  56.3%
4
  50.0%
9
  64.3%
7
  63.6%
1
  12.5%
3
  42.9%
6
  42.9%
5
  35.7%
9
  64.3%
53
  50.0%
Male
7
  43.8%
4
  50.0%
5
  35.7%
4
  36.4%
7
  87.5%
4
  57.1%
8
  57.1%
9
  64.3%
5
  35.7%
53
  50.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 8 participants 14 participants 11 participants 8 participants 7 participants 14 participants 14 participants 14 participants 106 participants
Hispanic or Latino
2
  12.5%
3
  37.5%
1
   7.1%
1
   9.1%
3
  37.5%
0
   0.0%
0
   0.0%
2
  14.3%
5
  35.7%
17
  16.0%
Not Hispanic or Latino
6
  37.5%
5
  62.5%
7
  50.0%
10
  90.9%
5
  62.5%
5
  71.4%
11
  78.6%
8
  57.1%
8
  57.1%
65
  61.3%
Unknown or Not Reported
8
  50.0%
0
   0.0%
6
  42.9%
0
   0.0%
0
   0.0%
2
  28.6%
3
  21.4%
4
  28.6%
1
   7.1%
24
  22.6%
Race/Ethnicity, Customized  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 8 participants 14 participants 11 participants 8 participants 7 participants 14 participants 14 participants 14 participants 106 participants
White
11
  68.8%
8
 100.0%
9
  64.3%
9
  81.8%
8
 100.0%
5
  71.4%
11
  78.6%
11
  78.6%
12
  85.7%
84
  79.2%
Not Collected or Reported
5
  31.3%
0
   0.0%
5
  35.7%
0
   0.0%
0
   0.0%
1
  14.3%
3
  21.4%
3
  21.4%
1
   7.1%
18
  17.0%
Other, Not Specified
0
   0.0%
0
   0.0%
0
   0.0%
2
  18.2%
0
   0.0%
1
  14.3%
0
   0.0%
0
   0.0%
0
   0.0%
3
   2.8%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   7.1%
1
   0.9%
Participants With Any Prior Cancer Treatment  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 16 participants 8 participants 14 participants 11 participants 8 participants 7 participants 14 participants 14 participants 14 participants 106 participants
Any Prior Cancer Treatment
16
 100.0%
8
 100.0%
14
 100.0%
11
 100.0%
8
 100.0%
7
 100.0%
14
 100.0%
14
 100.0%
14
 100.0%
106
 100.0%
Prior Radiation Therapy
9
  56.3%
4
  50.0%
11
  78.6%
7
  63.6%
6
  75.0%
6
  85.7%
12
  85.7%
10
  71.4%
10
  71.4%
75
  70.8%
Prior Cancer Surgeries
14
  87.5%
7
  87.5%
9
  64.3%
9
  81.8%
5
  62.5%
7
 100.0%
10
  71.4%
11
  78.6%
6
  42.9%
78
  73.6%
Prior Systemic Anticancer Therapy
16
 100.0%
8
 100.0%
14
 100.0%
11
 100.0%
8
 100.0%
7
 100.0%
14
 100.0%
14
 100.0%
14
 100.0%
106
 100.0%
Prior Systemic Anticancer Regimens
16
 100.0%
8
 100.0%
14
 100.0%
11
 100.0%
8
 100.0%
7
 100.0%
14
 100.0%
14
 100.0%
14
 100.0%
106
 100.0%
Prior Stem Cell Transplants
2
  12.5%
2
  25.0%
3
  21.4%
2
  18.2%
3
  37.5%
2
  28.6%
3
  21.4%
10
  71.4%
0
   0.0%
27
  25.5%
Other Prior Anticancer Therapies
2
  12.5%
0
   0.0%
1
   7.1%
3
  27.3%
2
  25.0%
0
   0.0%
1
   7.1%
6
  42.9%
0
   0.0%
15
  14.2%
Number of Prior Systemic Anticancer Regimens Received  
Mean (Standard Deviation)
Unit of measure:  Systemic anticancer regimens
Number Analyzed 16 participants 8 participants 14 participants 11 participants 8 participants 7 participants 14 participants 14 participants 14 participants 106 participants
3.69  (1.815) 3.25  (1.832) 3.64  (1.946) 3.64  (2.461) 3.00  (1.309) 3.00  (0.816) 2.50  (0.519) 2.14  (0.663) 2.21  (0.579) 2.99  (1.552)
1.Primary Outcome
Title Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)
Hide Description A DLT was defined as investigational product (IP)-related adverse events occurring during the DLT assessment period that led to treatment discontinuation or met one of the following criteria: - Common Terminology Criteria for Adverse Events (CTCAE) Grade (Gr) 3 or 4 nonhematologic toxicity (excluding transient transaminitis) - CTCAE Gr 3 or 4 nausea or vomiting that persisted > 5 days despite maximal anti-emetic treatment - CTCAE Gr 4 thrombocytopenia or anemia that persisted > 7 days or required transfusion > 7 days - CTCAE Gr 3 thrombocytopenia with bleeding - CTCAE Gr 4 uncomplicated neutropenia lasting > 7 days - Febrile neutropenia with confirmed bacterial infection - CTCAE Gr 3 hematologic toxicity requiring treatment (tx) delay > 21 days. Use of "..." in the table rows signifies the continuation of row title per the above list.
Time Frame DLT assessment period: For participants > 10 kg: the first 28-day cycle including Cycle 2 Day 1 predose evaluations; for participants ≤ 10 kg: the first two 28-day cycles including Cycle 3 Day 1 predose evaluations
Hide Outcome Measure Data
Hide Analysis Population Description
Dose Determining Set (DDS): all Phase 1 participants who received all 3 weekly doses of nab-paclitaxel at the cohort planned dose during Cycle 1 and had adequate safety assessments during the DLT assessment period or experienced a DLT. The DDS did not include participants who were enrolled at each dose once the dose had been determined to be safe.
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2
Hide Arm/Group Description:
nab-paclitaxel 120 mg/m^2 intravenously (IV) on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the recommended phase 2 dose (RP2D).
nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
Overall Number of Participants Analyzed 6 6 6 6 6 7
Measure Type: Count of Participants
Unit of Measure: Participants
At least 1 DLT
1
  16.7%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  14.3%
Gr 3/4 Nonhematologic Toxicity...
1
  16.7%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Gr 3/4 Nausea or Vomiting Persisting >5 days...
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Gr 4 Thrombocytopenia/Anemia Persisting >7 days...
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Gr 3 Thrombocytopenia with Bleeding
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Gr 4 Uncomplicated Neutropenia Lasting >7 days
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  14.3%
Febrile Neutropenia+Confirmed Bacterial Infection
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Gr3 Hematologic Toxicity Requiring Tx Delay...
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
2.Primary Outcome
Title Phase 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Hide Description An adverse event (AE) was defined as any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. A serious AE (SAE) is any AE occurring at any dose that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. TEAEs were defined as AEs that began or worsened in severity on or after the date of the first dose of study drug and within 28 days of the date of the last dose of study drug. The severity of an AE was graded according to the CTCAE, Version 4.0.
Time Frame Median treatment duration in Phase 1 was 7.0 weeks, with minimum and maximum duration of 1 and 49 weeks, respectively. Participants were followed for 28 days after discontinuing treatment for safety and monitoring of AEs.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Population: all participants who took at least 1 dose of study drug.
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2
Hide Arm/Group Description:
nab-paclitaxel 120 mg/m^2 intravenously (IV) on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the recommended phase 2 dose (RP2D).
nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
Overall Number of Participants Analyzed 16 8 14 11 8 7
Measure Type: Count of Participants
Unit of Measure: Participants
TEAE
16
 100.0%
8
 100.0%
14
 100.0%
11
 100.0%
8
 100.0%
7
 100.0%
Treatment-related (TR) TEAE
14
  87.5%
8
 100.0%
12
  85.7%
11
 100.0%
7
  87.5%
7
 100.0%
Grade 3 or 4 TEAE
13
  81.3%
8
 100.0%
10
  71.4%
10
  90.9%
8
 100.0%
7
 100.0%
TR Grade 3 or 4 TEAE
9
  56.3%
7
  87.5%
7
  50.0%
9
  81.8%
7
  87.5%
7
 100.0%
Serious TEAE
10
  62.5%
7
  87.5%
6
  42.9%
5
  45.5%
3
  37.5%
4
  57.1%
TR Serious TEAE
1
   6.3%
4
  50.0%
4
  28.6%
2
  18.2%
1
  12.5%
3
  42.9%
TEAE Leading to Drug Discontinuation
4
  25.0%
0
   0.0%
2
  14.3%
1
   9.1%
2
  25.0%
2
  28.6%
TR TEAE Leading to Drug Discontinuation
1
   6.3%
0
   0.0%
0
   0.0%
1
   9.1%
2
  25.0%
2
  28.6%
TEAE Leading to Dose Reduction
0
   0.0%
1
  12.5%
2
  14.3%
1
   9.1%
3
  37.5%
3
  42.9%
TR TEAE Leading to Dose Reduction
0
   0.0%
1
  12.5%
2
  14.3%
1
   9.1%
3
  37.5%
3
  42.9%
TEAE Leading to Drug Interruption
2
  12.5%
2
  25.0%
3
  21.4%
4
  36.4%
3
  37.5%
2
  28.6%
TR TEAE Leading to Drug Interruption
0
   0.0%
2
  25.0%
1
   7.1%
3
  27.3%
3
  37.5%
2
  28.6%
TEAE Leading to Death
2
  12.5%
1
  12.5%
0
   0.0%
0
   0.0%
1
  12.5%
1
  14.3%
TR TEAE Leading to Death
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
3.Primary Outcome
Title Phase 2: Overall Response Rate (ORR)
Hide Description Overall response rate was defined as the percentage of participants who achieved a complete response (CR; disappearance of all target lesions) or partial response (PR; at least a 30% decrease in the sum of diameters of target lesions) confirmed no less than 4 weeks after the criteria for response were first met using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. (For Phase 2 neuroblastoma participants who had both RECIST and Curie Score tumor evaluations, both tumor response results were considered and an overall response was derived.) Confidence interval was obtained using the Clopper-Pearson method.
Time Frame Median treatment duration in Phase 2 per group: Ewings Sarcoma = 14 weeks (3-31), Neuroblastoma = 7 weeks (3-23), Rhabdomyosarcoma = 5 weeks (1-13).
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Hide Analysis Population Description
Efficacy Evaluable Population: participants who met eligibility criteria for Phase 2, completed at least 1 dose of study drug, and had baseline and at least 1 postbaseline efficacy assessment if having not discontinued the investigational product prior to postbaseline efficacy assessment due to disease progression or systematic deterioration.
Arm/Group Title Phase 2: Ewing's Sarcoma Phase 2: Neuroblastoma Phase 2: Rhabdomyosarcoma
Hide Arm/Group Description:
Participants with Ewing's sarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Participants with neuroblastoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Participants with rhabdomyosarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Overall Number of Participants Analyzed 13 14 14
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
0
(0.0 to 24.7)
0
(0.0 to 23.2)
7.1
(0.2 to 33.9)
4.Secondary Outcome
Title Phase 1: ORR
Hide Description Overall response rate was defined as the percentage of participants who achieved a complete response (CR; disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions) confirmed no less than 4 weeks after the criteria for response were first met) using RECIST version 1.1 guidelines over the total number of participants available for the analysis. Confidence interval was obtained using the Clopper-Pearson method.
Time Frame Median treatment duration in Phase 1 was 7.0 weeks, with minimum and maximum duration of 1 and 49 weeks, respectively.
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Hide Analysis Population Description
Efficacy Evaluable Population: participants who met eligibility criteria for Phase 1, completed at least 1 dose of study drug, and had baseline and at least 1 postbaseline efficacy assessment if having not discontinued the investigational product prior to postbaseline efficacy assessment due to disease progression or systematic deterioration.
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2
Hide Arm/Group Description:
nab-paclitaxel 120 mg/m^2 intravenously (IV) on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the recommended phase 2 dose (RP2D).
nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
Overall Number of Participants Analyzed 14 8 12 10 8 7
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
0
(0.0 to 23.2)
0
(0.0 to 36.9)
0
(0.0 to 26.5)
0
(0.0 to 30.8)
12.5
(0.3 to 52.7)
14.3
(0.4 to 57.9)
5.Secondary Outcome
Title Phase 1: Maximum Observed Concentration of Paclitaxel in Blood Plasma (Cmax)
Hide Description [Not Specified]
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants <6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
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Hide Analysis Population Description
Pharmacokinetic (PK) population: all participannts who received at least one dose of nab-paclitaxel and had evaluable concentration data.
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2
Hide Arm/Group Description:
nab-paclitaxel 120 mg/m^2 intravenously (IV) on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the recommended phase 2 dose (RP2D).
nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
Overall Number of Participants Analyzed 13 7 12 9 7 6
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
3488
(73.7%)
5468
(38.0%)
5597
(33.4%)
5616
(63.9%)
7831
(23.1%)
8078
(41.5%)
6.Secondary Outcome
Title Phase 1: Cmax - Dose-Normalized
Hide Description [Not Specified]
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants <6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
Hide Outcome Measure Data
Hide Analysis Population Description
PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data.
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2
Hide Arm/Group Description:
nab-paclitaxel 120 mg/m^2 intravenously (IV) on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the recommended phase 2 dose (RP2D).
nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
Overall Number of Participants Analyzed 13 7 12 9 7 6
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL/[mg]
23.3
(87.5%)
25.4
(46.6%)
27.3
(47.3%)
23.2
(80.3%)
28.2
(48.7%)
21.0
(46.6%)
7.Secondary Outcome
Title Phase 1: Area Under the Plasma Concentration-Time Curve (AUC)
Hide Description Measurements include: AUC from time zero to the last measurable concentration (AUCt), AUC from time zero to 24 hours (AUC24), and AUC from time zero to infinity (AUCinf).
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants <6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
Hide Outcome Measure Data
Hide Analysis Population Description
PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data for given measure.
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2
Hide Arm/Group Description:
nab-paclitaxel 120 mg/m^2 intravenously (IV) on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the recommended phase 2 dose (RP2D).
nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
Overall Number of Participants Analyzed 13 7 12 9 7 6
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL
AUCt Number Analyzed 13 participants 7 participants 12 participants 9 participants 7 participants 6 participants
7844
(73.4%)
10374
(91.8%)
9690
(37.1%)
11817
(64.0%)
12706
(29.2%)
11245
(22.6%)
AUC24 Number Analyzed 13 participants 7 participants 12 participants 8 participants 7 participants 6 participants
6392
(79.0%)
8944
(85.9%)
8365
(37.7%)
10932
(66.3%)
11167
(27.4%)
9768
(20.7%)
AUCinf Number Analyzed 9 participants 6 participants 10 participants 6 participants 6 participants 5 participants
8867
(85.4%)
11992
(99.8%)
10087
(38.4%)
14361
(72.1%)
14242
(29.2%)
12424
(28.5%)
8.Secondary Outcome
Title Phase 1: AUC - Dose-Normalized
Hide Description Measurements include: AUC24 and AUCinf.
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants <6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
Hide Outcome Measure Data
Hide Analysis Population Description
PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data for given measure.
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2
Hide Arm/Group Description:
nab-paclitaxel 120 mg/m^2 intravenously (IV) on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the recommended phase 2 dose (RP2D).
nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
Overall Number of Participants Analyzed 13 7 12 8 7 6
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng*h/mL/[mg]
AUC24 Number Analyzed 13 participants 7 participants 12 participants 8 participants 7 participants 6 participants
42.7
(77.4%)
41.6
(87.0%)
40.8
(39.7%)
43.3
(63.6%)
40.2
(65.4%)
25.4
(26.1%)
AUCinf Number Analyzed 9 participants 6 participants 10 participants 6 participants 6 participants 5 participants
62.0
(75.7%)
49.2
(101%)
47.8
(39.8%)
64.8
(25.4%)
52.3
(67.4%)
31.3
(34.9%)
9.Secondary Outcome
Title Phase 1: Clearance (CL)
Hide Description Measurement of renal clearance from the body.
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants <6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
Hide Outcome Measure Data
Hide Analysis Population Description
PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data.
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2
Hide Arm/Group Description:
nab-paclitaxel 120 mg/m^2 intravenously (IV) on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the recommended phase 2 dose (RP2D).
nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
Overall Number of Participants Analyzed 9 6 10 6 6 5
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L/h
16.1
(75.6%)
20.3
(101%)
20.9
(39.9%)
15.4
(25.4%)
19.1
(67.4%)
31.9
(35.0%)
10.Secondary Outcome
Title Phase 1: CL - Body Surface Area (BSA)-Normalized
Hide Description Measurement of renal clearance from the body.
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants <6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
Hide Outcome Measure Data
Hide Analysis Population Description
PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data.
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2
Hide Arm/Group Description:
nab-paclitaxel 120 mg/m^2 intravenously (IV) on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the recommended phase 2 dose (RP2D).
nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
Overall Number of Participants Analyzed 9 6 10 6 6 5
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L/h/m^2
13.5
(85.1%)
12.5
(99.3%)
17.8
(38.3%)
14.6
(72.3%)
16.7
(29.2%)
21.8
(28.4%)
11.Secondary Outcome
Title Phase 1: Volume of Distribution (Vss)
Hide Description [Not Specified]
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants <6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
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Hide Analysis Population Description
PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data.
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2
Hide Arm/Group Description:
nab-paclitaxel 120 mg/m^2 intravenously (IV) on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the recommended phase 2 dose (RP2D).
nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
Overall Number of Participants Analyzed 9 6 10 6 6 5
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liters
127
(145%)
266
(78.3%)
146
(106%)
89.8
(45.1%)
175
(117%)
446
(17.6%)
12.Secondary Outcome
Title Phase 1: Vss - BSA-Normalized
Hide Description [Not Specified]
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants <6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
Hide Outcome Measure Data
Hide Analysis Population Description
PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data.
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2
Hide Arm/Group Description:
nab-paclitaxel 120 mg/m^2 intravenously (IV) on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the recommended phase 2 dose (RP2D).
nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D.
Overall Number of Participants Analyzed 9 6 10 6 6 5
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L/m^2
106
(95.3%)
164
(78.4%)
124
(82.8%)
84.9
(49.7%)
154
(56.5%)
304
(29.0%)
13.Secondary Outcome
Title Phase 1 and 2 Population PK: Volume of Distribution of the Central Compartment (V1)
Hide Description Population PK analysis was performed using nonlinear mixed effect modeling. The estimated allometric function for V1 was 0.888.
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants < 6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
Hide Outcome Measure Data
Hide Analysis Population Description
PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data.
Arm/Group Title PK Population
Hide Arm/Group Description:
Phase 1: nab-paclitaxel 120-270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. Phase 2: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Overall Number of Participants Analyzed 106
Measure Type: Number
Unit of Measure: liters
11.8
14.Secondary Outcome
Title Phase 1 and 2 Population PK: Maximum Elimination Rate From the Central Compartment (VMEL)
Hide Description Population PK analysis was performed using nonlinear mixed effect modeling. The estimated allometric function for VMEL was 1.12.
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants < 6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
Hide Outcome Measure Data
Hide Analysis Population Description
PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data
Arm/Group Title PK Population
Hide Arm/Group Description:
The PK population included all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data.
Overall Number of Participants Analyzed 106
Measure Type: Number
Unit of Measure: μg/h
31983
15.Secondary Outcome
Title Phase 1 and 2 Population PK: Concentration in the Central Compartment at 50% of VMEL (KMEL)
Hide Description Population PK analysis was performed using nonlinear mixed effect modeling.
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants < 6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
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PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data
Arm/Group Title PK Population
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Phase 1: nab-paclitaxel 120-270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. Phase 2: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Overall Number of Participants Analyzed 106
Measure Type: Number
Unit of Measure: μg/L
951
16.Secondary Outcome
Title Phase 1 and 2 Population PK: Intercompartmental CL Between the Central Compartment and the First Peripheral Compartment (Q2)
Hide Description Population PK analysis was performed using nonlinear mixed effect modeling. The estimated allometric function for Q2 was 1.12.
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants < 6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
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PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data.
Arm/Group Title PK Population
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Phase 1: nab-paclitaxel 120-270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. Phase 2: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Overall Number of Participants Analyzed 106
Measure Type: Number
Unit of Measure: L/h
22.4
17.Secondary Outcome
Title Phase 1 and 2 Population PK: Intercompartmental CL Between the Central Compartment and the Second Peripheral Compartment (Q3)
Hide Description Population PK analysis was performed using nonlinear mixed effect modeling. The estimated allometric function for Q3 was 1.12.
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants < 6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
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PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data.
Arm/Group Title PK Population
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Phase 1: nab-paclitaxel 120-270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. Phase 2: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Overall Number of Participants Analyzed 106
Measure Type: Number
Unit of Measure: L/h
34.8
18.Secondary Outcome
Title Phase 1 and 2 Population PK: Volume of Distribution of the First Peripheral Compartment (V2)
Hide Description Population PK analysis was performed using nonlinear mixed effect modeling. The estimated allometric function for V2 was 0.888.
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants < 6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
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PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data.
Arm/Group Title PK Population
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Phase 1: nab-paclitaxel 120-270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. Phase 2: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Overall Number of Participants Analyzed 106
Measure Type: Number
Unit of Measure: liters
545
19.Secondary Outcome
Title Phase 1 and 2 Population PK: Volume of Distribution of the Second Peripheral Compartment (V3)
Hide Description Population PK analysis was performed using nonlinear mixed effect modeling. The estimated allometric function for V3 was 0.888.
Time Frame Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants < 6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)
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PK population: all participants who received at least one dose of nab-paclitaxel and had evaluable concentration data.
Arm/Group Title PK Population
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Phase 1: nab-paclitaxel 120-270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. Phase 2: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Overall Number of Participants Analyzed 106
Measure Type: Number
Unit of Measure: liters
45.3
20.Secondary Outcome
Title Phase 2: Duration of Response (DOR)
Hide Description Duration of response was defined as the time from the date of the first response (CR/PR, using RECIST version 1.1 guidelines) to disease progression for participants with a confirmed CR or PR. Participants who did not have disease progression or had not died were censored at the time of their last disease assessment or at time of start of new anticancer therapy, whichever occurred first. (For Phase 2 neuroblastoma patients who had both RECIST version 1.1 and Curie Score tumor evaluations, both tumor responses results were considered and an overall response was derived.)
Time Frame Median treatment duration in Phase 2 per group: Ewings Sarcoma = 14 weeks (3-31), Neuroblastoma = 7 weeks (3-23), Rhabdomyosarcoma = 5 weeks (1-13). Participants were followed until disease progression (if applicable) up to a maximum of 100.3 weeks.
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Efficacy Evaluable Population: participants (with response) who met eligibility criteria for Phase 2, completed ≥ 1 dose of study drug, and had baseline and ≥ 1 postbaseline efficacy assessment if having not discontinued the investigational product prior to postbaseline efficacy assessment due to disease progression or systematic deterioration.
Arm/Group Title Phase 2: Ewing's Sarcoma Phase 2: Neuroblastoma Phase 2: Rhabdomyosarcoma
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Participants with Ewing's sarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Participants with neuroblastoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Participants with rhabdomyosarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Overall Number of Participants Analyzed 0 0 1
Median (Full Range)
Unit of Measure: weeks
6.14
(6.14 to 6.14)
21.Secondary Outcome
Title Phase 2: Disease Control Rate (DCR)
Hide Description Disease control rate was defined as the percentage of participants who achieved either a stable disease maintained for ≥ 16 weeks or confirmed CR (confirmed no less than 4 weeks after criteria for response were first met) or confirmed PR (confirmed no less than 4 weeks after criteria for response were first met) over the total number of participants available for the analysis. Confidence interval was obtained using the Clopper-Pearson method.
Time Frame Median treatment duration in Phase 2 per group: Ewings Sarcoma = 14 weeks (3-31), Neuroblastoma = 7 weeks (3-23), Rhabdomyosarcoma = 5 weeks (1-13).
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Efficacy Evaluable Population: participants who met eligibility criteria for Phase 2, completed at least 1 dose of study drug, and had baseline and at least 1 postbaseline efficacy assessment if having not discontinued the investigational product prior to postbaseline efficacy assessment due to disease progression or systematic deterioration.
Arm/Group Title Phase 2: Ewing's Sarcoma Phase 2: Neuroblastoma Phase 2: Rhabdomyosarcoma
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Participants with Ewing's sarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Participants with neuroblastoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Participants with rhabdomyosarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Overall Number of Participants Analyzed 13 14 14
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
30.8
(9.1 to 61.4)
7.1
(0.2 to 33.9)
7.1
(0.2 to 33.9)
22.Secondary Outcome
Title Phase 2: Progression-Free Survival (PFS)
Hide Description PFS was defined as the time from the first dose date to the start of disease progression or participant death (any cause), whichever occurred first. Disease progression was classed as either a disease progression observed as a response assessment, or a disease progression or symptomatic deterioration at treatment/study discontinuation. Participants who did not have disease progression or had not died were censored at the last known time that the participant was progression free. Disease progression was considered according to RECIST version 1.1 for Phase 2 Ewing's sarcoma and rhabdomyosarcoma participants. (For Phase 2 neuroblastoma participants who had both RECIST 1.1 and Curie score tumor evaluations, both tumor responses results were considered and an overall response was derived.) Median PFS time was estimated through Kaplan-Meier methods. 95% confidence interval about the median time to PFS event was obtained using Greenwood's method.
Time Frame Median treatment duration in Phase 2 per group: Ewings Sarcoma = 14 weeks (3-31), Neuroblastoma = 7 weeks (3-23), Rhabdomyosarcoma = 5 weeks (1-13). Participants were followed until disease progression (if applicable) up to a maximum of 100.3 weeks.
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Efficacy Evaluable Population: participants who met eligibility criteria for Phase 2, completed at least 1 dose of study drug, and had baseline and at least 1 postbaseline efficacy assessment if having not discontinued the investigational product prior to postbaseline efficacy assessment due to disease progression or systematic deterioration.
Arm/Group Title Phase 2: Ewing's Sarcoma Phase 2: Neuroblastoma Phase 2: Rhabdomyosarcoma
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Participants with Ewing's sarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Participants with neuroblastoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Participants with rhabdomyosarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Overall Number of Participants Analyzed 13 14 14
Median (95% Confidence Interval)
Unit of Measure: weeks
13
(7.4 to 16.1)
7.4
(4.6 to 8.1)
5.1
(2.1 to 7.9)
23.Secondary Outcome
Title Phase 2: Kaplan-Meier Estimate of Overall Survival Rate at 1 Year
Hide Description Overall survival was defined as the time from the first dose date to date of death (any cause). Participants who were alive were censored at the last known time that the participant was alive.
Time Frame 1 year
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Efficacy Evaluable Population: participants who met eligibility criteria for Phase 2, completed ≥1 dose of study drug, and had baseline and ≥1 postbaseline efficacy assessment if having not discontinued the investigational product prior to postbaseline efficacy assessment due to disease progression or systematic deterioration.
Arm/Group Title Phase 2: Ewing's Sarcoma Phase 2: Neuroblastoma Phase 2: Rhabdomyosarcoma
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Participants with Ewing's sarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Participants with neuroblastoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Participants with rhabdomyosarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Overall Number of Participants Analyzed 13 14 14
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
48
(14 to 76)
25
(4 to 54)
15
(2 to 39)
24.Secondary Outcome
Title Phase 2: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
Hide Description An AE was defined as any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. A SAE is any AE occurring at any dose that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. TEAEs were defined as AEs that began or worsened in severity on or after the date of the first dose of study drug and within 28 days of the date of the last dose of study drug. The severity of the AEs was graded according to the Common Terminology Criteria for Adverse Events, Version 4.0. Participants were followed for 28 days after discontinuing treatment for safety and monitoring of AEs.
Time Frame Median treatment duration in Phase 2 per group: Ewings Sarcoma = 14 weeks (3-31), Neuroblastoma = 7 weeks (3-23), Rhabdomyosarcoma = 5 weeks (1-13). Participants were followed for 28 days after discontinuing treatment for safety and monitoring of AEs.
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Safety Population: all participants who took at least 1 dose of study drug.
Arm/Group Title Phase 2: Ewing's Sarcoma Phase 2: Neuroblastoma Phase 2: Rhabdomyosarcoma
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Participants with Ewing's sarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Participants with neuroblastoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Participants with rhabdomyosarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
Overall Number of Participants Analyzed 14 14 14
Measure Type: Count of Participants
Unit of Measure: Participants
TEAE
14
 100.0%
14
 100.0%
14
 100.0%
Treatment-related (TR) TEAE
13
  92.9%
12
  85.7%
12
  85.7%
Grade 3 or 4 TEAE
12
  85.7%
13
  92.9%
12
  85.7%
TR Grade 3 or 4 TEAE
9
  64.3%
9
  64.3%
10
  71.4%
Serious TEAE
6
  42.9%
6
  42.9%
11
  78.6%
TR Serious TEAE
2
  14.3%
2
  14.3%
6
  42.9%
TEAE Leading to Drug Discontinuation
3
  21.4%
1
   7.1%
3
  21.4%
TR TEAE Leading to Drug Discontinuation
1
   7.1%
0
   0.0%
3
  21.4%
TEAE Leading to Dose Reduction
4
  28.6%
5
  35.7%
4
  28.6%
TR TEAE Leading to Dose Reduction
4
  28.6%
4
  28.6%
4
  28.6%
TEAE Leading to Drug Interruption
5
  35.7%
3
  21.4%
4
  28.6%
TR TEAE Leading to Drug Interruption
3
  21.4%
3
  21.4%
2
  14.3%
TEAE Leading to Death
0
   0.0%
2
  14.3%
3
  21.4%
TR TEAE Leading to Death
0
   0.0%
0
   0.0%
0
   0.0%
Time Frame Median treatment duration in Phase 1 was 7.0 weeks, with minimum and maximum duration of 1 and 49 weeks, respectively. Median treatment duration in Phase 2 per group: Ewings Sarcoma = 14 weeks (3-31), Neuroblastoma = 7 weeks (3-23), rhabdomyosarcoma = 5 weeks (1-13).
Adverse Event Reporting Description All participants in both portions of the study were followed for 28 days after discontinuing treatment for safety and monitoring of AEs. AE's were analyzed in terms of TEAEs, which were defined as any AEs that began or worsened in severity on or after the start of study drug through 28 days after the last dose of study drug.
 
Arm/Group Title Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2 Phase 2: Nab-Paclitaxel 240 mg/m^2
Hide Arm/Group Description nab-paclitaxel 120 mg/m^2 intravenously (IV) on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the recommended phase 2 dose (RP2D). nab-paclitaxel 150 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. nab-paclitaxel 180 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. nab-paclitaxel 210 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. nab-paclitaxel 240 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. nab-paclitaxel 270 mg/m^2 IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity to establish the RP2D. Participants with Ewing's sarcoma, neuroblastoma, or rhabdomyosarcoma: nab-paclitaxel at the RP2D (240 mg/m^2 in participants weighing > 10 kg and 11.5 mg/kg in participants weighing ≤ 10 kg) IV on Days 1, 8 and 15 of a 28-day cycle until disease progression, death, withdrawal of consent, or unacceptable toxicity.
All-Cause Mortality
Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2 Phase 2: Nab-Paclitaxel 240 mg/m^2
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   14/16 (87.50%)   7/8 (87.50%)   11/14 (78.57%)   5/11 (45.45%)   8/8 (100.00%)   5/7 (71.43%)   25/42 (59.52%) 
Hide Serious Adverse Events
Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2 Phase 2: Nab-Paclitaxel 240 mg/m^2
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   10/16 (62.50%)   7/8 (87.50%)   6/14 (42.86%)   5/11 (45.45%)   3/8 (37.50%)   4/7 (57.14%)   23/42 (54.76%) 
Blood and lymphatic system disorders               
Febrile neutropenia  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  4/42 (9.52%) 
Leukopenia  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Neutropenia  1  1/16 (6.25%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Thrombocytopenia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  2/42 (4.76%) 
Cardiac disorders               
Tachycardia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Gastrointestinal disorders               
Abdominal pain  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Diarrhoea  1  1/16 (6.25%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Nausea  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Vomiting  1  0/16 (0.00%)  1/8 (12.50%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  1/42 (2.38%) 
General disorders               
Chills  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
General physical health deterioration  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  4/42 (9.52%) 
Generalised oedema  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Oedema peripheral  1  1/16 (6.25%)  1/8 (12.50%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Pyrexia  1  0/16 (0.00%)  3/8 (37.50%)  2/14 (14.29%)  3/11 (27.27%)  1/8 (12.50%)  2/7 (28.57%)  6/42 (14.29%) 
Infections and infestations               
Cellulitis  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Device related infection  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Gastroenteritis  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Lower respiratory tract infection bacterial  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Pneumonia  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Soft tissue infection  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Staphylococcal bacteraemia  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Varicella  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Injury, poisoning and procedural complications               
Anaphylactic transfusion reaction  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Metabolism and nutrition disorders               
Dehydration  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hypercreatininaemia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hyponatraemia  1  0/16 (0.00%)  2/8 (25.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Musculoskeletal and connective tissue disorders               
Back pain  1  2/16 (12.50%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Bone pain  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Pain in extremity  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Cancer pain  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Osteosarcoma  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Osteosarcoma metastatic  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Refractory anaemia with an excess of blasts  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Tumour pain  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Nervous system disorders               
Dizziness  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Headache  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  2/42 (4.76%) 
Intracranial pressure increased  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Seizure  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  1/42 (2.38%) 
Slow speech  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Somnolence  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Tremor  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Psychiatric disorders               
Restlessness  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Renal and urinary disorders               
Acute kidney injury  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  2/42 (4.76%) 
Anuria  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Urinary retention  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Urinary tract obstruction  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Dyspnoea  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Hypoxia  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Pleural effusion  1  2/16 (12.50%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Pneumonitis  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Pneumothorax  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  2/42 (4.76%) 
Pulmonary embolism  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Respiratory failure  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Skin and subcutaneous tissue disorders               
Dermatitis acneiform  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Dermatitis bullous  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Erythema  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Skin exfoliation  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Vascular disorders               
Hypertension  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hypotension  1  0/16 (0.00%)  1/8 (12.50%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
1
Term from vocabulary, MedDRA 20.0
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Phase 1: Nab-Paclitaxel 120 mg/m^2 Phase 1: Nab-Paclitaxel 150 mg/m^2 Phase 1: Nab-Paclitaxel 180 mg/m^2 Phase 1: Nab-Paclitaxel 210 mg/m^2 Phase 1: Nab-Paclitaxel 240 mg/m^2 Phase 1: Nab-Paclitaxel 270 mg/m^2 Phase 2: Nab-Paclitaxel 240 mg/m^2
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   16/16 (100.00%)   8/8 (100.00%)   14/14 (100.00%)   11/11 (100.00%)   8/8 (100.00%)   7/7 (100.00%)   42/42 (100.00%) 
Blood and lymphatic system disorders               
Anaemia  1  8/16 (50.00%)  6/8 (75.00%)  6/14 (42.86%)  5/11 (45.45%)  6/8 (75.00%)  6/7 (85.71%)  27/42 (64.29%) 
Febrile neutropenia  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  1/42 (2.38%) 
Leukopenia  1  6/16 (37.50%)  1/8 (12.50%)  2/14 (14.29%)  5/11 (45.45%)  5/8 (62.50%)  3/7 (42.86%)  18/42 (42.86%) 
Lymphadenitis  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Lymphopenia  1  6/16 (37.50%)  2/8 (25.00%)  1/14 (7.14%)  2/11 (18.18%)  2/8 (25.00%)  3/7 (42.86%)  5/42 (11.90%) 
Neutropenia  1  7/16 (43.75%)  4/8 (50.00%)  6/14 (42.86%)  8/11 (72.73%)  7/8 (87.50%)  6/7 (85.71%)  23/42 (54.76%) 
Neutrophilia  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Thrombocytopenia  1  1/16 (6.25%)  2/8 (25.00%)  2/14 (14.29%)  1/11 (9.09%)  2/8 (25.00%)  4/7 (57.14%)  8/42 (19.05%) 
Thrombocytosis  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Cardiac disorders               
Aortic valve disease  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Palpitations  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Pericardial effusion  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Sinus bradycardia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Sinus tachycardia  1  0/16 (0.00%)  2/8 (25.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Congenital, familial and genetic disorders               
Hydrocele  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  1/42 (2.38%) 
Ear and labyrinth disorders               
Ear pain  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  3/42 (7.14%) 
Ear swelling  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Vertigo  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  1/42 (2.38%) 
Endocrine disorders               
Cushingoid  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Eye disorders               
Diplopia  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Dry eye  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Eye irritation  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Eye pain  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Eye pruritus  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Keratitis  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Lacrimation increased  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Periorbital oedema  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  2/11 (18.18%)  0/8 (0.00%)  1/7 (14.29%)  3/42 (7.14%) 
Photophobia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Vision blurred  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  5/42 (11.90%) 
Gastrointestinal disorders               
Abdominal distension  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Abdominal pain  1  2/16 (12.50%)  2/8 (25.00%)  3/14 (21.43%)  2/11 (18.18%)  3/8 (37.50%)  2/7 (28.57%)  6/42 (14.29%) 
Abdominal pain upper  1  0/16 (0.00%)  1/8 (12.50%)  2/14 (14.29%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Anal fissure  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  2/42 (4.76%) 
Anal incontinence  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Anal inflammation  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Anorectal discomfort  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Ascites  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Constipation  1  4/16 (25.00%)  3/8 (37.50%)  3/14 (21.43%)  6/11 (54.55%)  2/8 (25.00%)  1/7 (14.29%)  10/42 (23.81%) 
Diarrhoea  1  2/16 (12.50%)  4/8 (50.00%)  4/14 (28.57%)  3/11 (27.27%)  4/8 (50.00%)  2/7 (28.57%)  8/42 (19.05%) 
Diarrhoea haemorrhagic  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Dyspepsia  1  0/16 (0.00%)  2/8 (25.00%)  1/14 (7.14%)  0/11 (0.00%)  2/8 (25.00%)  0/7 (0.00%)  2/42 (4.76%) 
Eructation  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Flatulence  1  0/16 (0.00%)  0/8 (0.00%)  2/14 (14.29%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Gastrointestinal pain  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Gastrooesophageal reflux disease  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Haematochezia  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Haemorrhoids  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Nausea  1  6/16 (37.50%)  3/8 (37.50%)  2/14 (14.29%)  4/11 (36.36%)  2/8 (25.00%)  3/7 (42.86%)  10/42 (23.81%) 
Odynophagia  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Salivary hypersecretion  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Stomatitis  1  1/16 (6.25%)  1/8 (12.50%)  0/14 (0.00%)  2/11 (18.18%)  1/8 (12.50%)  2/7 (28.57%)  8/42 (19.05%) 
Toothache  1  0/16 (0.00%)  1/8 (12.50%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  2/42 (4.76%) 
Vomiting  1  8/16 (50.00%)  3/8 (37.50%)  2/14 (14.29%)  3/11 (27.27%)  3/8 (37.50%)  1/7 (14.29%)  14/42 (33.33%) 
General disorders               
Asthenia  1  1/16 (6.25%)  1/8 (12.50%)  1/14 (7.14%)  1/11 (9.09%)  3/8 (37.50%)  1/7 (14.29%)  9/42 (21.43%) 
Catheter site pain  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Face oedema  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  2/42 (4.76%) 
Fatigue  1  3/16 (18.75%)  3/8 (37.50%)  4/14 (28.57%)  4/11 (36.36%)  2/8 (25.00%)  0/7 (0.00%)  2/42 (4.76%) 
General physical health deterioration  1  0/16 (0.00%)  1/8 (12.50%)  1/14 (7.14%)  1/11 (9.09%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Generalised oedema  1  0/16 (0.00%)  1/8 (12.50%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Influenza like illness  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Malaise  1  1/16 (6.25%)  2/8 (25.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Non-cardiac chest pain  1  0/16 (0.00%)  2/8 (25.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Oedema peripheral  1  3/16 (18.75%)  3/8 (37.50%)  2/14 (14.29%)  1/11 (9.09%)  1/8 (12.50%)  0/7 (0.00%)  8/42 (19.05%) 
Pain  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Pyrexia  1  6/16 (37.50%)  3/8 (37.50%)  5/14 (35.71%)  5/11 (45.45%)  4/8 (50.00%)  2/7 (28.57%)  14/42 (33.33%) 
Xerosis  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Hepatobiliary disorders               
Hyperbilirubinaemia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Infections and infestations               
Bacillus bacteraemia  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Cellulitis  1  1/16 (6.25%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Clostridium difficile infection  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Conjunctivitis  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Cystitis  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Device related infection  1  0/16 (0.00%)  0/8 (0.00%)  2/14 (14.29%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Ear infection  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Herpes zoster  1  0/16 (0.00%)  1/8 (12.50%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Infection  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Lung infection  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  1/42 (2.38%) 
Mucosal infection  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Oral candidiasis  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Oropharyngeal candidiasis  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Otitis externa  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Otitis media  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Paronychia  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Rash pustular  1  0/16 (0.00%)  1/8 (12.50%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Rhinitis  1  0/16 (0.00%)  1/8 (12.50%)  2/14 (14.29%)  1/11 (9.09%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Skin infection  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  1/7 (14.29%)  0/42 (0.00%) 
Upper respiratory tract infection  1  2/16 (12.50%)  0/8 (0.00%)  1/14 (7.14%)  1/11 (9.09%)  1/8 (12.50%)  0/7 (0.00%)  1/42 (2.38%) 
Urinary tract infection  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  2/42 (4.76%) 
Vulvitis  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Injury, poisoning and procedural complications               
Arthropod bite  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Contusion  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Excoriation  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Fall  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  2/8 (25.00%)  0/7 (0.00%)  0/42 (0.00%) 
Humerus fracture  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Muscle injury  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Recall phenomenon  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Scar  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Vascular access complication  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Wound secretion  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Investigations               
Activated partial thromboplastin time prolonged  1  1/16 (6.25%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Alanine aminotransferase increased  1  0/16 (0.00%)  3/8 (37.50%)  1/14 (7.14%)  3/11 (27.27%)  1/8 (12.50%)  1/7 (14.29%)  2/42 (4.76%) 
Aspartate aminotransferase increased  1  0/16 (0.00%)  2/8 (25.00%)  1/14 (7.14%)  1/11 (9.09%)  1/8 (12.50%)  0/7 (0.00%)  3/42 (7.14%) 
Blood alkaline phosphatase increased  1  0/16 (0.00%)  4/8 (50.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Blood bicarbonate decreased  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Blood bilirubin increased  1  1/16 (6.25%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Blood creatinine increased  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Blood lactate dehydrogenase increased  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Blood urea increased  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
C-reactive protein increased  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  2/11 (18.18%)  1/8 (12.50%)  0/7 (0.00%)  1/42 (2.38%) 
Candida test positive  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Electrocardiogram QT prolonged  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Electroencephalogram abnormal  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Gamma-glutamyltransferase increased  1  1/16 (6.25%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Glucose urine present  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
International normalised ratio increased  1  1/16 (6.25%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Neutrophil count decreased  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  1/7 (14.29%)  1/42 (2.38%) 
Platelet count decreased  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Urine output decreased  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Weight decreased  1  2/16 (12.50%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  2/8 (25.00%)  2/7 (28.57%)  1/42 (2.38%) 
Weight increased  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Metabolism and nutrition disorders               
Acidosis  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Cachexia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Decreased appetite  1  3/16 (18.75%)  3/8 (37.50%)  5/14 (35.71%)  1/11 (9.09%)  1/8 (12.50%)  1/7 (14.29%)  6/42 (14.29%) 
Dehydration  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hyperchloraemia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hypercreatininaemia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hyperglycaemia  1  2/16 (12.50%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hyperkalaemia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hypermagnesaemia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hypernatraemia  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hyperphosphataemia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Hypertriglyceridaemia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hypoalbuminaemia  1  2/16 (12.50%)  3/8 (37.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  2/42 (4.76%) 
Hypocalcaemia  1  2/16 (12.50%)  2/8 (25.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Hypochloraemia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hypoglycaemia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hypokalaemia  1  1/16 (6.25%)  3/8 (37.50%)  2/14 (14.29%)  1/11 (9.09%)  1/8 (12.50%)  2/7 (28.57%)  5/42 (11.90%) 
Hypomagnesaemia  1  1/16 (6.25%)  1/8 (12.50%)  1/14 (7.14%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  2/42 (4.76%) 
Hyponatraemia  1  1/16 (6.25%)  4/8 (50.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  1/42 (2.38%) 
Hypophosphataemia  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Polydipsia  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Musculoskeletal and connective tissue disorders               
Arthralgia  1  1/16 (6.25%)  2/8 (25.00%)  0/14 (0.00%)  4/11 (36.36%)  2/8 (25.00%)  2/7 (28.57%)  3/42 (7.14%) 
Back pain  1  2/16 (12.50%)  2/8 (25.00%)  3/14 (21.43%)  0/11 (0.00%)  2/8 (25.00%)  0/7 (0.00%)  1/42 (2.38%) 
Bone pain  1  1/16 (6.25%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Coccydynia  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Epiphysiolysis  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Flank pain  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Groin pain  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  1/42 (2.38%) 
Joint swelling  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  1/42 (2.38%) 
Muscular weakness  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Musculoskeletal chest pain  1  1/16 (6.25%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  1/42 (2.38%) 
Musculoskeletal pain  1  2/16 (12.50%)  1/8 (12.50%)  1/14 (7.14%)  1/11 (9.09%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Myalgia  1  0/16 (0.00%)  4/8 (50.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Neck pain  1  1/16 (6.25%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Pain in extremity  1  2/16 (12.50%)  3/8 (37.50%)  2/14 (14.29%)  0/11 (0.00%)  3/8 (37.50%)  1/7 (14.29%)  17/42 (40.48%) 
Pain in jaw  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Spinal pain  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Cancer pain  1  1/16 (6.25%)  0/8 (0.00%)  2/14 (14.29%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Skin papilloma  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Tumour haemorrhage  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Tumour pain  1  2/16 (12.50%)  1/8 (12.50%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  1/7 (14.29%)  3/42 (7.14%) 
Nervous system disorders               
Depressed level of consciousness  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Dizziness  1  1/16 (6.25%)  2/8 (25.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  2/42 (4.76%) 
Dysaesthesia  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Dysgeusia  1  1/16 (6.25%)  1/8 (12.50%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  1/7 (14.29%)  1/42 (2.38%) 
Headache  1  3/16 (18.75%)  2/8 (25.00%)  3/14 (21.43%)  2/11 (18.18%)  1/8 (12.50%)  1/7 (14.29%)  11/42 (26.19%) 
Lethargy  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Neuralgia  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  3/42 (7.14%) 
Neuropathy peripheral  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Paraesthesia  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  1/7 (14.29%)  1/42 (2.38%) 
Peripheral motor neuropathy  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  2/8 (25.00%)  0/7 (0.00%)  0/42 (0.00%) 
Peripheral sensory neuropathy  1  1/16 (6.25%)  0/8 (0.00%)  2/14 (14.29%)  0/11 (0.00%)  3/8 (37.50%)  2/7 (28.57%)  3/42 (7.14%) 
Posterior reversible encephalopathy syndrome  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Sciatica  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Somnolence  1  1/16 (6.25%)  1/8 (12.50%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Spinal cord compression  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Visual field defect  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Psychiatric disorders               
Anxiety  1  2/16 (12.50%)  3/8 (37.50%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Confusional state  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Depression  1  1/16 (6.25%)  2/8 (25.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Enuresis  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Insomnia  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  2/11 (18.18%)  0/8 (0.00%)  1/7 (14.29%)  2/42 (4.76%) 
Mood altered  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Restlessness  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Renal and urinary disorders               
Acute kidney injury  1  1/16 (6.25%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Dysuria  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  2/42 (4.76%) 
Haematuria  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  1/42 (2.38%) 
Ketonuria  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Pollakiuria  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Polyuria  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Renal pain  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Urinary incontinence  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Urinary retention  1  0/16 (0.00%)  1/8 (12.50%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Urinary tract obstruction  1  1/16 (6.25%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Urinary tract pain  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Reproductive system and breast disorders               
Genital pain  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Menstruation irregular  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Oedema genital  1  0/16 (0.00%)  2/8 (25.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Scrotal oedema  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Vaginal haemorrhage  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Vulvovaginal discomfort  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Atelectasis  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Cough  1  2/16 (12.50%)  3/8 (37.50%)  2/14 (14.29%)  4/11 (36.36%)  3/8 (37.50%)  0/7 (0.00%)  6/42 (14.29%) 
Dysaesthesia pharynx  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Dysphonia  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Dyspnoea  1  3/16 (18.75%)  0/8 (0.00%)  2/14 (14.29%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  2/42 (4.76%) 
Epistaxis  1  1/16 (6.25%)  2/8 (25.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  2/7 (28.57%)  5/42 (11.90%) 
Haemoptysis  1  0/16 (0.00%)  1/8 (12.50%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Hypoxia  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Lung consolidation  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Nasal congestion  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Oropharyngeal pain  1  0/16 (0.00%)  2/8 (25.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Pharyngeal erythema  1  0/16 (0.00%)  2/8 (25.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Pharyngeal inflammation  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Pleural effusion  1  2/16 (12.50%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Productive cough  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Pulmonary haemorrhage  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Rhinitis allergic  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  1/42 (2.38%) 
Tachypnoea  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Wheezing  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  1/42 (2.38%) 
Skin and subcutaneous tissue disorders               
Alopecia  1  2/16 (12.50%)  4/8 (50.00%)  4/14 (28.57%)  5/11 (45.45%)  3/8 (37.50%)  2/7 (28.57%)  6/42 (14.29%) 
Dermatitis  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Dermatitis acneiform  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  1/11 (9.09%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Dermatitis atopic  1  1/16 (6.25%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/7 (0.00%)  0/42 (0.00%) 
Dry skin  1  0/16 (0.00%)  0/8 (0.00%)  1/14 (7.14%)  2/11 (18.18%)  2/8 (25.00%)  2/7 (28.57%)  2/42 (4.76%) 
Ecchymosis  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Erythema  1  0/16 (0.00%)  1/8 (12.50%)  0/14 (0.00%)  2/11 (18.18%)  2/8 (25.00%)  1/7 (14.29%)  7/42 (16.67%) 
Haemorrhage subcutaneous  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Intertrigo  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  1/7 (14.29%)  0/42 (0.00%) 
Nail bed inflammation  1  0/16 (0.00%)  0/8 (0.00%)  0/14 (0.00%)  0/11 (0.00%)  1/8 (12.50%)  0/7 (0.00%)  0/42 (0.00%) 
Nail discolouration