Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Talazoparib and Temozolomide in Treating Younger Patients With Refractory or Recurrent Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02116777
Recruitment Status : Completed
First Posted : April 17, 2014
Results First Posted : March 26, 2021
Last Update Posted : March 26, 2021
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Sequential Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Conditions Adult Solid Neoplasm
Childhood Solid Neoplasm
Recurrent Childhood Central Nervous System Neoplasm
Recurrent Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor
Recurrent Malignant Solid Neoplasm
Refractory Central Nervous System Neoplasm
Interventions Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Drug: Talazoparib
Drug: Temozolomide
Enrollment 40
Recruitment Details  
Pre-assignment Details Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.
Arm/Group Title 400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day
Hide Arm/Group Description

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 2: Part B

Part B: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET (Phase 2)

Period Title: Overall Study
Started 3 3 3 13 6 3 9
Completed 0 0 0 0 0 0 0
Not Completed 3 3 3 13 6 3 9
Reason Not Completed
Adverse Event             0             0             0             0             2             2             0
Death             0             0             0             1             0             0             0
Lack of Efficacy             3             3             3             8             4             1             9
Physician Decision             0             0             0             2             0             0             0
Protocol Violation             0             0             0             1             0             0             0
Withdrawal by Subject             0             0             0             1             0             0             0
Arm/Group Title 400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day Total
Hide Arm/Group Description

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 2: Part B

Part B: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET (Phase 2)

Total of all reporting groups
Overall Number of Baseline Participants 3 3 3 13 6 3 9 40
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 13 participants 6 participants 3 participants 9 participants 40 participants
<=18 years
2
  66.7%
2
  66.7%
3
 100.0%
12
  92.3%
5
  83.3%
3
 100.0%
3
  33.3%
30
  75.0%
Between 18 and 65 years
1
  33.3%
1
  33.3%
0
   0.0%
1
   7.7%
1
  16.7%
0
   0.0%
6
  66.7%
10
  25.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Median (Full Range)
Unit of measure:  Years
Number Analyzed 3 participants 3 participants 3 participants 13 participants 6 participants 3 participants 9 participants 40 participants
18
(16 to 19)
16
(7 to 19)
14
(13 to 14)
13
(5 to 19)
13.5
(4 to 20)
12
(6 to 15)
22
(16 to 25)
15.5
(4 to 25)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 13 participants 6 participants 3 participants 9 participants 40 participants
Female
1
  33.3%
1
  33.3%
1
  33.3%
3
  23.1%
4
  66.7%
2
  66.7%
4
  44.4%
16
  40.0%
Male
2
  66.7%
2
  66.7%
2
  66.7%
10
  76.9%
2
  33.3%
1
  33.3%
5
  55.6%
24
  60.0%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 13 participants 6 participants 3 participants 9 participants 40 participants
Hispanic or Latino
0
   0.0%
2
  66.7%
1
  33.3%
2
  15.4%
0
   0.0%
0
   0.0%
1
  11.1%
6
  15.0%
Not Hispanic or Latino
3
 100.0%
1
  33.3%
2
  66.7%
11
  84.6%
6
 100.0%
2
  66.7%
7
  77.8%
32
  80.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
  33.3%
1
  11.1%
2
   5.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 13 participants 6 participants 3 participants 9 participants 40 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Asian
0
   0.0%
0
   0.0%
1
  33.3%
1
   7.7%
0
   0.0%
0
   0.0%
0
   0.0%
2
   5.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
1
  33.3%
0
   0.0%
0
   0.0%
2
  15.4%
1
  16.7%
0
   0.0%
0
   0.0%
4
  10.0%
White
2
  66.7%
3
 100.0%
2
  66.7%
7
  53.8%
5
  83.3%
2
  66.7%
8
  88.9%
29
  72.5%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
3
  23.1%
0
   0.0%
1
  33.3%
1
  11.1%
5
  12.5%
1.Primary Outcome
Title The Number of Participants With Dose Limiting Toxicities to Determine the Maximum Tolerated Dose of Temozolomide and Talazoparib Combination Therapy
Hide Description The Maximum Tolerated Dose (MTD) reflects the highest dose of Talazoparib (BMN 673) when combined with a dose of temozolomide that did not cause a Grade 3 or higher toxicity in children with refractory or recurrent solid tumors.
Time Frame 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
Patients with toxicity grade 3 or above.
Arm/Group Title 400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30 mg/m²/Dose TEM,Max 1000 mcg/Day
Hide Arm/Group Description:

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Part PK
Overall Number of Participants Analyzed 3 3 3 7 6 3 6
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
1
  33.3%
2
  28.6%
2
  33.3%
2
  66.7%
0
   0.0%
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection 400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day, 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day, 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day, 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day, 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day, 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day, 600 mcg/m²/Dose BMN 673 BID+30 mg/m²/Dose TEM,Max 1000 mcg/Day
Comments [Not Specified]
Type of Statistical Test Other
Comments Maximum Tolerate Dose Level was determined by the rolling-6 design.
Method of Estimation Estimation Parameter Maximum Tolerate Dose Level
Estimated Value 4
Estimation Comments Maximum Tolerate Dose Level is Dose Level 4 (600 mcg/m²/dose +30 mg/m2/dose (BMN 673) BID + 30 mg/m²/dose (TEM), Max 1000 mcg/day). MTD determined by using the Rolling-6 Design.
2.Primary Outcome
Title All Cycle 1 Toxicities >=Grade 3
Hide Description The number of patients with at least one toxicity (DLT or non-DLT) in cycle 1 that is at least possibly attributable to study agent
Time Frame Up to 28 days
Hide Outcome Measure Data
Hide Analysis Population Description
Patients with toxicity grade 3 or above.
Arm/Group Title 400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day
Hide Arm/Group Description:

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 2: Part B

Part B: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET (Phase 2)

Overall Number of Participants Analyzed 3 3 3 13 6 3 9
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
2
  66.7%
7
  53.8%
5
  83.3%
3
 100.0%
5
  55.6%
3.Primary Outcome
Title T Max of Talazoparib
Hide Description Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.
Time Frame Cycle 1 Day 1 pre-dose, and 1, 2, 4, 8 and 24 hours after the first talazoparib dose.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 28
Median (Full Range)
Unit of Measure: Hours
2
(1 to 24)
4.Primary Outcome
Title C Max of Talazoparib
Hide Description Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.
Time Frame Cycle 1 Day 1 pre-dose, and 1, 2, 4, 8 and 24 hours after the first talazoparib dose.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 28
Median (Full Range)
Unit of Measure: ng/mL
4670
(708 to 19300)
5.Primary Outcome
Title AUC of Talazoparib
Hide Description Median with minimum and maximum for the area under the drug concentration over time curve.
Time Frame Cycle 1 Day 1 pre-dose, and 1, 2, 4 and 8 hours after the first talazoparib dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 4 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 27
Median (Full Range)
Unit of Measure: h•µg/L
17.55
(2.15 to 63.14)
6.Primary Outcome
Title Accumulation Half-life of Talazoparib in Combination With Temozolomide.
Hide Description Median with minimum and maximum for the time required for the serum concentration to fall to 50% of its starting dose.
Time Frame Cycle 1 Day 1 pre-dose, and 1, 2, 4 and 8 hours after the first talazoparib dose. Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 4 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 27
Median (Full Range)
Unit of Measure: Hours
46.8
(18.20 to 253.27)
7.Primary Outcome
Title T Max of Talazoparib in Combination With Temozolomide
Hide Description Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.
Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 28
Median (Full Range)
Unit of Measure: Hours
1.04
(1 to 8)
8.Primary Outcome
Title C Max of Talazoparib in Combination With Temozolomide
Hide Description Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.
Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 28
Median (Full Range)
Unit of Measure: pg/ml
16450
(7070 to 56300)
9.Primary Outcome
Title AUC of Talazoparib in Combination With Temozolomide
Hide Description Median with minimum and maximum area under the drug concentration over time curve
Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 28
Median (Full Range)
Unit of Measure: h•µg/L
82.08
(41.92 to 226.70)
10.Primary Outcome
Title AUC of Talazoparib in Combination With Temozolomide
Hide Description Median with minimum and maximum area under the drug concentration over time curve
Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 28
Median (Full Range)
Unit of Measure: h•µg/L
173.08
(83.61 to 456.28)
11.Primary Outcome
Title Clearance of Talazoparib in Combination With Temozolomide
Hide Description Median with minimum and maximum for the rate of elimination of the drug.
Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 3 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 28
Median (Full Range)
Unit of Measure: L/hr/m²
3.08
(1.34 to 6.19)
12.Primary Outcome
Title Accumulation Ratio of Talazoparib in Combination With Temozolomide
Hide Description Median with minimum and maximum of the accumulation ratio.
Time Frame Cycle 1 Day 1 pre-dose, and 1, 2, 4 and 8 hours after the first talazoparib dose. Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the talazoparib dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 4 patients in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 27
Median (Full Range)
Unit of Measure: Ratio
3.34
(1.67 to 15.73)
13.Primary Outcome
Title Half-life of Temozolomide in Combination With Talazoparib
Hide Description Median with minimum and maximum for the time required for the serum concentration to fall to 50% of its starting dose.
Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 1 patient in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 30
Median (Full Range)
Unit of Measure: Hours
1.74
(1.33 to 4.92)
14.Primary Outcome
Title T Max of Temozolomide in Combination With Talazoparib
Hide Description Median with minimum and maximum for the time at which the maximum (peak) serum concentration occurs.
Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 1 patient in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 30
Median (Full Range)
Unit of Measure: Hours
1.03
(1 to 4)
15.Primary Outcome
Title C Max of Temozolomide in Combination With Talazoparib
Hide Description Median with minimum and maximum for the maximum (peak) serum concentration.
Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 1 patient in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 30
Median (Full Range)
Unit of Measure: ng/mL
1234.1
(346.56 to 6593.17)
16.Primary Outcome
Title AUC of Temozolomide in Combination With Talazoparib
Hide Description Median with minimum and maximum for the area under the drug concentration over time curve.
Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 1 patient in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 30
Median (Full Range)
Unit of Measure: h•µg/L
4352.16
(1174.08 to 21653.96)
17.Primary Outcome
Title Clearance of Temozolomide in Combination With Talazoparib
Hide Description Median with minimum and maximum for the rate of elimination of the drug.
Time Frame Cycle 1 Day 5 or 6 pre-dose, and 1, 2, 4 and 8 hours after the temozolomide dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) studies were completed for all but 1 patient in Phase 1. PK analysis was performed regardless of dose level as pre-specified in the protocol. PK was not performed in Phase 2
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 30
Median (Full Range)
Unit of Measure: L/hr/m²
6.49
(2.59 to 30.08)
18.Primary Outcome
Title Number of Ewing/Peripheral PNET Participants in Phase 2 With Complete Response (CR) or Partial Response (PR)
Hide Description Frequency of Ewing sarcoma and peripheral PNET participants with Complete Response (CR) or Partial Response (PR) per the Response Evaluation Criteria In Solid Tumors (RECIST)
Time Frame Up to 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 2
Hide Arm/Group Description:

(Part B): Relapse/Refractory EWS or PNET Patients receive MTD from Phase 1 portion of study. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 9
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
19.Secondary Outcome
Title Number of Solid Tumor Patients With Complete Response (CR) or Partial Response (PR)
Hide Description Frequency of solid tumor participants with Complete Response (CR) or Partial Response (PR) per the Response Evaluation Criteria In Solid Tumors (RECIST)
Time Frame Up to 24 months
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Treatment (Talazoparib, Temozolomide): Phase 1
Hide Arm/Group Description:

(Part A): Patients receive talazoparib PO QD or BID on days 1-6 and temozolomide PO QD on days 2-6. Treatment repeats every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis: Correlative studies

Pharmacological Study: Correlative studies

Talazoparib: Given PO

Temozolomide: Given PO

Overall Number of Participants Analyzed 31
Measure Type: Count of Participants
Unit of Measure: Participants
1
   3.2%
Time Frame Up to 24 months
Adverse Event Reporting Description Adverse event reporting is collected routinely using case report forms. The SAE table reflects NCI Common Terminology Criteria for Adverse Events (CTCAEs) submitted by the institution via expedited reporting (NCI AdEERs / CAeRs). All remaining CTCAEs collected by means other than expedited reporting are non-serious and are reported in the "AE Other" table. Ineligible patients are excluded from reporting of adverse events. All-Cause Mortality includes all deaths collected on the study.
 
Arm/Group Title 400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day
Hide Arm/Group Description

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 1: Part A

Part A1: Patients with relapsed or refractory solid tumors and CNS tumors

Part A2: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET

Phase 2: Part B

Part B: Patients with relapsed or refractory Ewing sarcoma or Peripheral PNET (Phase 2)

All-Cause Mortality
400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/3 (0.00%)   0/3 (0.00%)   0/3 (0.00%)   2/13 (15.38%)   1/6 (16.67%)   0/3 (0.00%)   0/9 (0.00%) 
Hide Serious Adverse Events
400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/3 (66.67%)   2/3 (66.67%)   2/3 (66.67%)   11/13 (84.62%)   6/6 (100.00%)   3/3 (100.00%)   8/9 (88.89%) 
Blood and lymphatic system disorders               
Anemia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  3/13 (23.08%)  1/6 (16.67%)  2/3 (66.67%)  5/9 (55.56%) 
Febrile neutropenia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  1/3 (33.33%)  1/9 (11.11%) 
Cardiac disorders               
Sinus tachycardia   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Ear and labyrinth disorders               
Ear pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Eye disorders               
Optic nerve disorder   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Gastrointestinal disorders               
Abdominal pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Dysphagia   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Intra-abdominal hemorrhage   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Nausea   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Typhlitis   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Vomiting   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
General disorders               
Edema face   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Fever   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Gait disturbance   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Non-cardiac chest pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Infections and infestations               
Catheter related infection   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  1/3 (33.33%)  0/9 (0.00%) 
Lung infection   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Periorbital infection   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Pharyngitis   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Sepsis   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Skin infection   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Injury, poisoning and procedural complications               
Vascular access complication   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations               
Activated partial thromboplastin time prolonged   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Alanine aminotransferase increased   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Aspartate aminotransferase increased   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
GGT increased   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Lymphocyte count decreased   0/3 (0.00%)  2/3 (66.67%)  0/3 (0.00%)  4/13 (30.77%)  2/6 (33.33%)  2/3 (66.67%)  6/9 (66.67%) 
Lymphocyte count increased   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Neutrophil count decreased   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  8/13 (61.54%)  5/6 (83.33%)  3/3 (100.00%)  5/9 (55.56%) 
Platelet count decreased   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  4/13 (30.77%)  3/6 (50.00%)  2/3 (66.67%)  5/9 (55.56%) 
Urine output decreased   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Weight loss   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
White blood cell decreased   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  3/13 (23.08%)  2/6 (33.33%)  2/3 (66.67%)  5/9 (55.56%) 
Metabolism and nutrition disorders               
Anorexia   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  1/6 (16.67%)  1/3 (33.33%)  1/9 (11.11%) 
Hyperglycemia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Hyperkalemia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Hypokalemia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Hyponatremia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Hypophosphatemia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Obesity   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Musculoskeletal and connective tissue disorders               
Generalized muscle weakness   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Muscle weakness lower limb   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Muscle weakness right-sided   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, PROGRESSIVE DISEASE   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, PROGRESSIVE DISEASE   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Tumor pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Nervous system disorders               
Ataxia   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Dysarthria   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Dysphasia   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Headache   0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Hydrocephalus   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Hypersomnia   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Nervous system disorders - Other, HYPOTONIC   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Nervous system disorders - Other, PARALYSIS   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Oculomotor nerve disorder   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Peripheral motor neuropathy   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Peripheral sensory neuropathy   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Seizure   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Psychiatric disorders               
Anxiety   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Insomnia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Renal and urinary disorders               
Hematuria   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Reproductive system and breast disorders               
Irregular menstruation   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Respiratory, thoracic and mediastinal disorders               
Dyspnea   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Hypoxia   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  1/13 (7.69%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Pleural hemorrhage   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Respiratory, thoracic and mediastinal disorders - Other, VOCAL CORD PARALYSIS   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Stridor   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders               
Hyperhidrosis   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Skin atrophy   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Skin ulceration   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Urticaria   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Vascular disorders               
Hypotension   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
400 mcg/m²/Dose BMN 673 QD+20mg/m²/Dose TEM,Max 800 mcg/Day 400 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 800 mcg/Day 600 mcg/m²/Dose BMN 673 BID+20mg/m²/Dose TEM,Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+40mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/doseBMN 673 BID+55mg/m²/Dose TEM, Max 1000 mcg/Day 600 mcg/m²/Dose BMN 673 BID+30mg/m²/Dose TEM,Max 1000 mcg/Day
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   3/3 (100.00%)   3/3 (100.00%)   3/3 (100.00%)   13/13 (100.00%)   6/6 (100.00%)   3/3 (100.00%)   9/9 (100.00%) 
Blood and lymphatic system disorders               
Anemia   2/3 (66.67%)  2/3 (66.67%)  2/3 (66.67%)  12/13 (92.31%)  6/6 (100.00%)  3/3 (100.00%)  8/9 (88.89%) 
Cardiac disorders               
Cardiac disorders - Other, HEART MURMUR   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Cardiac disorders - Other, MURMUR LUSB   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Cardiac disorders - Other, NON RESTRICTIVE CARDIOMYOPATHY   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Pericardial effusion   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Sinus bradycardia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Sinus tachycardia   0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  5/13 (38.46%)  2/6 (33.33%)  3/3 (100.00%)  3/9 (33.33%) 
Ear and labyrinth disorders               
Ear and labyrinth disorders - Other, DECREASED HEARING   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Ear and labyrinth disorders - Other, HEARING LOSS   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Ear pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Hearing impaired   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Tinnitus   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Endocrine disorders               
Adrenal insufficiency   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Cushingoid   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Endocrine disorders - Other, PANHYPOPITUITARISM   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Hypothyroidism   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  0/9 (0.00%) 
Precocious puberty   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Eye disorders               
Blurred vision   1/3 (33.33%)  0/3 (0.00%)  1/3 (33.33%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Cataract   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Eye disorders - Other, DOUBLE VISION   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Eye disorders - Other, LEFT ORBITAL RECONSTRUCTION   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Eye disorders - Other, SPOTS IN VISUAL FIELD   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Eye disorders - Other, VISION IMPAIRMENT   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Photophobia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Gastrointestinal disorders               
Abdominal distension   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Abdominal pain   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  2/13 (15.38%)  2/6 (33.33%)  2/3 (66.67%)  2/9 (22.22%) 
Ascites   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Cheilitis   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Constipation   1/3 (33.33%)  0/3 (0.00%)  1/3 (33.33%)  5/13 (38.46%)  4/6 (66.67%)  2/3 (66.67%)  4/9 (44.44%) 
Dental caries   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Diarrhea   1/3 (33.33%)  1/3 (33.33%)  1/3 (33.33%)  5/13 (38.46%)  2/6 (33.33%)  1/3 (33.33%)  3/9 (33.33%) 
Dyspepsia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Dysphagia   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  1/13 (7.69%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Esophageal stenosis   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Fecal incontinence   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Flatulence   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Gastroesophageal reflux disease   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Gastrointestinal disorders - Other, GINGIVAL BLEEDING   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Gastrointestinal disorders - Other, OROPHARYNGEAL ERYTHEMA   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Gastrointestinal disorders - Other, VOMITING WITH BLOOD STREAKS   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Mucositis oral   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  1/6 (16.67%)  1/3 (33.33%)  0/9 (0.00%) 
Nausea   1/3 (33.33%)  1/3 (33.33%)  3/3 (100.00%)  6/13 (46.15%)  4/6 (66.67%)  2/3 (66.67%)  7/9 (77.78%) 
Oral pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Stomach pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Toothache   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Vomiting   0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  5/13 (38.46%)  4/6 (66.67%)  3/3 (100.00%)  3/9 (33.33%) 
General disorders               
Chills   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  1/3 (33.33%)  0/9 (0.00%) 
Edema limbs   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  3/13 (23.08%)  3/6 (50.00%)  0/3 (0.00%)  1/9 (11.11%) 
Fatigue   3/3 (100.00%)  1/3 (33.33%)  0/3 (0.00%)  10/13 (76.92%)  5/6 (83.33%)  3/3 (100.00%)  6/9 (66.67%) 
Fever   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  1/6 (16.67%)  1/3 (33.33%)  3/9 (33.33%) 
Gait disturbance   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  2/13 (15.38%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Infusion related reaction   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Irritability   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  0/9 (0.00%) 
Malaise   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Non-cardiac chest pain   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  4/9 (44.44%) 
Pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  2/6 (33.33%)  0/3 (0.00%)  3/9 (33.33%) 
Immune system disorders               
Allergic reaction   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Infections and infestations               
Infections and infestations - Other, HHV6   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Infections and infestations - Other, SHINGLES ZOSTER   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Infections and infestations - Other, THRUSH   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Infections and infestations - Other, URI   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Lip infection   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Mucosal infection   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  1/3 (33.33%)  1/9 (11.11%) 
Otitis media   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Papulopustular rash   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Paronychia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Pharyngitis   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Skin infection   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Upper respiratory infection   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Injury, poisoning and procedural complications               
Bruising   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  2/13 (15.38%)  1/6 (16.67%)  1/3 (33.33%)  0/9 (0.00%) 
Burn   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  1/13 (7.69%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Fall   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Injury, poisoning and procedural complications - Other, EAR CUT   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Injury, poisoning and procedural complications - Other, LEG LACERATION   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Injury, poisoning and procedural complications - Other, SCRATCHES   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Intraoperative neurological injury   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Vascular access complication   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Wound dehiscence   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations               
Activated partial thromboplastin time prolonged   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Alanine aminotransferase increased   1/3 (33.33%)  1/3 (33.33%)  0/3 (0.00%)  3/13 (23.08%)  4/6 (66.67%)  1/3 (33.33%)  3/9 (33.33%) 
Alkaline phosphatase increased   1/3 (33.33%)  1/3 (33.33%)  1/3 (33.33%)  2/13 (15.38%)  1/6 (16.67%)  1/3 (33.33%)  7/9 (77.78%) 
Aspartate aminotransferase increased   1/3 (33.33%)  1/3 (33.33%)  1/3 (33.33%)  2/13 (15.38%)  2/6 (33.33%)  1/3 (33.33%)  5/9 (55.56%) 
Blood bilirubin increased   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  1/6 (16.67%)  0/3 (0.00%)  3/9 (33.33%) 
Cholesterol high   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Creatinine increased   1/3 (33.33%)  0/3 (0.00%)  1/3 (33.33%)  4/13 (30.77%)  3/6 (50.00%)  2/3 (66.67%)  3/9 (33.33%) 
Hemoglobin increased   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Investigations - Other, ALK PHOS DECREASED   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, ALT DECREASED   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, ANION GAP INCREASED   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, AST DECREASED   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, BICARBONATE DECREASED   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Investigations - Other, BICARBONATE INCREASED   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Investigations - Other, BICARBONATE LOW   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Investigations - Other, BICARBONATE SERUM LOW   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, BUN DECREASED   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, CHLORIDE INCREASED   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, ELEVATED BUN   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, ELEVATED LDH   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, HARD STOOL   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, HCT INCREASED   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, HIGH PLATELET COUNT   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, HYPOCHLOREMIA   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, INCREASED WBC L   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, LOW BICARBONATE   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, MONOCYTE COUNT INCREASED   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, NEUTROPHIL COUNT INCREASED   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Investigations - Other, PLATELETS INCREASED   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Lymphocyte count decreased   1/3 (33.33%)  2/3 (66.67%)  2/3 (66.67%)  10/13 (76.92%)  4/6 (66.67%)  1/3 (33.33%)  4/9 (44.44%) 
Neutrophil count decreased   1/3 (33.33%)  2/3 (66.67%)  1/3 (33.33%)  7/13 (53.85%)  3/6 (50.00%)  0/3 (0.00%)  5/9 (55.56%) 
Platelet count decreased   2/3 (66.67%)  1/3 (33.33%)  1/3 (33.33%)  9/13 (69.23%)  4/6 (66.67%)  2/3 (66.67%)  5/9 (55.56%) 
Weight gain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  2/6 (33.33%)  0/3 (0.00%)  0/9 (0.00%) 
Weight loss   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  1/6 (16.67%)  2/3 (66.67%)  1/9 (11.11%) 
White blood cell decreased   1/3 (33.33%)  2/3 (66.67%)  2/3 (66.67%)  10/13 (76.92%)  5/6 (83.33%)  3/3 (100.00%)  7/9 (77.78%) 
Metabolism and nutrition disorders               
Anorexia   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  7/13 (53.85%)  1/6 (16.67%)  2/3 (66.67%)  3/9 (33.33%) 
Dehydration   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Hypercalcemia   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  2/9 (22.22%) 
Hyperglycemia   2/3 (66.67%)  1/3 (33.33%)  2/3 (66.67%)  5/13 (38.46%)  2/6 (33.33%)  0/3 (0.00%)  3/9 (33.33%) 
Hypermagnesemia   1/3 (33.33%)  1/3 (33.33%)  0/3 (0.00%)  3/13 (23.08%)  0/6 (0.00%)  0/3 (0.00%)  5/9 (55.56%) 
Hypernatremia   0/3 (0.00%)  2/3 (66.67%)  0/3 (0.00%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  2/9 (22.22%) 
Hypoalbuminemia   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  5/13 (38.46%)  3/6 (50.00%)  2/3 (66.67%)  4/9 (44.44%) 
Hypocalcemia   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  2/13 (15.38%)  1/6 (16.67%)  2/3 (66.67%)  3/9 (33.33%) 
Hypoglycemia   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  1/6 (16.67%)  1/3 (33.33%)  0/9 (0.00%) 
Hypokalemia   1/3 (33.33%)  0/3 (0.00%)  1/3 (33.33%)  2/13 (15.38%)  0/6 (0.00%)  2/3 (66.67%)  2/9 (22.22%) 
Hypomagnesemia   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  1/9 (11.11%) 
Hyponatremia   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  1/6 (16.67%)  2/3 (66.67%)  4/9 (44.44%) 
Hypophosphatemia   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  4/13 (30.77%)  2/6 (33.33%)  0/3 (0.00%)  2/9 (22.22%) 
Metabolism and nutrition disorders - Other, CHLORIDE LEVEL   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Obesity   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Musculoskeletal and connective tissue disorders               
Arthralgia   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Avascular necrosis   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Back pain   2/3 (66.67%)  0/3 (0.00%)  0/3 (0.00%)  3/13 (23.08%)  3/6 (50.00%)  2/3 (66.67%)  3/9 (33.33%) 
Bone pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Buttock pain   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Chest wall pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Flank pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Generalized muscle weakness   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  1/13 (7.69%)  2/6 (33.33%)  0/3 (0.00%)  0/9 (0.00%) 
Joint range of motion decreased   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Kyphosis   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Muscle weakness left-sided   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Muscle weakness lower limb   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Muscle weakness right-sided   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  3/13 (23.08%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Muscle weakness trunk   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Muscle weakness upper limb   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  1/6 (16.67%)  1/3 (33.33%)  0/9 (0.00%) 
Musculoskeletal and connective tissue disorder - Other, L WRIST CONTRACTURE   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Musculoskeletal and connective tissue disorder - Other, LARGE OCCIPITAL SKULL DEFECT   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Musculoskeletal and connective tissue disorder - Other, LEG CRAMPS   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Musculoskeletal and connective tissue disorder - Other, LEG SPASMS   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Myalgia   0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Neck pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  1/6 (16.67%)  0/3 (0.00%)  2/9 (22.22%) 
Pain in extremity   1/3 (33.33%)  0/3 (0.00%)  1/3 (33.33%)  3/13 (23.08%)  3/6 (50.00%)  2/3 (66.67%)  5/9 (55.56%) 
Scoliosis   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)               
Tumor pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Nervous system disorders               
Abducens nerve disorder   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Ataxia   0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  3/13 (23.08%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Brachial plexopathy   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Cognitive disturbance   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Concentration impairment   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Depressed level of consciousness   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Dizziness   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  1/6 (16.67%)  1/3 (33.33%)  3/9 (33.33%) 
Dysarthria   0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  1/13 (7.69%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Dysgeusia   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Dysphasia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Encephalopathy   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Facial nerve disorder   0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  5/13 (38.46%)  1/6 (16.67%)  1/3 (33.33%)  0/9 (0.00%) 
Glossopharyngeal nerve disorder   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Headache   3/3 (100.00%)  1/3 (33.33%)  1/3 (33.33%)  3/13 (23.08%)  0/6 (0.00%)  3/3 (100.00%)  5/9 (55.56%) 
Hydrocephalus   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Hypoglossal nerve disorder   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
IVth nerve disorder   0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Lethargy   0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Memory impairment   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Nervous system disorders - Other, DIFFICULTIES WITH BALANCE   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Nervous system disorders - Other, LEFT HEMIPLEGIA   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Neuralgia   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Nystagmus   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Oculomotor nerve disorder   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Paresthesia   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Peripheral motor neuropathy   1/3 (33.33%)  0/3 (0.00%)  1/3 (33.33%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Peripheral sensory neuropathy   1/3 (33.33%)  0/3 (0.00%)  1/3 (33.33%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Presyncope   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Pyramidal tract syndrome   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Recurrent laryngeal nerve palsy   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Seizure   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Somnolence   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Spasticity   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Tremor   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Psychiatric disorders               
Agitation   0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  1/13 (7.69%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Anxiety   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  4/13 (30.77%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Confusion   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  2/6 (33.33%)  0/3 (0.00%)  0/9 (0.00%) 
Delirium   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Depression   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Hallucinations   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Insomnia   1/3 (33.33%)  1/3 (33.33%)  1/3 (33.33%)  0/13 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  1/9 (11.11%) 
Psychiatric disorders - Other, HX OF ADHD   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Restlessness   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Renal and urinary disorders               
Cystitis noninfective   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Hematuria   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  1/3 (33.33%)  0/9 (0.00%) 
Hemoglobinuria   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Proteinuria   0/3 (0.00%)  1/3 (33.33%)  1/3 (33.33%)  1/13 (7.69%)  1/6 (16.67%)  0/3 (0.00%)  3/9 (33.33%) 
Renal and urinary disorders - Other, BLADDER PAIN   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Renal and urinary disorders - Other, GLUCOSE IN URINE   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Urinary frequency   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Urinary incontinence   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Urinary retention   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  1/3 (33.33%)  1/9 (11.11%) 
Urinary tract obstruction   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Urinary tract pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Urinary urgency   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Urine discoloration   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Reproductive system and breast disorders               
Penile pain   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Respiratory, thoracic and mediastinal disorders               
Allergic rhinitis   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  0/9 (0.00%) 
Atelectasis   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Cough   1/3 (33.33%)  0/3 (0.00%)  2/3 (66.67%)  3/13 (23.08%)  3/6 (50.00%)  1/3 (33.33%)  2/9 (22.22%) 
Dyspnea   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  3/13 (23.08%)  0/6 (0.00%)  0/3 (0.00%)  2/9 (22.22%) 
Epistaxis   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  3/13 (23.08%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Hiccups   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Hypoxia   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  2/9 (22.22%) 
Nasal congestion   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  2/6 (33.33%)  0/3 (0.00%)  2/9 (22.22%) 
Pleural effusion   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Productive cough   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Respiratory, thoracic and mediastinal disorders - Other, ASTHMA   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Respiratory, thoracic and mediastinal disorders - Other, OBSTRUCTIVE SLEEP APNEA   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Respiratory, thoracic and mediastinal disorders - Other, REQUIRES TRACH WITH FLOW OVERNIGHT   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Respiratory, thoracic and mediastinal disorders - Other, RETRACTIONS   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Respiratory, thoracic and mediastinal disorders - Other, RHINORRHEA   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Respiratory, thoracic and mediastinal disorders - Other, SHORTNESS OF BREATH   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Respiratory, thoracic and mediastinal disorders - Other, TACHYPNEA   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Respiratory, thoracic and mediastinal disorders - Other, WHEEZING   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Sore throat   0/3 (0.00%)  0/3 (0.00%)  2/3 (66.67%)  2/13 (15.38%)  1/6 (16.67%)  1/3 (33.33%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders               
Alopecia   1/3 (33.33%)  1/3 (33.33%)  1/3 (33.33%)  6/13 (46.15%)  2/6 (33.33%)  1/3 (33.33%)  3/9 (33.33%) 
Dry skin   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  2/13 (15.38%)  2/6 (33.33%)  0/3 (0.00%)  0/9 (0.00%) 
Hirsutism   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Hyperhidrosis   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Pain of skin   0/3 (0.00%)  0/3 (0.00%)  1/3 (33.33%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Periorbital edema   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Pruritus   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Rash acneiform   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Rash maculo-papular   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders - Other, ABRASION ON LEG   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders - Other, ERYTHEMA   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Skin and subcutaneous tissue disorders - Other, LEFT LOWER LEG ERYTHEMA   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders - Other, MOM NOTICED DARK VEINS ON BACK   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders - Other, PEELING LEFT HEEL   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders - Other, PEELING SKIN ON HEEL AREA   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  1/3 (33.33%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders - Other, PEELING SKIN, FINGERTIPS   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders - Other, POISON IVY RASH   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders - Other, RASH   0/3 (0.00%)  1/3 (33.33%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders - Other, RED HANDS AND CHEEKS   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders - Other, RIGHT UPPER HEAD AND RIGHT POSTERIOR HEAD LESION   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders - Other, SKIN LESIONS   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Skin and subcutaneous tissue disorders - Other, TENDERNESS OVER SPINE   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  0/9 (0.00%) 
Skin hyperpigmentation   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Skin hypopigmentation   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Skin ulceration   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  0/6 (0.00%)  0/3 (0.00%)  1/9 (11.11%) 
Vascular disorders               
Hypertension   1/3 (33.33%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  2/6 (33.33%)  2/3 (66.67%)  1/9 (11.11%) 
Hypotension   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  2/13 (15.38%)  0/6 (0.00%)  0/3 (0.00%)  2/9 (22.22%) 
Lymphedema   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  1/13 (7.69%)  0/6 (0.00%)  0/3 (0.00%)  0/9 (0.00%) 
Thromboembolic event   0/3 (0.00%)  0/3 (0.00%)  0/3 (0.00%)  0/13 (0.00%)  1/6 (16.67%)  0/3 (0.00%)  1/9 (11.11%) 
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Results Reporting Coordinator
Organization: Children's Oncology Group
Phone: 626-447-0064
EMail: resultsreportingcoordinator@childrensoncologygroup.org
Layout table for additonal information
Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02116777    
Other Study ID Numbers: NCI-2014-00804
NCI-2014-00804 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
ADVL1411 ( Other Identifier: Pediatric Early Phase Clinical Trial Network )
ADVL1411 ( Other Identifier: CTEP )
UM1CA097452 ( U.S. NIH Grant/Contract )
First Submitted: April 15, 2014
First Posted: April 17, 2014
Results First Submitted: February 12, 2020
Results First Posted: March 26, 2021
Last Update Posted: March 26, 2021