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A Phase I Clinical and Pharmacodynamic Study of MLN8237, A Novel Aurora A Kinase Inhibitor, in Participants With Advanced Malignancies

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ClinicalTrials.gov Identifier: NCT00651664
Recruitment Status : Completed
First Posted : April 3, 2008
Results First Posted : March 15, 2019
Last Update Posted : March 15, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Study Type Interventional
Study Design Allocation: Non-Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Advanced Malignancies
Intervention Drug: alisertib
Enrollment 59
Recruitment Details Participants took part in the study at 2 investigative sites in Spain from 22 October 2007 to 05 April 2011.
Pre-assignment Details Participants with a diagnosis of advanced malignancies were enrolled in a dose escalation study, alisertib 5, 80 150 mg once daily (QD) for 7 days; 50, 60, 75, 100 mg twice daily for 7 days; 50 mg QD for 14 days; 50, 70 mg QD for 21 days.
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Hide Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles). Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles). Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Period Title: Overall Study
Started 3 3 3 14 6 3 6 7 7 7
Completed 0 0 0 0 0 0 0 0 0 0
Not Completed 3 3 3 14 6 3 6 7 7 7
Reason Not Completed
Occurrence of Adverse Event(s)             0             0             0             0             0             0             1             0             1             0
Unsatisfactory Therapeutic Response             0             0             0             0             1             1             0             1             0             1
Progressive Disease             3             3             3             12             4             1             3             6             5             5
Patient Declined Further Treatment             0             0             0             1             1             1             0             0             0             1
Symptomatic Deterioration             0             0             0             1             0             0             1             0             1             0
Reason not Specified             0             0             0             0             0             0             1             0             0             0
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D Total
Hide Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles). Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles). Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles). Total of all reporting groups
Overall Number of Baseline Participants 3 3 3 14 6 3 6 7 7 7 59
Hide Baseline Analysis Population Description
Safety population was defined as all participants who received any amount of study drug.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3 participants 3 participants 3 participants 14 participants 6 participants 3 participants 6 participants 7 participants 7 participants 7 participants 59 participants
52.7  (9.07) 62.3  (13.80) 55.7  (20.79) 62.5  (11.67) 59.2  (18.74) 48.3  (14.84) 58.7  (8.69) 58.0  (13.83) 53.0  (11.08) 64.7  (5.53) 58.8  (12.46)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 14 participants 6 participants 3 participants 6 participants 7 participants 7 participants 7 participants 59 participants
Female
0
   0.0%
1
  33.3%
2
  66.7%
6
  42.9%
4
  66.7%
0
   0.0%
2
  33.3%
2
  28.6%
3
  42.9%
2
  28.6%
22
  37.3%
Male
3
 100.0%
2
  66.7%
1
  33.3%
8
  57.1%
2
  33.3%
3
 100.0%
4
  66.7%
5
  71.4%
4
  57.1%
5
  71.4%
37
  62.7%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 14 participants 6 participants 3 participants 6 participants 7 participants 7 participants 7 participants 59 participants
Hispanic/Latino 3 3 3 14 6 3 6 7 6 5 56
Not Hispanic/Latino 0 0 0 0 0 0 0 0 1 2 3
Race/Ethnicity, Customized   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 3 participants 3 participants 3 participants 14 participants 6 participants 3 participants 6 participants 7 participants 7 participants 7 participants 59 participants
3 3 3 14 6 3 6 7 7 7 59
[1]
Measure Description: White
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Spain Number Analyzed 3 participants 3 participants 3 participants 14 participants 6 participants 3 participants 6 participants 7 participants 7 participants 7 participants 59 participants
3 3 3 14 6 3 6 7 7 7 59
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 3 participants 3 participants 3 participants 14 participants 6 participants 3 participants 6 participants 7 participants 7 participants 7 participants 59 participants
164.0  (7.21) 164.3  (10.79) 167.3  (1.53) 165.8  (9.26) 160.5  (4.76) 171.3  (10.26) 165.2  (10.21) 169.9  (10.92) 160.4  (11.57) 167.6  (8.40) 165.4  (9.15)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 3 participants 3 participants 3 participants 14 participants 6 participants 3 participants 6 participants 7 participants 7 participants 7 participants 59 participants
83.7  (32.13) 75.2  (10.56) 70.3  (4.24) 74.4  (16.48) 64.8  (6.83) 90.5  (7.74) 69.6  (16.22) 76.7  (15.06) 69.1  (14.78) 77.9  (11.91) 74.0  (14.95)
Body Surface Area (BSA)   [1] 
Mean (Standard Deviation)
Unit of measure:  M^2
Number Analyzed 3 participants 3 participants 3 participants 14 participants 6 participants 3 participants 6 participants 7 participants 7 participants 7 participants 59 participants
1.93  (0.393) 1.85  (0.191) 1.81  (0.047) 1.85  (0.225) 1.70  (0.102) 2.07  (0.098) 1.78  (0.244) 1.87  (0.204) 1.75  (0.231) 1.90  (0.145) 1.84  (0.208)
[1]
Measure Description: BSA = square root [ height (cm) x weight (kg) / 3600 ]
1.Primary Outcome
Title Number of Participants With Dose-Limiting Toxicity (DLT)
Hide Description

DLT was evaluated using the National Cancer Institutes Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0; defined as any of the following events related to alisertib therapy:

  1. Grade 4 neutropenia lasting for ≥7 consecutive days during recovery
  2. Grade 4 neutropenia with fever and/or infection
  3. Confirmed platelet count <25,000/mm^3
  4. ≥Grade 3 nausea and/or emesis despite the use of an antiemetic prophylaxis
  5. ≥Grade 3 diarrhea that occurred despite therapy with loperamide
  6. Any other Grade 3 or greater nonhematologic toxicity, with the following exceptions: Grade 3 arthralgia/myalgias, Any grade of alopecia, Brief (< 1 week) Grade 3 fatigue
  7. Treatment delay of >1 week because of a failure of adequate hematologic or nonhematologic recovery from the previous cycle of treatment.
  8. Other alisertib-related nonhematologic toxicities ≥ Grade 2 that, in the opinion of the investigator, required a dose reduction or discontinuation of therapy with alisertib.
Time Frame First dose through 30 days following the last dose of study drug (up to 730 days)
Hide Outcome Measure Data
Hide Analysis Population Description
DLT Evaluable Population was defined as all participants who received at least 75% of their planned alisertib doses for their first cycle of treatment (unless interrupted by DLT) and had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Hide Arm/Group Description:
Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).
Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).
Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).
Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).
Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Overall Number of Participants Analyzed 3 3 3 12 6 2 6 6 7 6
Measure Type: Number
Unit of Measure: participants
0 0 0 0 2 2 3 1 1 3
2.Primary Outcome
Title Maximum Tolerated Dose (MTD) of Alisertib
Hide Description The MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 participants.
Time Frame Signing of the Informed Consent through 30 days following the last dose of study drug (up to 730 days)
Hide Outcome Measure Data
Hide Analysis Population Description
DLT Evaluable Population was defined as all participants who received at least 75% of their planned alisertib doses for their first cycle of treatment (unless interrupted by DLT) and had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.
Arm/Group Title Alisertib
Hide Arm/Group Description:
Alisertib 5, 80 or 150 mg, capsules, orally, once daily (QD) for 7 days, followed by a 14-day recovery period or alisertib 50, 60, 75 or 100 mg, capsules, orally, twice daily (BID) for 7 days, followed by a 14-day recovery period or alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period or alisertib 50 or 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
Overall Number of Participants Analyzed 54
Measure Type: Number
Unit of Measure: mg BID for 7 Days
50
3.Secondary Outcome
Title Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
Hide Arm/Group Description:
Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).
Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).
Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).
Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
Overall Number of Participants Analyzed 3 3 3 14 6 3 6
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nanomolar (nM)
Day 1 Number Analyzed 3 participants 3 participants 3 participants 14 participants 6 participants 3 participants 6 participants
123.15
(6.554%)
1774.12
(36.496%)
2014.81
(22.038%)
1035.3
(75.70%)
1536.1
(44.70%)
1266.6
(45.69%)
3196.4
(51.11%)
Day 7 Number Analyzed 3 participants 3 participants 3 participants 10 participants 6 participants 3 participants 5 participants
109.13
(34.458%)
1502.89
(32.818%)
4136.24
(26.253%)
1964.4
(46.26%)
3412.5
(27.06%)
5710.4
(23.89%)
4694.2
(38.86%)
4.Secondary Outcome
Title Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7
Hide Outcome Measure Data
Hide Analysis Population Description
PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
Hide Arm/Group Description:
Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).
Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).
Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).
Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
Overall Number of Participants Analyzed 3 3 3 14 6 3 6
Median (Full Range)
Unit of Measure: hour(hr)
Day 1 Number Analyzed 3 participants 3 participants 3 participants 14 participants 6 participants 3 participants 6 participants
1.920
(1.58 to 2.00)
2.730
(1.70 to 4.00)
4.000
(2.00 to 5.90)
2.040
(2.00 to 6.17)
2.000
(2.00 to 4.08)
2.000
(2.00 to 2.10)
3.835
(1.98 to 4.08)
Day 7 Number Analyzed 3 participants 3 participants 3 participants 12 participants 6 participants 3 participants 5 participants
1.670
(1.00 to 1.97)
1.580
(1.50 to 6.00)
1.550
(1.42 to 3.43)
2.000
(1.25 to 8.00)
2.000
(0.92 to 4.00)
4.170
(1.75 to 5.83)
1.580
(1.00 to 6.00)
5.Secondary Outcome
Title AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7
Hide Outcome Measure Data
Hide Analysis Population Description
PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
Hide Arm/Group Description:
Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).
Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).
Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).
Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
Overall Number of Participants Analyzed 3 3 3 14 6 3 6
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nM*hour(h)
Day 1 Number Analyzed 1 participants 3 participants 3 participants 12 participants 4 participants 2 participants 4 participants
975.0 [1] 
(NA%)
18204.2
(36.19%)
27262.7
(38.0%)
6314.1
(82.32%)
9771.5
(53.77%)
6895.3
(9.21%)
16541.5
(65.99%)
Day 7 Number Analyzed 2 participants 3 participants 3 participants 9 participants 6 participants 3 participants 5 participants
658.5
(35.64%)
16101.6
(38.81%)
48421.8
(36.53%)
17795.6
(43.87%)
25853.3
(41.44%)
51684.4
(24.87%)
40166.7
(51.90%)
[1]
CV was not calculated for 1 participant.
6.Secondary Outcome
Title Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7 or 8 (BID arms)
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for t1/2 analysis.
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
Hide Arm/Group Description:
Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).
Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).
Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).
Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
Overall Number of Participants Analyzed 0 2 3 9 6 3 6
Mean (Standard Deviation)
Unit of Measure: hr
18.25  (8.697) 19.80  (6.129) 15.913  (6.4766) 19.475  (15.5019) 18.500  (7.6295) 13.637  (6.8712)
7.Secondary Outcome
Title Accumulation Ratio (Rac) for Alisertib 7 Day Dosing
Hide Description Rac for Day 7=AUCt Day 7/AUCt Day 1.
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis Rac.
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
Hide Arm/Group Description:
Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).
Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).
Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).
Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
Overall Number of Participants Analyzed 1 3 3 8 4 2 4
Mean (Standard Deviation)
Unit of Measure: ratio
0.874  (0) 0.892  (0.1331) 1.954  (0.9092) 2.295  (0.9846) 2.583  (0.8959) 7.765  (1.9163) 2.350  (1.4926)
8.Secondary Outcome
Title Peak/Trough Ratio for Aliserib 7 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis.
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
Hide Arm/Group Description:
Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).
Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).
Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).
Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
Overall Number of Participants Analyzed 2 3 3 9 6 3 5
Mean (Standard Deviation)
Unit of Measure: ratio
5.950  (0.3253) 4.650  (0.2163) 4.507  (0.3029) 3.083  (2.2296) 3.050  (1.4056) 1.867  (0.6009) 2.256  (1.2013)
9.Secondary Outcome
Title CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for CLss/F analysis.
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
Hide Arm/Group Description:
Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).
Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).
Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).
Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
Overall Number of Participants Analyzed 3 3 3 9 6 3 5
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: liter(L)/hr
14.055
(27.6995%)
9.604
(35.5110%)
5.967
(31.2592%)
5.414
(57.9221%)
4.182
(51.2761%)
2.795
(23.5794%)
4.798
(49.4182%)
10.Secondary Outcome
Title Cmax: Maximum Observed Concentration for Alisertib 14 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Hide Outcome Measure Data
Hide Analysis Population Description
PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 14D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
Overall Number of Participants Analyzed 7
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nM
Day 1 Number Analyzed 7 participants
1145.4
(53.09%)
Day 7 Number Analyzed 6 participants
1418.1
(70.96%)
Day 14 Number Analyzed 6 participants
1671.1
(51.66%)
11.Secondary Outcome
Title Tmax: Time of First Occurrence of Cmax for Alisertib 14 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Hide Outcome Measure Data
Hide Analysis Population Description
PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 14D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
Overall Number of Participants Analyzed 7
Median (Full Range)
Unit of Measure: hr
Day 1 Number Analyzed 7 participants
2.030
(1.00 to 6.00)
Day 7 Number Analyzed 6 participants
2.000
(2.00 to 4.00)
Day 14 Number Analyzed 6 participants
2.000
(1.02 to 4.00)
12.Secondary Outcome
Title AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 14 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 14D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
Overall Number of Participants Analyzed 7
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nM*hr
Day 1 Number Analyzed 5 participants
15363.0
(24.82%)
Day 7 Number Analyzed 6 participants
17918.8
(78.55%)
Day 14 Number Analyzed 6 participants
16449.8
(59.87%)
13.Secondary Outcome
Title Terminal Half-Life (t1/2) for Alisertib 14 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data for analysis of t1/2. No data was available for analysis at Day 7.
Arm/Group Title Alisertib 50 mg QD 14D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
Overall Number of Participants Analyzed 5
Mean (Standard Deviation)
Unit of Measure: hr
26.62  (13.611)
14.Secondary Outcome
Title Accumulation Ratio (Rac) for Alisertib 14 Day Dosing
Hide Description Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1.
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis Rac. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 14D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
Overall Number of Participants Analyzed 7
Mean (Standard Deviation)
Unit of Measure: ratio
Day 7 Number Analyzed 5 participants
1.671  (0.8242)
Day 14 Number Analyzed 4 participants
1.813  (0.5001)
15.Secondary Outcome
Title Peak/Trough Ratio for Aliserib 14 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 14D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
Overall Number of Participants Analyzed 7
Mean (Standard Deviation)
Unit of Measure: ratio
Day 7 Number Analyzed 6 participants
4.415  (2.5016)
Day 14 Number Analyzed 6 participants
7.412  (4.2472)
16.Secondary Outcome
Title CLss/F: Apparent Oral Clearance at Steady State 14 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for CLss/F analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 14D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
Overall Number of Participants Analyzed 7
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L/hr
Day 7 Number Analyzed 6 participants
5.381
(92.8272%)
Day 14 Number Analyzed 6 participants
5.856
(98.2758%)
17.Secondary Outcome
Title Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Hide Outcome Measure Data
Hide Analysis Population Description
PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).
Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Overall Number of Participants Analyzed 7 7
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nM
Day 1 Number Analyzed 7 participants 7 participants
1112.3
(42.99%)
2220.3
(47.57%)
Day 14 Number Analyzed 7 participants 5 participants
1524.1
(64.25%)
2595.0
(42.98%)
Day 21 Number Analyzed 6 participants 4 participants
1651.7
(30.70%)
2093.7
(11.68%)
18.Secondary Outcome
Title Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Hide Outcome Measure Data
Hide Analysis Population Description
PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).
Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Overall Number of Participants Analyzed 7 7
Median (Full Range)
Unit of Measure: hr
Day 1 Number Analyzed 7 participants 7 participants
4.000
(2.00 to 6.17)
2.000
(2.00 to 2.02)
Day 14 Number Analyzed 7 participants 5 participants
2.070
(1.00 to 4.00)
2.130
(2.00 to 5.08)
Day 21 Number Analyzed 6 participants 4 participants
2.100
(2.00 to 24.80)
2.125
(2.00 to 2.33)
19.Secondary Outcome
Title AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetic (PK) Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).
Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Overall Number of Participants Analyzed 7 7
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: nM*hr
Day 1 Number Analyzed 7 participants 7 participants
11701.0
(49.78%)
18953.4
(56.89%)
Day 14 Number Analyzed 7 participants 4 participants
20262.8
(71.34%)
30918.3
(55.68%)
Day 21 Number Analyzed 5 participants 4 participants
18264.9
(28.67%)
24515.6
(23.80%)
20.Secondary Outcome
Title Terminal Half-Life (t1/2) for Alisertib 21 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 21
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for t1/2 analysis.
Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).
Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Overall Number of Participants Analyzed 6 3
Mean (Standard Deviation)
Unit of Measure: hr
20.13  (6.326) 26.13  (9.780)
21.Secondary Outcome
Title Accumulation Ratio (Rac) for Alisertib 21 Day Dosing
Hide Description Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1. Rac for Day 21=AUCt Day 21/AUCt Day 1.
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis Rac. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).
Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Overall Number of Participants Analyzed 7 7
Mean (Standard Deviation)
Unit of Measure: ratio
Day 14 Number Analyzed 7 participants 4 participants
2.482  (2.7166) 2.103  (0.3861)
Day 21 Number Analyzed 5 participants 4 participants
1.678  (0.7587) 1.933  (1.1104)
22.Secondary Outcome
Title Peak/Trough Ratio for Aliserib 21 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).
Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Overall Number of Participants Analyzed 7 7
Mean (Standard Deviation)
Unit of Measure: ratio
Day 14 Number Analyzed 7 participants 4 participants
4.070  (2.4751) 3.628  (0.4864)
Day 21 Number Analyzed 5 participants 4 participants
4.792  (2.5652) 4.658  (2.1825)
23.Secondary Outcome
Title CLss/F: Apparent Oral Clearance at Steady State 21 Day Dosing
Hide Description [Not Specified]
Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for CLss/F analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).
Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Overall Number of Participants Analyzed 7 7
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: L/hr
Day 14 Number Analyzed 7 participants 4 participants
4.753
(70.5636%)
4.364
(47.3164%)
Day 21 Number Analyzed 5 participants 4 participants
5.276
(28.1356%)
5.593
(21.8384%)
24.Secondary Outcome
Title Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing
Hide Description Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time Frame Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Day 7, 6 and 24 hours post-dose.
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
Hide Arm/Group Description:
Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).
Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).
Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).
Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
Overall Number of Participants Analyzed 3 3 3 13 6 3 6
Mean (Standard Deviation)
Unit of Measure: cells/mm
Day 1, 6 Hours Post-Dose Number Analyzed 3 participants 3 participants 3 participants 13 participants 6 participants 2 participants 6 participants
0.187  (0.0709) 0.107  (0.0777) 0.197  (0.0814) 0.310  (0.2087) 0.378  (0.4107) 0.175  (0.2333) 0.850  (1.0741)
Day 7, 6 Hours Post-Dose Number Analyzed 3 participants 3 participants 3 participants 11 participants 6 participants 3 participants 6 participants
0.193  (0.1650) 0.617  (0.7514) 2.703  (0.7112) 3.489  (2.6893) 6.220  (5.7549) 8.757  (4.0493) 9.150  (8.9050)
Day 7, 24 Hours Post-Dose Number Analyzed 3 participants 3 participants 2 participants 9 participants 1 participants 2 participants 3 participants
0.140  (0.1179) 0.397  (0.2159) 5.270  (3.8325) 3.184  (4.4984) 1.250  (0.0000) 25.190  (1.7678) 17.123  (9.4877)
25.Secondary Outcome
Title Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing
Hide Description Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time Frame Cycle 1: Pre-dose (Baseline) and Day 1 and 7, 6 hours post-dose; Day 14, 6 and 24 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 14D
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Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
Overall Number of Participants Analyzed 7
Mean (Standard Deviation)
Unit of Measure: cells/mm
Day 1, 6 Hours Post-Dose Number Analyzed 1 participants
1.180  (0.0000)
Day 7, 6 Hours Post-Dose Number Analyzed 5 participants
0.950  (0.9963)
Day 14, 6 Hours Post-Dose Number Analyzed 5 participants
1.146  (1.6239)
Day 7, 24 Hours Post-Dose Number Analyzed 4 participants
0.368  (0.4464)
26.Secondary Outcome
Title Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing
Hide Description Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time Frame Cycle 1: Pre-dose (Baseline) and Day 7, 14 and 21, 6 hours post-dose
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Hide Analysis Population Description
Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).
Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Overall Number of Participants Analyzed 7 7
Mean (Standard Deviation)
Unit of Measure: cells/mm
Day 7, 6 Hours Post-Dose Number Analyzed 7 participants 7 participants
1.534  (1.9201) 1.900  (2.2774)
Day 14, 6 Hours Post-Dose Number Analyzed 7 participants 5 participants
0.341  (0.3182) 1.168  (0.7587)
Day 21, 6 Hours Post-Dose Number Analyzed 5 participants 4 participants
0.250  (1.453) 0.565  (0.5565)
27.Secondary Outcome
Title Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing
Hide Description Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
Time Frame Cycle 1: Day 1, 6 hours post-dose; Days 7 6 and 24 hours post-dose; Day 21: 6 hours post-dose
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Hide Analysis Population Description
Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
Hide Arm/Group Description:
Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).
Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).
Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).
Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
Overall Number of Participants Analyzed 3 3 3 13 6 3 6
Mean (Standard Deviation)
Unit of Measure: cells/mm
Day 1, 6 hour post-dose Number Analyzed 3 participants 3 participants 3 participants 13 participants 6 participants 2 participants 6 participants
0.080  (0.0693) 0.000  (0.0000) 0.097  (0.0850) 0.040  (0.0634) 0.000  (0.0000) 0.055  (0.0778) 0.242  (0.2566)
Day 7, 6 hour post-dose Number Analyzed 3 participants 3 participants 3 participants 11 participants 6 participants 3 participants 6 participants
0.040  (0.0693) 0.560  (0.9699) 1.303  (0.5950) 1.525  (2.2399) 3.173  (4.3170) 6.040  (1.9928) 5.162  (2.2801)
Day 7, 24 hour post-dose Number Analyzed 3 participants 3 participants 2 participants 9 participants 1 participants 2 participants 3 participants
0.040  (0.0693) 0.343  (0.4944) 2.145  (1.6476) 1.050  (1.749) 0.830  (0.00) 7.715  (0.1202) 4.713  (1.1924)
28.Secondary Outcome
Title Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing
Hide Description Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
Time Frame Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose
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Hide Analysis Population Description
Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 14D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
Overall Number of Participants Analyzed 7
Mean (Standard Deviation)
Unit of Measure: cells/mm
Day 1, 6 hours post-dose Number Analyzed 1 participants
0.000  (0.000)
Day 7, 6 hours post-dose Number Analyzed 5 participants
0.390  (0.8721)
Day 14, 6 hours post-dose Number Analyzed 5 participants
0.484  (0.7869)
Day 14, 24 hours post-dose Number Analyzed 4 participants
0.260  (0.3834)
29.Secondary Outcome
Title Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing
Hide Description Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
Time Frame Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose; Day 21: 6 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).
Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Overall Number of Participants Analyzed 7 7
Mean (Standard Deviation)
Unit of Measure: cells/mm
Day 7, 6 hours post-dose Number Analyzed 7 participants 7 participants
0.606  (0.9954) 0.379  (0.6276)
Day 14, 6 hours post-dose Number Analyzed 7 participants 5 participants
0.146  (0.2355) 0.404  (0.4334)
Day 21, 6 hours post-dose Number Analyzed 5 participants 4 participants
0.134  (0.1698) 0.230  (0.1283)
30.Secondary Outcome
Title Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing
Hide Description Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
Time Frame Cycle 1: Pre-dose (Baseline) and Days 1 and 7, 6 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
Hide Arm/Group Description:
Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles).
Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).
Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).
Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).
Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
Overall Number of Participants Analyzed 3 3 3 13 6 3 6
Mean (Standard Deviation)
Unit of Measure: percentage of cells
Day 1, 6 hours post-dose Number Analyzed 2 participants 1 participants 2 participants 5 participants 2 participants 1 participants 3 participants
0.125  (0.1061) 0.610  (0.0000) 6.460  (9.1075) 1.464  (1.3294) 1.080  (0.3394) 0.090  (0.0000) 2.907  (2.0284)
Day 7, 6 hours post-dose Number Analyzed 2 participants 1 participants 2 participants 5 participants 2 participants 1 participants 3 participants
1.145  (0.0354) 0.590  (0.0000) 15.500  (13.5623) 2.020  (2.9567) 3.115  (3.1608) 5.840  (0.0000) 3.527  (2.1258)
31.Secondary Outcome
Title Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 14 Day Dosing
Hide Description Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
Time Frame Cycle 1: Pre-dose (Baseline) and Day 7, 6 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamics Evaluable Population was defined as all participants who received at least the first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment.
Arm/Group Title Alisertib 50 mg QD 14D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
Overall Number of Participants Analyzed 7
Mean (Standard Deviation)
Unit of Measure: percentage of cells
0.008  (0.0000)
32.Secondary Outcome
Title Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing
Hide Description Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
Time Frame Cycle 1: Pre-dose (Baseline) and Days 7 and 21, 6 hours post-dose
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Hide Arm/Group Description:
Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).
Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Overall Number of Participants Analyzed 7 7
Mean (Standard Deviation)
Unit of Measure: percentage of cells
Day 7, 6 hours post-dose Number Analyzed 3 participants 4 participants
0.027  (0.0171) 0.050  (0.0243)
Day 21, 6 hours post-dose Number Analyzed 2 participants 2 participants
0.014  (0.0072) 0.054  (0.0038)
33.Other Pre-specified Outcome
Title Percentage of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1
Hide Description A blood sample was collected prior to alisertib dosing for the purpose of genotyping for polymorphisms in UGT1A1. The percentage of participants in the polymorphism categories: wt/wt, wt/*28, *28/*28, *28/wt, *28/other and other/other is reported. wt=wild type. *28 polymorphism in the promoter region of a UGT1A1 allele resulting in reduced UGT1A1 expression.
Time Frame Cycle 1: Pre-dose
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Safety population was defined as all participants who received any amount of study drug. A blood sample was not evaluable for 3 participants and was missing for 5 participants. Data is presented for one arm because the data was collected prior to the participant receiving their assigned treatment.
Arm/Group Title Alisertib
Hide Arm/Group Description:
Alisertib 5, 80 or 150 mg, capsules, orally, once daily (QD) for 7 days, followed by a 14-day recovery period or alisertib 50, 60, 75 or 100 mg, capsules, orally, twice daily (BID) for 7 days, followed by a 14-day recovery period or alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period or alisertib 50 or 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
Overall Number of Participants Analyzed 59
Measure Type: Number
Unit of Measure: percentage of participants
wt/wt 34
wt/*28 44
*28/*28 7
*28/wt 0
*28/other 0
other/other 2
Time Frame Signing of the Informed Consent through 30 days following the last dose of study drug (up to 730 days)
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
 
Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Hide Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles). Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles). Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
All-Cause Mortality
Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/3 (33.33%)      1/3 (33.33%)      1/3 (33.33%)      6/14 (42.86%)      3/6 (50.00%)      1/3 (33.33%)      5/6 (83.33%)      1/7 (14.29%)      3/7 (42.86%)      4/7 (57.14%)    
Blood and lymphatic system disorders                     
Neutropenia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 1/6 (16.67%)  1 0/3 (0.00%)  0 2/6 (33.33%)  2 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Febrile neutropenia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Lymphadenopathy  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Gastrointestinal disorders                     
Diarrhoea  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 1/6 (16.67%)  1 0/3 (0.00%)  0 2/6 (33.33%)  2 0/7 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1
Stomatitis  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 3/6 (50.00%)  3 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Enteritis  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1
Lower gastrointestinal haemorrhage  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Vomiting  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
General disorders                     
Pyrexia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 1/6 (16.67%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1
Infections and infestations                     
Escherichia urinary tract infection  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Pneumonia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0
Respiratory tract infection  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0
Injury, poisoning and procedural complications                     
Accidental overdose  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Incorrect dose administered  1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Metabolism and nutrition disorders                     
Hypomagnesaemia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Musculoskeletal and connective tissue disorders                     
Pathological fracture  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)                     
Cancer pain  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0
Metastases to central nervous system  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1
Metastases to meninges  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1
Nervous system disorders                     
Headache  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Somnolence  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Spinal cord compression  1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Psychiatric disorders                     
Bradyphrenia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1
Renal and urinary disorders                     
Renal failure  1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Respiratory, thoracic and mediastinal disorders                     
Pulmonary embolism  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 8.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   3/39 (7.69%)      3/30 (10.00%)      3/101 (2.97%)      14/142 (9.86%)      6/68 (8.82%)      3/68 (4.41%)      6/194 (3.09%)      7/119 (5.88%)      7/67 (10.45%)      7/68 (10.29%)    
Blood and lymphatic system disorders                     
Anaemia  1  2/3 (66.67%)  2 2/3 (66.67%)  3 2/3 (66.67%)  3 8/14 (57.14%)  11 4/6 (66.67%)  4 3/3 (100.00%)  4 5/6 (83.33%)  6 5/7 (71.43%)  6 4/7 (57.14%)  4 1/7 (14.29%)  1
Leukopenia  1  0/3 (0.00%)  0 1/3 (33.33%)  2 2/3 (66.67%)  8 8/14 (57.14%)  11 3/6 (50.00%)  3 2/3 (66.67%)  7 6/6 (100.00%)  9 2/7 (28.57%)  3 1/7 (14.29%)  1 4/7 (57.14%)  4
Neutropenia  1  0/3 (0.00%)  0 1/3 (33.33%)  1 3/3 (100.00%)  9 4/14 (28.57%)  5 4/6 (66.67%)  6 2/3 (66.67%)  7 3/6 (50.00%)  8 2/7 (28.57%)  2 3/7 (42.86%)  4 2/7 (28.57%)  2
Lymphopenia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 2/3 (66.67%)  4 9/14 (64.29%)  11 2/6 (33.33%)  2 1/3 (33.33%)  1 0/6 (0.00%)  0 6/7 (85.71%)  10 2/7 (28.57%)  2 0/7 (0.00%)  0
Thrombocytopenia  1  0/3 (0.00%)  0 1/3 (33.33%)  1 2/3 (66.67%)  5 5/14 (35.71%)  8 2/6 (33.33%)  4 1/3 (33.33%)  3 5/6 (83.33%)  6 2/7 (28.57%)  4 0/7 (0.00%)  0 1/7 (14.29%)  1
Febrile neutropenia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  3 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Leukocytosis  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Cardiac disorders                     
Palpitations  1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Ear and labyrinth disorders                     
Ear pain  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Eye disorders                     
Keratitis  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 1/6 (16.67%)  1 2/3 (66.67%)  3 2/6 (33.33%)  12 0/7 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0
Dry eye  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Vision blurred  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Gastrointestinal disorders                     
Nausea  1  1/3 (33.33%)  3 0/3 (0.00%)  0 2/3 (66.67%)  8 1/14 (7.14%)  1 2/6 (33.33%)  2 1/3 (33.33%)  1 4/6 (66.67%)  9 2/7 (28.57%)  2 3/7 (42.86%)  6 5/7 (71.43%)  5
Stomatitis  1  0/3 (0.00%)  0 1/3 (33.33%)  1 2/3 (66.67%)  6 3/14 (21.43%)  3 2/6 (33.33%)  2 2/3 (66.67%)  7 3/6 (50.00%)  6 0/7 (0.00%)  0 3/7 (42.86%)  3 1/7 (14.29%)  1
Diarrhoea  1  1/3 (33.33%)  4 0/3 (0.00%)  0 1/3 (33.33%)  2 2/14 (14.29%)  2 3/6 (50.00%)  3 2/3 (66.67%)  4 2/6 (33.33%)  9 1/7 (14.29%)  3 2/7 (28.57%)  4 2/7 (28.57%)  3
Vomiting  1  1/3 (33.33%)  5 0/3 (0.00%)  0 1/3 (33.33%)  4 0/14 (0.00%)  0 2/6 (33.33%)  3 1/3 (33.33%)  1 3/6 (50.00%)  3 3/7 (42.86%)  4 2/7 (28.57%)  7 3/7 (42.86%)  3
Abdominal pain  1  0/3 (0.00%)  0 1/3 (33.33%)  1 1/3 (33.33%)  1 1/14 (7.14%)  2 2/6 (33.33%)  2 0/3 (0.00%)  0 2/6 (33.33%)  3 3/7 (42.86%)  3 0/7 (0.00%)  0 0/7 (0.00%)  0
Dyspepsia  1  1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  2 0/14 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 1/7 (14.29%)  1 1/7 (14.29%)  1
Abdominal pain upper  1  2/3 (66.67%)  2 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 1/6 (16.67%)  3 0/3 (0.00%)  0 0/6 (0.00%)  0 2/7 (28.57%)  2 0/7 (0.00%)  0 0/7 (0.00%)  0
Constipation  1  1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  2 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 3/7 (42.86%)  3
Enteritis  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 3/14 (21.43%)  3 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 2/7 (28.57%)  4 0/7 (0.00%)  0 0/7 (0.00%)  0
Dry mouth  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 2/6 (33.33%)  2 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Proctalgia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 3/6 (50.00%)  4 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Rectal tenesmus  1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  2 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 2/6 (33.33%)  5 0/7 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1
Rectal haemorrhage  1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  1 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 2/6 (33.33%)  3 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Anal fissure  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 2/6 (33.33%)  2 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Haematochezia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Abdominal distension  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Aphthous stomatitis  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Ascites  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Colonic haemorrhage  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Dysphagia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Flatulence  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 1/6 (16.67%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Haemorrhoids  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Odynophagia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Oral pain  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Perianal erythema  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
General disorders                     
Asthenia  1  3/3 (100.00%)  3 0/3 (0.00%)  0 2/3 (66.67%)  9 3/14 (21.43%)  3 3/6 (50.00%)  3 2/3 (66.67%)  2 5/6 (83.33%)  10 3/7 (42.86%)  3 6/7 (85.71%)  6 4/7 (57.14%)  4
Pyrexia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 1/3 (33.33%)  4 1/14 (7.14%)  1 1/6 (16.67%)  1 1/3 (33.33%)  1 5/6 (83.33%)  8 4/7 (57.14%)  5 1/7 (14.29%)  1 2/7 (28.57%)  2
Oedema peripheral  1  1/3 (33.33%)  1 0/3 (0.00%)  0 1/3 (33.33%)  1 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 1/7 (14.29%)  1
Chills  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 2/6 (33.33%)  2 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Chest pain  1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1
Feeling jittery  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Gait disturbance  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Red man syndrome  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Hepatobiliary disorders                     
Hepatic pain  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/14 (14.29%)  2 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Hyperbilirubinaemia  1  0/3 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  2
Jaundice  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Infections and infestations                     
Nasopharyngitis  1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 1/6 (16.67%)  1 2/3 (66.67%)  2 3/6 (50.00%)  3 2/7 (28.57%)  2 1/7 (14.29%)  2 0/7 (0.00%)  0
Oral candidiasis  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Respiratory tract infection  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 1/7 (14.29%)  2 0/7 (0.00%)  0
Bronchitis  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Catheter related infection  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Gastroenteritis escherichia coli  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Herpes simplex  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1
Nail infection  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Urinary tract infection  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Injury, poisoning and procedural complications                     
Accidental overdose  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1
Incorrect dose administered  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Upper limb fracture  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0
Investigations                     
Blood alkaline phosphatase increased  1  1/3 (33.33%)  1 1/3 (33.33%)  1 0/3 (0.00%)  0 5/14 (35.71%)  6 0/6 (0.00%)  0 1/3 (33.33%)  1 4/6 (66.67%)  4 3/7 (42.86%)  3 0/7 (0.00%)  0 2/7 (28.57%)  2
Alanine aminotransferase increased  1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 7/14 (50.00%)  8 1/6 (16.67%)  1 1/3 (33.33%)  1 1/6 (16.67%)  1 3/7 (42.86%)  5 1/7 (14.29%)  1 1/7 (14.29%)  1
Aspartate aminotransferase increased  1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 4/14 (28.57%)  6 2/6 (33.33%)  2 0/3 (0.00%)  0 0/6 (0.00%)  0 2/7 (28.57%)  3 1/7 (14.29%)  1 2/7 (28.57%)  2
Gamma-glutamyltransferase increased  1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 4/14 (28.57%)  4 0/6 (0.00%)  0 1/3 (33.33%)  1 3/6 (50.00%)  3 2/7 (28.57%)  3 0/7 (0.00%)  0 1/7 (14.29%)  1
Blood creatinine increased  1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 2/14 (14.29%)  2 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 1/7 (14.29%)  1 0/7 (0.00%)  0 1/7 (14.29%)  1
Blood bilirubin increased  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 0/6 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Blood urea increased  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 2/14 (14.29%)  2 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Activated partial thromboplastin time prolonged  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Platelet count decreased  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1 0/7 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0
Blood creatinine decreased  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Red blood cell count decreased  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 1/14 (7.14%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Transaminases increased  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 1/3 (33.33%)  1 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Weight decreased  1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 0/14 (0.00%)  0 0/6 (0.00%)  0 0/3 (0.00%)  0 0/6 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0 0/7 (0.00%)  0
Metabolism and nutrition disorders                     
Anorexia  1  2/3 (66.67%)  2 0/3 (0.00%)  0 2/3 (66.67%)  5 1/14 (7.14%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 2/6 (33.33%)  8 1/7 (14.29%)  1 4/7 (57.14%)  4 2/7 (28.57%)  3
Hyperkalaemia  1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 3/14 (21.43%)  4 1/6 (16.67%)  1 0/3 (0.00%)  0 2/6 (33.33%)  2 2/7 (28.57%)  4 0/7 (0.00%)  0 1/7 (14.29%)  1
Hyperglycaemia  1  0/3 (0.00%)  0 0/3 (0.00%)  0 0/3 (0.00%)  0 5/14 (35.71%)  5 1/6 (16.67%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 2/7 (28.57%)  2 0/7 (0.00%)  0 0/7 (0.00%)  0
Hyponatraemia  1  0/3 (0.00%)  0 1/3 (33.33%)  1 0/3 (0.00%)  0 3/14 (21.43%)  6 1/6 (16.67%)  1 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 1/7 (14.29%)  1 1/7 (14.29%)  1
Hypercholesterolaemia  1  1/3 (33.33%)  1 0/3 (0.00%)  0 0/3 (0.00%)  0 3/14 (21.43%)  3 2/6 (33.33%)  2 0/3 (0.00%)  0 0/6 (0.00%)  0 1/7 (14.29%)  1 0/7 (0.00%)  0 0/7 (0.00%)  0
Hypocalcaemia  1  0/3 (0.00%)  0 1/3 (33.33%)  2 0/3 (0.00%)  0 1/14 (7.14%)  1 0/6 (0.00%)  0 0/3 (0.00%)  0 1/6 (16.67%)  1