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Clinical Trial Results:
Randomized Phase 2 Study of MLN8237, an Aurora A Kinase Inhibitor, Plus Weekly Paclitaxel or Weekly Paclitaxel Alone in Patients with Recurrent Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer, Preceded by a Phase 1 Portion in Patients with Ovarian or Breast Cancer

Summary
EudraCT number	2009-011428-79
Trial protocol	PL
Global end of trial date	19 Jul 2017

Results information
Results version number	v1(current)
This version publication date	11 Mar 2018
First version publication date	11 Mar 2018
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

C14008

ISRCTN number

US NCT number

NCT01091428

WHO universal trial number (UTN)

U1111-1191-6584

Sponsor organisation name

Takeda

Sponsor organisation address

40 Landsdowne Street, Cambridge, MA, United States, 02139

Public contact

Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosures@takeda.com

Scientific contact

Medical Director, Clinical Science, Takeda, +1 877-825-3327, trialdisclosures@takeda.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

19 Jul 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

12 Aug 2014

Global end of trial reached?

Yes

Global end of trial date

19 Jul 2017

Was the trial ended prematurely?

Main objective of the trial

The main objective of the trial is to evaluate MLN8237 in combination with weekly paclitaxel in adult female subjects with advanced breast cancer (Phase 1 portion only) and recurrent ovarian cancer (both Phase 1 and Phase 2 portions).

Protection of trial subjects

All study subjects were required to read and sign an Informed Consent Form.

Background therapy

Evidence for comparator

Actual start date of recruitment

16 Apr 2010

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 142

Country: Number of subjects enrolled

France: 31

Country: Number of subjects enrolled

Poland: 18

Worldwide total number of subjects

191

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

131

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects took part in the study at 33 investigative sites in France, Poland and the United States from 16 April 2010 to 19 July 2017. Data cutoff for the primary analysis was 12 August 2014.

Screening details

Subjects with a diagnosis of ovarian cancer or breast cancer were enrolled equally in a dose escalation study to determine the recommended Phase 2 dose. In Phase 2 subjects were randomized equally to receive alisertib 40 mg BID + paclitaxel 60 mg/m^2 or single-agent paclitaxel 80 mg/m^2.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Alisertib (Phase 1 - Ovarian Cancer)

Arm description

Subjects with ovarian cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).

Arm type

Experimental

Investigational medicinal product name

Alisertib

Investigational medicinal product code

Other name

MLN8237

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Alisertib Tablets

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel Intravenous Infusion

Alisertib (Phase 1 - Breast Cancer)

Arm description

Subjects with breast cancer received alisertib (MLN8237) 10, 20, 30 or 40 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 or 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1 (Up to 37 cycles).

Arm type

Experimental

Investigational medicinal product name

Alisertib

Investigational medicinal product code

Other name

MLN8237

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Alisertib Tablets

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel Intravenous Infusion

Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)

Arm description

Alisertib 40 mg, orally, BID on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

Arm type

Experimental

Investigational medicinal product name

Alisertib

Investigational medicinal product code

Other name

MLN8237

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Alisertib Tablets

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel intravenous Infusion

Paclitaxel 80 mg/m^2 (Phase 2)

Arm description

Paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

Arm type

Experimental

Investigational medicinal product name

Paclitaxel

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

Paclitaxel Intravenous Infusion

Number of subjects in period 1	Alisertib (Phase 1 - Ovarian Cancer)	Alisertib (Phase 1 - Breast Cancer)	Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)	Paclitaxel 80 mg/m^2 (Phase 2)
Started	38	11	73	69
Completed	0	0	0	0
Not completed	38	11	73	69
Unsatisfactory Therapeutic Response	-	-	1	1
Consent withdrawn by subject	7	-	9	8
Single-Patient IND	2	-	-	-
Physician Decision	-	-	2	-
Adverse event, non-fatal	2	-	12	5
Progressive Disease	24	8	44	46
Symptomatic Deterioration	3	2	1	6
Reason not specified	-	1	4	3

Baseline characteristics

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Reporting group title

Alisertib (Phase 1 - Ovarian Cancer)

Reporting group description

Reporting group title

Alisertib (Phase 1 - Breast Cancer)

Reporting group description

Reporting group title

Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)

Reporting group description

Alisertib 40 mg, orally, BID on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

Reporting group title

Paclitaxel 80 mg/m^2 (Phase 2)

Reporting group description

Paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

Reporting group values	Alisertib (Phase 1 - Ovarian Cancer)	Alisertib (Phase 1 - Breast Cancer)	Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)	Paclitaxel 80 mg/m^2 (Phase 2)	Total
Number of subjects	38	11	73	69	191
Age categorical
Units: Subjects
Age Continuous
Units: years
arithmetic mean (standard deviation)	55.8 ± 10.29	58.6 ± 10.06	61.0 ± 11.60	60.8 ± 8.41	-
Gender, Male/Female
Units: Subjects
Female	38	11	73	69	191
Male	0	0	0	0	0
Race/Ethnicity, Customized
Units: Subjects
Hispanic or Latino	4	0	1	4	9
Not Hispanic or Latino	34	10	64	62	170
Not Reported	0	1	7	3	11
Missing	0	0	1	0	1
Race/Ethnicity, Customized
Units: Subjects
White	34	11	66	55	166
Black or African American	3	0	2	6	11
Asian	1	0	1	2	4
American Indian or Alaskan Native	0	0	0	2	2
Other	0	0	1	1	2
Not Reported	0	0	2	3	5
Missing	0	0	1	0	1
Region of Enrollment
Units: Subjects
United States	38	11	48	45	142
Poland	0	0	10	8	18
France	0	0	15	16	31
Height
Units: cm
arithmetic mean (standard deviation)	164.2 ± 6.41	164.5 ± 6.38	162.4 ± 7.02	161.9 ± 7.30	-
Weight
Units: kg
arithmetic mean (standard deviation)	75.86 ± 16.41	76.29 ± 7.29	70.42 ± 14.78	72.50 ± 18.71	-
Body Surface Area
Body Surface Area (m^2) = square root [height (cm) x weight (kg) / 3600].
Units: m^2
arithmetic mean (standard deviation)	1.850 ± 0.21	1.865 ± 0.10	1.776 ± 0.20	1.794 ± 0.24	-

End points

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Reporting group title

Alisertib (Phase 1 - Ovarian Cancer)

Reporting group description

Reporting group title

Alisertib (Phase 1 - Breast Cancer)

Reporting group description

Reporting group title

Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)

Reporting group description

Alisertib 40 mg, orally, BID on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

Reporting group title

Paclitaxel 80 mg/m^2 (Phase 2)

Reporting group description

Paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

Subject analysis set title

Alisertib + Paclitaxel (Phase 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Alisertib + Paclitaxel

Subject analysis set type

Sub-group analysis

Subject analysis set description

Paclitaxel 60 or 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

Subject analysis set title

Alisertib 10 mg BID + Paclitaxel 80 mg/m^2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Alisertib (MLN8237) 10 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

Subject analysis set title

Alisertib 20 mg BID + Paclitaxel 80 mg/m^2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Alisertib 20 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

Subject analysis set title

Alisertib 20 mg BID + Paclitaxel 60 mg/m^2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Alisertib 20 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

Subject analysis set title

Alisertib 30 mg BID + Paclitaxel 60 mg/m^2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Alisertib 30 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase

Subject analysis set title

Alisertib 40 mg BID + Paclitaxel 60 mg/m^2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Alisertib 10 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

Subject analysis set title

Alisertib 50 mg BID + Paclitaxel 60 mg/m^2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Alisertib 10 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1

Subject analysis set title

Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 (Phase 2)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Alisertib 40 mg, orally, BID on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

Primary: Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) for Alisertib in Combination with Paclitaxel

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End point title

Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) for Alisertib in Combination with Paclitaxel ^[1]

End point description

MTD: Dose range at which ≤1 of 6 evaluable subjects experience dose limiting toxicities (DLT). DLT evaluated a/c to National Cancer Institute's Common Terminology Criteria for Adverse v4.02 & as any of events: 1.Grade 4 neutropenia & thrombocytopenia lasting ≥7 consecutive days; 2.Grade 4 neutropenia with fever/infection; 3.Platelet count <10,000/mm^3; 4.Grade 3 thrombocytopenia with bleeding; 5.Any other ≥Grade3 nonhematologic toxicity, with exceptions: ≥Grade3 nausea/emesis, ≥Grade3 diarrhoea, Grade3 fatigue, Grade3 nonhematological toxicity that is controlled to ≤Grade 2 with appropriate treatment; 6.Other alisertib-related nonhematologic toxicities ≥Grade2 that, in investigator opinion, required a dose reduction/discontinuation of therapy with alisertib. DLT-Evaluable Population: all subjects in phase 1 who experienced DLT during Cycle 1/completed treatment with 15 of planned 18 doses of alisertib & 2 of planned 3 doses of paclitaxel in Cycle 1 & had sufficient follow-up data.

End point type

Primary

End point timeframe

Cycle 1 (Up to 28 days)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses are reported for this endpoint.

End point values	Alisertib + Paclitaxel (Phase 1)
Number of subjects analysed	49
Units: mg	40

No statistical analyses for this end point

Primary: Phase 1: MTD and RP2D for Paclitaxel in Combination with Alisertib

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End point title

Phase 1: MTD and RP2D for Paclitaxel in Combination with Alisertib ^[2]

End point description

The RP2D is the maximum tolerated dose (MTD) or less. The MTD is defined as the dose range at which ≤ 1 of 6 evaluable subjects experience dose limiting toxicities (DLT) within the first 28 days of treatment (end of cycle 1). DLT-Evaluable Population was defined as all subjects in the phase 1 who either experienced DLT during Cycle 1 or completed treatment with at least 15 of the planned 18 doses of alisertib and 2 of the planned 3 doses of paclitaxel in Cycle 1 and had sufficient follow-up data.

End point type

Primary

End point timeframe

Cycle 1 (Up to 28 days)

Notes
[2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses are reported for this endpoint.

End point values	Alisertib + Paclitaxel
Number of subjects analysed	49
Units: mg/m^2	60

No statistical analyses for this end point

Primary: Phase 1: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Phase 1: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) ^[3] ^[4]

End point description

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation subject administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. Safety population was defined as all subjects who received at least 1 dose of any study drug.

End point type

Primary

End point timeframe

First dose to 30 days past last dose (Up to 36 Months)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses are reported for this endpoint.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the Baseline Period are applicable to this Endpoint.

End point values	Alisertib (Phase 1 - Ovarian Cancer)	Alisertib (Phase 1 - Breast Cancer)
Number of subjects analysed	38	11
Units: subjects
AEs	38	11
SAEs	13	2

No statistical analyses for this end point

Primary: Phase 1: Number of Subjects with Clinically Significant Laboratory Values

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End point title

Phase 1: Number of Subjects with Clinically Significant Laboratory Values ^[5] ^[6]

End point description

Abnormal clinical laboratory values (serum chemistry, hematology and urinalysis) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention. Safety population was defined as all subjects who received at least 1 dose of any study drug.

End point type

Primary

End point timeframe

First dose to 30 days past last dose (Up to 36 Months)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses are reported for this endpoint.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the Baseline Period are applicable to this Endpoint.

End point values	Alisertib (Phase 1 - Ovarian Cancer)	Alisertib (Phase 1 - Breast Cancer)
Number of subjects analysed	38	11
Units: subjects
Neutrophil count decreased	3	0
White blood cell count decreased	1	1
Aspartate aminotransferase increased	3	1
Alanine aminotransferase increased	2	0
Ammonia increased	1	0
Transaminases increased	1	0
Blood alkaline phosphatase increased	1	1
High density lipoprotein decreased	1	0
Urine output decreased	1	0
Granulocyte count decreased	0	1

No statistical analyses for this end point

Primary: Phase 1: Number of Subjects with Clinically Significant Vital Sign Findings

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End point title

Phase 1: Number of Subjects with Clinically Significant Vital Sign Findings ^[7] ^[8]

End point description

Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study. Safety population was defined as all subjects who received at least 1 dose of any study drug.

End point type

Primary

End point timeframe

First dose to 30 days past last dose (Up to 36 Months)

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses are reported for this endpoint.
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the Baseline Period are applicable to this Endpoint.

End point values	Alisertib (Phase 1 - Ovarian Cancer)	Alisertib (Phase 1 - Breast Cancer)
Number of subjects analysed	38	11
Units: subjects
Pyrexia	8	5
Heart rate irregular	1	0
Blood pressure increased	0	1
Weight decreased	3	0

No statistical analyses for this end point

Primary: Phase 1: Number of Subjects with Hypersensitivity and Neurotoxicity

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End point title

Phase 1: Number of Subjects with Hypersensitivity and Neurotoxicity ^[9] ^[10]

End point description

Safety population was defined as all subjects who received at least 1 dose of any study drug.

End point type

Primary

End point timeframe

Baseline up to Month 36

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses are reported for this endpoint.
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the Baseline Period are applicable to this Endpoint.

End point values	Alisertib (Phase 1 - Ovarian Cancer)	Alisertib (Phase 1 - Breast Cancer)
Number of subjects analysed	38	11
Units: subjects
Hypersensitivity\|	1	0
Neurotoxicity\|	0	0

No statistical analyses for this end point

Primary: Phase 2: Progression-Free Survival (PFS)

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End point title

Phase 2: Progression-Free Survival (PFS) ^[11] ^[12]

End point description

PFS is defined as the time from the date randomization for Phase 2 subjects to the date of first documented progressive disease (PD) or death as assessed by the investigator using both RECIST 1.1 criteria and CA-125 criteria. PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease or CA-125 criteria with elevated (>70 units/mL) levels on 2 occasions. CA 125 progression for subjects with normal CA 125 levels is defined as a CA 125 level >2 times the upper limit of normal and for subjects with elevated values during the trial, is defined as a CA 125 level greater than 2 times the nadir value of CA 125. The modified intent-to-treat (mITT) population was defined as all subjects who were randomized and received at least 1 dose of any study drug. For a subject that has not progressed and has not died or has started the alternate therapy, PFS is censored at the last response assessment that is stable disease (SD) or better.

End point type

Primary

End point timeframe

At the end of Cycle 2 and at the completion of every 2 cycles until PD was documented or up to data cut-off: 12 August 2014 (approximately 24 months)

Notes
[11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analyses are reported for this endpoint.
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the Baseline Period are applicable to this Endpoint.

End point values	Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)	Paclitaxel 80 mg/m^2 (Phase 2)
Number of subjects analysed	73	69
Units: days
median (confidence interval 80%)	204 (175 to 230)	142 (117 to 148)

No statistical analyses for this end point

Secondary: Phase 1: Combined Best Overall Response Rate (ORR) in Subjects with Recurrent Ovarian Cancer or Breast Cancer

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End point title

Phase 1: Combined Best Overall Response Rate (ORR) in Subjects with Recurrent Ovarian Cancer or Breast Cancer ^[13]

End point description

Combined objective response rate: Percentage of subjects with Complete Response (CR)+Partial Response (PR) as assessed by investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 or response by Cancer antigen (CA) 125 criteria. According to RECIST: CR-disappearance of all target lesions & PR- 30% decrease in sum of longest diameter of target lesions. CA-125 response criteria: 50% decrease from 2 initially elevated samples; sample demonstrating 50% decrease must be confirmed by a fourth sample 28 days later (total of 4 samples required) or serial decrease of >75% over 3 samples; third sample was obtained 28 days after second (total of 3 samples required). Response evaluable population: Subjects who were randomized & had measurable disease according to RECIST or assessable disease by CA-125 criteria, who received at least 1 dose of any study drug & who had at least 1 available post-Baseline response assessment as per either RECIST or CA-125 criteria.

End point type

Secondary

End point timeframe

At the end of Cycle 2 and at the completion of every 2 cycles until PD was documented or up to data cut-off: 12 August 2014 (approximately 24 months)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the Baseline Period are applicable to this Endpoint.

End point values	Alisertib (Phase 1 - Ovarian Cancer)	Alisertib (Phase 1 - Breast Cancer)
Number of subjects analysed	38	11
Units: percentage of subjects
number (confidence interval 80%)	47 (36 to 59)	55 (32 to 76)

No statistical analyses for this end point

Secondary: Cmax: Maximum Observed Concentration for Alisertib in Phase 1

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End point title

Cmax: Maximum Observed Concentration for Alisertib in Phase 1

End point description

Pharmacokinetic (PK) analysis set for alisertib was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

End point type

Secondary

End point timeframe

Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose

End point values	Alisertib 10 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 60 mg/m^2	Alisertib 30 mg BID + Paclitaxel 60 mg/m^2	Alisertib 40 mg BID + Paclitaxel 60 mg/m^2	Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
Number of subjects analysed	15	6	4	6	15	3
Units: nM
arithmetic mean (standard deviation)
Cycle1 (Day1)	428.7 ± 189.59	766.8 ± 312.10	900.00 ± 392.17	1365.3 ± 466.51	1398.7 ± 607.70	1960.0 ± 515.65
Cycle1 (Day3)	594.3 ± 228.46	1042.3 ± 280.95	871.3 ± 268.23	1708.5 ± 820.54	2493.4 ± 955.31	4456.7 ± 947.33

No statistical analyses for this end point

Secondary: Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1

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End point title

Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1

End point description

PK analysis set for alisertib was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

End point type

Secondary

End point timeframe

Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose

End point values	Alisertib 10 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 60 mg/m^2	Alisertib 30 mg BID + Paclitaxel 60 mg/m^2	Alisertib 40 mg BID + Paclitaxel 60 mg/m^2	Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
Number of subjects analysed	15	6	4	6	15	3
Units: hour
median (full range (min-max))
Cycle 1, Day 1	3.0 (1 to 5)	3.1 (2 to 4)	2.6 (2 to 3)	2.5 (2 to 9)	3.0 (2 to 9)	2.0 (2 to 9)
Cycle 1, Day 3	2.2 (0 to 5)	3.0 (1 to 3)	3.5 (2 to 5)	2.0 (1 to 4)	2.0 (1 to 9)	2.0 (2 to 3)

No statistical analyses for this end point

Secondary: AUC(tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1

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End point title

AUC(tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1

End point description

End point type

Secondary

End point timeframe

Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose

End point values	Alisertib 10 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 60 mg/m^2	Alisertib 30 mg BID + Paclitaxel 60 mg/m^2	Alisertib 40 mg BID + Paclitaxel 60 mg/m^2	Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
Number of subjects analysed	15	6	4	6	15	3
Units: nM*hour
arithmetic mean (standard deviation)
Cycle 1, Day 1	2519.3 ± 937.52	5175.0 ± 1766.11	5610.0 ± 2105.42	8581.7 ± 3225.64	9594.0 ± 4600.42	14666.7 ± 3707.20
Cycle 1, Day3	3966.7 ± 1112.11	7745.0 ± 2233.91	6155.0 ± 1737.69	12478.3 ± 6013.93	17557.3 ± 7856.30	35500.0 ± 12842.12

No statistical analyses for this end point

Secondary: AUClast: Area under the Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1

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End point title

AUClast: Area under the Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1

End point description

End point type

Secondary

End point timeframe

Days 1 and 3 in Cycle 1: pre-dose and at multiple timepoints (up to 12 hours) post morning dose

End point values	Alisertib 10 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 60 mg/m^2	Alisertib 30 mg BID + Paclitaxel 60 mg/m^2	Alisertib 40 mg BID + Paclitaxel 60 mg/m^2	Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
Number of subjects analysed	15	6	4	6	15	3
Units: nM*hour
arithmetic mean (standard deviation)
Cycle 1, Day 1	2519.3 ± 937.52	5175.0 ± 1766.11	5610.0 ± 2105.42	8581.7 ± 3225.64	9594.0 ± 4600.42	14666.7 ± 3707.20
Cycle 1, Day 3	3966.7 ± 1112.11	7745.0 ± 2233.91	6155.0 ± 1737.69	12478.3 ± 6013.93	17557.3 ± 7856.30	35500.0 ± 12842.12

No statistical analyses for this end point

Secondary: Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1

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End point title

Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1

End point description

PK analysis set for paclitaxel was defined as all subjects in the phase 1 portion of the study for whom there was sufficient dosing and paclitaxel concentration-time data to permit noncompartmental PK analysis. Number analyzed is the number of subjects with evaluable data at the specified time-point.

End point type

Secondary

End point timeframe

Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion

End point values	Alisertib 10 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 60 mg/m^2	Alisertib 30 mg BID + Paclitaxel 60 mg/m^2	Alisertib 40 mg BID + Paclitaxel 60 mg/m^2	Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
Number of subjects analysed	15	6	4	6	15	3
Units: ng/mL*hr
arithmetic mean (standard deviation)
Cycle 1, Day 1 (n=15,6,4,5,15,3)	3097.3 ± 1114.51	3120.0 ± 447.75	2117.5 ± 745.54	2448.0 ± 988.65	1917.3 ± 528.32	1338.7 ± 617.94
Cycle 2, Day 1 (n=13,6,3,6,13,2)	2654.6 ± 696.45	3231.7 ± 615.64	1733.3 ± 541.97	2478.3 ± 878.39	1492.7 ± 558.14	1750.0 ± 183.85

No statistical analyses for this end point

Secondary: AUClast: Area under the Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1

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End point title

AUClast: Area under the Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1

End point description

End point type

Secondary

End point timeframe

Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion

End point values	Alisertib 10 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 60 mg/m^2	Alisertib 30 mg BID + Paclitaxel 60 mg/m^2	Alisertib 40 mg BID + Paclitaxel 60 mg/m^2	Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
Number of subjects analysed	15	6	4	6	15	3
Units: ng/mL*hr
arithmetic mean (standard deviation)
Cycle 1, Day 1 (n=13,6,4,5,15,3)	4437.7 ± 1053.87	4825.0 ± 735.17	3355.0 ± 865.89	3366.0 ± 1139.25	2652.7 ± 651.32	2190.0 ± 387.43
Cycle 2, Day 1 (n=12,6,3,5,13,2)	4061.7 ± 1298.86	5301.7 ± 1183.31	2660.0 ± 307.90	3056.0 ± 812.67	2231.5 ± 604.76	2460.0 ± 14.14

No statistical analyses for this end point

Secondary: AUC0-∞: Area under the Concentration-Time Curve from Time 0 to Infinity, Calculated using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1

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End point title

AUC0-∞: Area under the Concentration-Time Curve from Time 0 to Infinity, Calculated using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1

End point description

End point type

Secondary

End point timeframe

Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion

End point values	Alisertib 10 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 60 mg/m^2	Alisertib 30 mg BID + Paclitaxel 60 mg/m^2	Alisertib 40 mg BID + Paclitaxel 60 mg/m^2	Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
Number of subjects analysed	15	6	4	6	15	3
Units: ng/mL*hr
arithmetic mean (standard deviation)
Cycle 1, Day 1 (n=9,5,3,4,11,2)	5317.8 ± 1052.40	5238.0 ± 812.26	3860.0 ± 824.20	3375.0 ± 1130.56	3175.5 ± 933.10	2535.0 ± 657.61
Cycle 2, Day 1 (n=11,5,2,4,10,0)	4606.4 ± 1391.35	5584.0 ± 1367.51	3185.0 ± 176.78	3415.0 ± 1010.82	2680.0 ± 607.22	99999 ± 99999

No statistical analyses for this end point

Secondary: t½: Terminal Half-Life for Paclitaxel in Phase 1

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End point title

t½: Terminal Half-Life for Paclitaxel in Phase 1

End point description

End point type

Secondary

End point timeframe

Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion

End point values	Alisertib 10 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 60 mg/m^2	Alisertib 30 mg BID + Paclitaxel 60 mg/m^2	Alisertib 40 mg BID + Paclitaxel 60 mg/m^2	Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
Number of subjects analysed	15	6	4	6	15	3
Units: hour
arithmetic mean (standard deviation)
Cycle 1, Day 1 (n=11,5,3,5,11,2)	17.2 ± 4.20	17.5 ± 1.87	17.3 ± 4.16	13.9 ± 4.68	16.8 ± 6.83	18.4 ± 8.70
Cycle 2, Day 1 (n=12,5,2,4,10,2)	17.0 ± 3.63	16.2 ± 5.05	17.3 ± 5.23	16.5 ± 4.32	13.3 ± 5.59	14.6 ± 2.19

No statistical analyses for this end point

Secondary: CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1

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End point title

CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1

End point description

End point type

Secondary

End point timeframe

Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion

End point values	Alisertib 10 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 60 mg/m^2	Alisertib 30 mg BID + Paclitaxel 60 mg/m^2	Alisertib 40 mg BID + Paclitaxel 60 mg/m^2	Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
Number of subjects analysed	15	6	4	6	15	3
Units: liter per hour
arithmetic mean (standard deviation)
Cycle 1, Day 1 (n=9,5,3,4,11,2)	29.756 ± 6.8175	28.220 ± 5.1804	26.800 ± 7.5386	40.950 ± 17.5268	38.055 ± 13.7095	38.950 ± 11.2430
Cycle 2, Day 1 (n=11,5,2,4,10,0)	35.827 ± 10.4005	28.240 ± 7.3748	33.900 ± 5.2326	34.250 ± 8.2614	42.440 ± 10.4296	99999 ± 99999

No statistical analyses for this end point

Secondary: Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1

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End point title

Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1

End point description

End point type

Secondary

End point timeframe

Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion

End point values	Alisertib 10 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 60 mg/m^2	Alisertib 30 mg BID + Paclitaxel 60 mg/m^2	Alisertib 40 mg BID + Paclitaxel 60 mg/m^2	Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
Number of subjects analysed	15	6	4	6	15	3
Units: liter
arithmetic mean (standard deviation)
Cycle 1, Day 1 (n=9,5,3,4,11,2)	313.444 ± 118.6593	310.800 ± 86.9235	330.000 ± 208.8851	357.000 ± 158.1834	433.909 ± 179.7757	460.500 ± 103.9447
Cycle 2, Day 1 (n=11,5,2,4,10,0)	391.364 ± 64.3137	283.200 ± 121.1123	413.500 ± 242.5376	377.000 ± 118.9650	372.600 ± 180.7332	99999 ± 99999

No statistical analyses for this end point

Secondary: Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1

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End point title

Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1

End point description

End point type

Secondary

End point timeframe

Day 1 in Cycles 1 and 2: pre-infusion and at multiple timepoints (up to 47 hours) post-infusion

End point values	Alisertib 10 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 80 mg/m^2	Alisertib 20 mg BID + Paclitaxel 60 mg/m^2	Alisertib 30 mg BID + Paclitaxel 60 mg/m^2	Alisertib 40 mg BID + Paclitaxel 60 mg/m^2	Alisertib 50 mg BID + Paclitaxel 60 mg/m^2
Number of subjects analysed	15	6	4	6	15	3
Units: liter
arithmetic mean (standard deviation)
Cycle 1, Day 1 (n=9,5,3,4,11,2)	705.000 ± 179.0223	721.600 ± 203.8021	694.000 ± 352.1534	850.500 ± 291.0401	872.727 ± 328.6202	956.500 ± 188.7975
Cycle 2, Day 1 (n=11,5,2,4,10,0)	829.364 ± 156.6060	663.200 ± 321.3070	865.500 ± 388.2016	777.250 ± 103.7027	733.000 ± 208.4898	99999 ± 99999

No statistical analyses for this end point

Secondary: Phase 2: Combined Best Overall Response Rate (ORR)

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End point title

Phase 2: Combined Best Overall Response Rate (ORR) ^[14]

End point description

Combined objective response rate: Percentage of subjects with CR+ PR as assessed by the investigator according to RECIST criteria 1.1 or response by CA-125 criteria. According to RECIST: CR- the disappearance of all target lesions and PR- 30% decrease in the sum of the longest diameter of target lesions. CA-125 response criteria is defined as either: A 50% decrease from 2 initially elevated samples; the sample demonstrating the 50% decrease must have been confirmed by a fourth sample 28 days later (a total of 4 samples required) or A serial decrease of >75% over 3 samples; the third sample was to be obtained 28 days after the second (a total of 3 samples required). Response evaluable population was defined as all subjects who were randomized and had measurable disease according to RECIST or assessable disease by CA-125 criteria, who received at least 1 dose of any study drug, and who had at least 1 available post-Baseline response assessment as per either RECIST or CA-125 criteria.

End point type

Secondary

End point timeframe

At the end of Cycle 2 and at the completion of every 2 cycles until PD was documented or up to data cut-off: 12 August 2014 (approximately 24 months)

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the Baseline Period are applicable to this Endpoint.

End point values	Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)	Paclitaxel 80 mg/m^2 (Phase 2)
Number of subjects analysed	67	64
Units: percentage of subjects
number (confidence interval 80%)	60 (51 to 68)	52 (43 to 60)

No statistical analyses for this end point

Secondary: Phase 2: Duration of Response (DOR)

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End point title

Phase 2: Duration of Response (DOR) ^[15]

End point description

DOR: Time from date of first documentation of response to date of first documentation of PD or last response assessment i.e. stable disease (SD) or better for subject who started alternate therapy without progression. PD: 20% increase in sum of longest diameter of target lesions for measurable neoplastic disease or per CA-125 criteria with elevated (>70 units/mL) levels on 2 occasions. CA-125 progression for subjects with normal CA-125 levels: CA-125 level >2 times upper limit of normal and for subjects with elevated values during trial: CA-125 level >2 times nadir value of CA-125. A responder that did not experience disease progression is censored at last response assessment i.e. SD. Response evaluable population: subjects who were randomized and had measurable disease according to RECIST 1.1 or assessable disease by CA-125 criteria, who received 1 dose of study drug, and who had 1 available post-Baseline response assessment per RECIST 1.1 or CA-125 criteria, who were responders.

End point type

Secondary

End point timeframe

Up to data-cut off: 12 August 2014 (approximately 24 months)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the Baseline Period are applicable to this Endpoint.

End point values	Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)	Paclitaxel 80 mg/m^2 (Phase 2)
Number of subjects analysed	40	33
Units: days
median (confidence interval 80%)	201 (181 to 218)	169 (120 to 231)

No statistical analyses for this end point

Secondary: Phase 2: Time to Disease Progression (TTP)

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End point title

Phase 2: Time to Disease Progression (TTP) ^[16]

End point description

TTP was defined as the time from the date of randomization to the date of first documentation of PD. PD is defined as 20% increase in the sum of the longest diameter of target lesions for measurable neoplastic disease or per CA-125 criteria with elevated (>70 units/mL) levels on 2 occasions. CA 125 progression for subjects with normal CA 125 levels is defined as a CA 125 level >2 times the upper limit of normal and for subjects with elevated values during the trial, is defined as a CA 125 level greater than 2 times the nadir value of CA 125. mITT Population was defined as all subjects who were randomized and received at least 1 dose of any study drug. For a subject that has not progressed, TTP is censored at the last response assessment that is SD or better.

End point type

Secondary

End point timeframe

Up to data-cut off: 12 August 2014 (approximately 24 months)

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the Baseline Period are applicable to this Endpoint.

End point values	Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)	Paclitaxel 80 mg/m^2 (Phase 2)
Number of subjects analysed	73	69
Units: days
median (confidence interval 80%)	204 (175 to 232)	142 (117 to 161)

No statistical analyses for this end point

Secondary: Phase 2: Overall Survival (OS)

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End point title

Phase 2: Overall Survival (OS) ^[17]

End point description

OS was defined as the time form the date of the randomization to the date of death. mITT Population was defined as all subjects who were randomized and received at least 1 dose of any study drug. For a subject that is alive, OS will be censored at the last known date. Here, 99999 indicates that Median, upper and lower limits of CI were not reached due to low number of subjects with events.

End point type

Secondary

End point timeframe

Up to data-cut off: 12 August 2014 (approximately 24 months)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the Baseline Period are applicable to this Endpoint.

End point values	Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)	Paclitaxel 80 mg/m^2 (Phase 2)
Number of subjects analysed	73	69
Units: days
median (confidence interval 80%)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Phase 2: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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End point title

Phase 2: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) ^[18]

End point description

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation subject administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. Safety population was defined as all subjects who received at least 1 dose of any study drug.

End point type

Secondary

End point timeframe

First dose to 30 days past last dose (Up to 27 Months)

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the Baseline Period are applicable to this Endpoint.

End point values	Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)	Paclitaxel 80 mg/m^2 (Phase 2)
Number of subjects analysed	73	69
Units: subjects
AEs	73	66
SAEs	30	19

No statistical analyses for this end point

Secondary: Phase 2: Number of Subjects With Clinically Significant Laboratory Values

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End point title

Phase 2: Number of Subjects With Clinically Significant Laboratory Values ^[19]

End point description

Abnormal clinical laboratory values (serum chemistry, hematology, and urinalysis) were reported as AEs if they were considered by the investigator to be a clinically significant change from Baseline or led to premature discontinuation of study treatment, dose modification, or other therapeutic intervention. Safety population was defined as all subjects who received at least 1 dose of any study drug.

End point type

Secondary

End point timeframe

First dose to 30 days past last dose (Up to 27 Months)

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the Baseline Period are applicable to this Endpoint.

End point values	Paclitaxel 80 mg/m^2 (Phase 2)	Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 (Phase 2)
Number of subjects analysed	69	73
Units: subjects
Neutrophil count decreased	4	14
White blood cell count decreased	1	6
Lymphocyte count decreased	1	1
Aspartate aminotransferase increased	3	1
Alanine aminotransferase increased	4	1
Gamma-glutamyltransferase increased	1	0
Blood alkaline phosphatase increased	2	2
Haemoglobin decreased	1	3
Blood magnesium decreased	3	0
Blood creatinine increased	2	1
Platelet count decreased	0	2
International normalised ratio increased	0	1
Blood albumin decreased	0	1
Troponin T increased	1	0

No statistical analyses for this end point

Secondary: Phase 2: Number of Subjects with Clinically Significant Vital Sign Findings

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End point title

Phase 2: Number of Subjects with Clinically Significant Vital Sign Findings ^[20]

End point description

End point type

Secondary

End point timeframe

First dose to 30 days past last dose (Up to 27 Months)

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Not all arms in the Baseline Period are applicable to this Endpoint.

End point values	Paclitaxel 80 mg/m^2 (Phase 2)	Alisertib 40 mg BID + Paclitaxel 60 mg/m^2 (Phase 2)
Number of subjects analysed	69	73
Units: Subjects
Pyrexia	8	15
Heart rate increased	0	1
Blood pressure increased	0	1
Weight decreased	2	8

No statistical analyses for this end point

Other pre-specified: Banked Tumor Specimens for Candidate Markers of Response to Alisertib and Taxanes

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End point title

Banked Tumor Specimens for Candidate Markers of Response to Alisertib and Taxanes

End point description

This Outcome Measure was originally registered as a Secondary but this Outcome Measure was Exploratory and no data was collected.

End point type

Other pre-specified

End point timeframe

Up to 24 Months

End point values	Alisertib + Paclitaxel (Phase 1)
Number of subjects analysed	0 ^[21]
Units: levels
arithmetic mean (standard deviation)	±

Notes
[21] - This endpoint was registered as a Secondary but this was Exploratory and no data was collected.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Phase 1: First dose to 30 days past last dose (Up to 36 Months); Phase 2: First dose to 30 days past last dose (Up to 27 Months)

Adverse event reporting additional description

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the subject or observed by the investigator was recorded, irrespective of the relation to study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.0

Reporting group title

Alisertib (Phase 1 - Ovarian cancer)

Reporting group description

Alisertib (MLN8237) 10 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

Reporting group title

Alisertib (Phase 1 - Breast cancer)

Reporting group description

Alisertib 20 mg, orally, twice daily (BID) on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 1.

Reporting group title

Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)

Reporting group description

Alisertib 40 mg, orally, BID on Days 1-3, 8-10 and 15-17, combined with weekly paclitaxel 60 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

Reporting group title

Paclitaxel 80 mg/m^2 (Phase 2)

Reporting group description

Paclitaxel 80 mg/m^2, intravenous infusion, weekly (Days 1, 8, 15) in 28-day cycles in Phase 2 (Up to 28 cycles).

Serious adverse events	Alisertib (Phase 1 - Ovarian cancer)	Alisertib (Phase 1 - Breast cancer)	Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)	Paclitaxel 80 mg/m^2 (Phase 2)
Total subjects affected by serious adverse events
subjects affected / exposed	13 / 38 (34.21%)	2 / 11 (18.18%)	30 / 73 (41.10%)	19 / 69 (27.54%)
number of deaths (all causes)	0	0	1	1
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant pleural effusion
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	3 / 73 (4.11%)	2 / 69 (2.90%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	2 / 73 (2.74%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tachypnoea
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary alveolar haemorrhage
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Neutrophil count decreased
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
White blood cell count decreased
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Troponin T increased
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Vascular access complication
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pubis fracture
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	6 / 38 (15.79%)	0 / 11 (0.00%)	9 / 73 (12.33%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	6 / 9	0 / 0	9 / 9	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	6 / 73 (8.22%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	6 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anaemia
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	2 / 73 (2.74%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 1	0 / 0	2 / 4	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic anaemia
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Hearing impaired
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Nausea
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	3 / 73 (4.11%)	2 / 69 (2.90%)
occurrences causally related to treatment / all	0 / 1	0 / 0	2 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	2 / 73 (2.74%)	2 / 69 (2.90%)
occurrences causally related to treatment / all	0 / 1	0 / 0	2 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	4 / 73 (5.48%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	2 / 73 (2.74%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	1 / 1	0 / 0	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
Additional description: One treatment-emergent death occurred during treatment with alisertib and paclitaxel and was not related.
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	2 / 73 (2.74%)	2 / 69 (2.90%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
Constipation
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	2 / 73 (2.74%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal hernia obstructive
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Proctalgia
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric perforation
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic ascites
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic failure
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Paraneoplastic dermatomyositis
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Postrenal failure
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Flank pain
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Device related infection
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abscess soft tissue
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	3 / 73 (4.11%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Catheter site cellulitis
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
Additional description: One treatment-emergent death occurred during treatment with paclitaxel and was not related.
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Gastroenteritis
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	4 / 73 (5.48%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 38 (2.63%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Alisertib (Phase 1 - Ovarian cancer)	Alisertib (Phase 1 - Breast cancer)	Alisertib 40 mg BID+ Paclitaxel 60 mg/m^2 (Phase 2)	Paclitaxel 80 mg/m^2 (Phase 2)
Total subjects affected by non serious adverse events
subjects affected / exposed	38 / 38 (100.00%)	11 / 11 (100.00%)	73 / 73 (100.00%)	64 / 69 (92.75%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Vascular disorders
Flushing
subjects affected / exposed	2 / 38 (5.26%)	1 / 11 (9.09%)	3 / 73 (4.11%)	1 / 69 (1.45%)
occurrences all number	2	1	5	2
Hot flush
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	1 / 73 (1.37%)	2 / 69 (2.90%)
occurrences all number	4	0	1	3
Hypotension
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	4 / 73 (5.48%)	2 / 69 (2.90%)
occurrences all number	0	0	5	2
Deep vein thrombosis
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences all number	1	1	1	1
Lymphoedema
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	1	1	1	0
Orthostatic hypotension
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	3	0	0	0
Blood pressure fluctuation
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Superior vena cava stenosis
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	26 / 38 (68.42%)	8 / 11 (72.73%)	43 / 73 (58.90%)	31 / 69 (44.93%)
occurrences all number	29	10	82	37
Oedema peripheral
subjects affected / exposed	15 / 38 (39.47%)	3 / 11 (27.27%)	12 / 73 (16.44%)	18 / 69 (26.09%)
occurrences all number	24	3	15	25
Pyrexia
subjects affected / exposed	8 / 38 (21.05%)	4 / 11 (36.36%)	13 / 73 (17.81%)	7 / 69 (10.14%)
occurrences all number	11	7	18	10
Asthenia
subjects affected / exposed	5 / 38 (13.16%)	2 / 11 (18.18%)	10 / 73 (13.70%)	8 / 69 (11.59%)
occurrences all number	6	2	20	11
Chills
subjects affected / exposed	10 / 38 (26.32%)	0 / 11 (0.00%)	6 / 73 (8.22%)	0 / 69 (0.00%)
occurrences all number	12	0	6	0
Non-cardiac chest pain
subjects affected / exposed	2 / 38 (5.26%)	2 / 11 (18.18%)	3 / 73 (4.11%)	0 / 69 (0.00%)
occurrences all number	2	2	4	0
Catheter site pain
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	2 / 73 (2.74%)	1 / 69 (1.45%)
occurrences all number	5	0	2	1
Peripheral swelling
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	2 / 73 (2.74%)	1 / 69 (1.45%)
occurrences all number	3	0	4	1
Pain
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences all number	2	0	1	1
Chest discomfort
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	2	0	0	0
Early satiety
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	1	1	0	0
Localised oedema
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Immune system disorders
Seasonal allergy
subjects affected / exposed	3 / 38 (7.89%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	3	1	0	0
Reproductive system and breast disorders
Vaginal haemorrhage
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	0 / 73 (0.00%)	2 / 69 (2.90%)
occurrences all number	4	0	0	2
Genital discomfort
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	1	1	1	0
Vulvovaginal pain
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	3	0	0	0
Cystocele
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	1	1	0	0
Postmenopausal haemorrhage
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	11 / 38 (28.95%)	3 / 11 (27.27%)	17 / 73 (23.29%)	4 / 69 (5.80%)
occurrences all number	13	3	20	4
Dyspnoea
subjects affected / exposed	10 / 38 (26.32%)	3 / 11 (27.27%)	9 / 73 (12.33%)	11 / 69 (15.94%)
occurrences all number	11	3	10	19
Epistaxis
subjects affected / exposed	7 / 38 (18.42%)	1 / 11 (9.09%)	6 / 73 (8.22%)	7 / 69 (10.14%)
occurrences all number	11	1	6	11
Oropharyngeal pain
subjects affected / exposed	10 / 38 (26.32%)	1 / 11 (9.09%)	6 / 73 (8.22%)	2 / 69 (2.90%)
occurrences all number	12	1	7	2
Nasal congestion
subjects affected / exposed	4 / 38 (10.53%)	1 / 11 (9.09%)	3 / 73 (4.11%)	0 / 69 (0.00%)
occurrences all number	5	1	5	0
Rhinorrhoea
subjects affected / exposed	4 / 38 (10.53%)	1 / 11 (9.09%)	2 / 73 (2.74%)	0 / 69 (0.00%)
occurrences all number	4	1	2	0
Pleural effusion
subjects affected / exposed	2 / 38 (5.26%)	1 / 11 (9.09%)	2 / 73 (2.74%)	1 / 69 (1.45%)
occurrences all number	2	2	2	1
Dysphonia
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences all number	2	0	1	1
Rhinitis allergic
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences all number	3	0	0	2
Hypoxia
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	1	1	1	0
Pulmonary embolism
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences all number	1	1	0	1
Throat irritation
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	1	1	0	0
Sinus disorder
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Psychiatric disorders
Insomnia
subjects affected / exposed	6 / 38 (15.79%)	2 / 11 (18.18%)	8 / 73 (10.96%)	7 / 69 (10.14%)
occurrences all number	6	2	8	8
Anxiety
subjects affected / exposed	3 / 38 (7.89%)	1 / 11 (9.09%)	11 / 73 (15.07%)	7 / 69 (10.14%)
occurrences all number	3	1	11	9
Depression
subjects affected / exposed	4 / 38 (10.53%)	1 / 11 (9.09%)	6 / 73 (8.22%)	4 / 69 (5.80%)
occurrences all number	4	1	7	4
Aggression
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Product issues
Device malfunction
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	2	0	0
Investigations
Neutrophil count decreased
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	13 / 73 (17.81%)	4 / 69 (5.80%)
occurrences all number	4	0	22	5
Weight decreased
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	8 / 73 (10.96%)	2 / 69 (2.90%)
occurrences all number	3	0	11	2
White blood cell count decreased
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	6 / 73 (8.22%)	1 / 69 (1.45%)
occurrences all number	2	6	14	1
Aspartate aminotransferase increased
subjects affected / exposed	3 / 38 (7.89%)	1 / 11 (9.09%)	1 / 73 (1.37%)	3 / 69 (4.35%)
occurrences all number	3	2	2	4
Alanine aminotransferase increased
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	4 / 69 (5.80%)
occurrences all number	3	0	2	4
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	2 / 73 (2.74%)	2 / 69 (2.90%)
occurrences all number	1	2	3	3
Blood pressure increased
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	0	1	1	0
Cardiac murmur
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	2	0	0	0
Granulocyte count decreased
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	2	0	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	8 / 38 (21.05%)	0 / 11 (0.00%)	1 / 73 (1.37%)	3 / 69 (4.35%)
occurrences all number	14	0	1	3
Limb injury
subjects affected / exposed	2 / 38 (5.26%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	2	1	0	0
Skin abrasion
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	3	0	0	0
Fibula fracture
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	2	0	0
Procedural pain
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Cardiac disorders
Tachycardia
subjects affected / exposed	5 / 38 (13.16%)	1 / 11 (9.09%)	1 / 73 (1.37%)	2 / 69 (2.90%)
occurrences all number	5	1	1	2
Palpitations
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences all number	5	0	0	1
Nervous system disorders
Neuropathy peripheral
subjects affected / exposed	8 / 38 (21.05%)	4 / 11 (36.36%)	12 / 73 (16.44%)	13 / 69 (18.84%)
occurrences all number	8	4	15	16
Headache
subjects affected / exposed	6 / 38 (15.79%)	1 / 11 (9.09%)	8 / 73 (10.96%)	13 / 69 (18.84%)
occurrences all number	9	1	11	22
Dizziness
subjects affected / exposed	8 / 38 (21.05%)	0 / 11 (0.00%)	10 / 73 (13.70%)	6 / 69 (8.70%)
occurrences all number	14	0	16	9
Peripheral sensory neuropathy
subjects affected / exposed	4 / 38 (10.53%)	2 / 11 (18.18%)	9 / 73 (12.33%)	8 / 69 (11.59%)
occurrences all number	4	2	9	9
Dysgeusia
subjects affected / exposed	7 / 38 (18.42%)	0 / 11 (0.00%)	4 / 73 (5.48%)	5 / 69 (7.25%)
occurrences all number	9	0	4	6
Somnolence
subjects affected / exposed	2 / 38 (5.26%)	1 / 11 (9.09%)	7 / 73 (9.59%)	0 / 69 (0.00%)
occurrences all number	3	1	9	0
Paraesthesia
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	5 / 69 (7.25%)
occurrences all number	2	0	1	8
Restless legs syndrome
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	3 / 73 (4.11%)	2 / 69 (2.90%)
occurrences all number	3	0	3	2
Memory impairment
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	2 / 69 (2.90%)
occurrences all number	2	0	1	2
Amnesia
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences all number	1	1	1	1
Hyperaesthesia
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	2	0	0	0
Tremor
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences all number	2	0	1	1
Blood and lymphatic system disorders
Neutropenia
subjects affected / exposed	24 / 38 (63.16%)	10 / 11 (90.91%)	52 / 73 (71.23%)	10 / 69 (14.49%)
occurrences all number	100	58	179	17
Anaemia
subjects affected / exposed	22 / 38 (57.89%)	7 / 11 (63.64%)	33 / 73 (45.21%)	20 / 69 (28.99%)
occurrences all number	37	13	61	36
Leukopenia
subjects affected / exposed	20 / 38 (52.63%)	8 / 11 (72.73%)	11 / 73 (15.07%)	3 / 69 (4.35%)
occurrences all number	47	32	27	6
Thrombocytopenia
subjects affected / exposed	0 / 38 (0.00%)	2 / 11 (18.18%)	4 / 73 (5.48%)	1 / 69 (1.45%)
occurrences all number	0	17	7	2
Granulocytopenia
subjects affected / exposed	3 / 38 (7.89%)	1 / 11 (9.09%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences all number	4	4	0	1
Febrile neutropenia
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	1	1	1	0
Ear and labyrinth disorders
Ear pain
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	3 / 73 (4.11%)	1 / 69 (1.45%)
occurrences all number	4	0	3	1
Ear congestion
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences all number	0	1	0	1
Eye disorders
Dry eye
subjects affected / exposed	4 / 38 (10.53%)	2 / 11 (18.18%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences all number	5	2	1	1
Lacrimation increased
subjects affected / exposed	2 / 38 (5.26%)	2 / 11 (18.18%)	2 / 73 (2.74%)	1 / 69 (1.45%)
occurrences all number	2	2	2	1
Visual impairment
subjects affected / exposed	3 / 38 (7.89%)	1 / 11 (9.09%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	3	1	1	0
Cataract
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	2 / 73 (2.74%)	0 / 69 (0.00%)
occurrences all number	1	1	2	0
Eye pruritus
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences all number	2	0	1	1
Vision blurred
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences all number	4	0	1	1
Vitreous floaters
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	1	1	0	0
Conjunctivitis allergic
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Meibomian gland dysfunction
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	27 / 38 (71.05%)	8 / 11 (72.73%)	46 / 73 (63.01%)	15 / 69 (21.74%)
occurrences all number	49	11	96	19
Nausea
subjects affected / exposed	23 / 38 (60.53%)	5 / 11 (45.45%)	32 / 73 (43.84%)	32 / 69 (46.38%)
occurrences all number	33	6	54	46
Stomatitis
subjects affected / exposed	15 / 38 (39.47%)	8 / 11 (72.73%)	46 / 73 (63.01%)	6 / 69 (8.70%)
occurrences all number	32	10	91	8
Constipation
subjects affected / exposed	15 / 38 (39.47%)	3 / 11 (27.27%)	26 / 73 (35.62%)	17 / 69 (24.64%)
occurrences all number	22	4	33	23
Abdominal pain
subjects affected / exposed	12 / 38 (31.58%)	3 / 11 (27.27%)	21 / 73 (28.77%)	20 / 69 (28.99%)
occurrences all number	19	3	39	26
Vomiting
subjects affected / exposed	13 / 38 (34.21%)	4 / 11 (36.36%)	20 / 73 (27.40%)	18 / 69 (26.09%)
occurrences all number	42	4	31	25
Abdominal pain upper
subjects affected / exposed	3 / 38 (7.89%)	1 / 11 (9.09%)	11 / 73 (15.07%)	4 / 69 (5.80%)
occurrences all number	5	1	12	6
Dyspepsia
subjects affected / exposed	5 / 38 (13.16%)	1 / 11 (9.09%)	9 / 73 (12.33%)	3 / 69 (4.35%)
occurrences all number	5	1	12	3
Abdominal distension
subjects affected / exposed	2 / 38 (5.26%)	2 / 11 (18.18%)	9 / 73 (12.33%)	4 / 69 (5.80%)
occurrences all number	2	2	10	4
Ascites
subjects affected / exposed	3 / 38 (7.89%)	1 / 11 (9.09%)	8 / 73 (10.96%)	5 / 69 (7.25%)
occurrences all number	3	1	11	7
Haemorrhoids
subjects affected / exposed	4 / 38 (10.53%)	0 / 11 (0.00%)	9 / 73 (12.33%)	2 / 69 (2.90%)
occurrences all number	4	0	10	4
Gastrooesophageal reflux disease
subjects affected / exposed	4 / 38 (10.53%)	0 / 11 (0.00%)	6 / 73 (8.22%)	4 / 69 (5.80%)
occurrences all number	4	0	7	5
Oral pain
subjects affected / exposed	5 / 38 (13.16%)	0 / 11 (0.00%)	6 / 73 (8.22%)	0 / 69 (0.00%)
occurrences all number	6	0	6	0
Dry mouth
subjects affected / exposed	3 / 38 (7.89%)	2 / 11 (18.18%)	1 / 73 (1.37%)	3 / 69 (4.35%)
occurrences all number	3	2	1	3
Abdominal discomfort
subjects affected / exposed	5 / 38 (13.16%)	2 / 11 (18.18%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	6	2	1	0
Flatulence
subjects affected / exposed	6 / 38 (15.79%)	1 / 11 (9.09%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	9	3	1	0
Aphthous stomatitis
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	5 / 73 (6.85%)	2 / 69 (2.90%)
occurrences all number	0	0	9	2
Dysphagia
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	4 / 73 (5.48%)	1 / 69 (1.45%)
occurrences all number	1	1	6	2
Toothache
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	2 / 73 (2.74%)	2 / 69 (2.90%)
occurrences all number	2	0	2	4
Rectal haemorrhage
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	2 / 73 (2.74%)	0 / 69 (0.00%)
occurrences all number	2	0	2	0
Abdominal pain lower
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences all number	4	0	0	1
Tongue ulceration
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	1	1	2	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	26 / 38 (68.42%)	5 / 11 (45.45%)	28 / 73 (38.36%)	22 / 69 (31.88%)
occurrences all number	29	6	36	24
Rash
subjects affected / exposed	8 / 38 (21.05%)	2 / 11 (18.18%)	5 / 73 (6.85%)	2 / 69 (2.90%)
occurrences all number	9	2	5	2
Dry skin
subjects affected / exposed	4 / 38 (10.53%)	1 / 11 (9.09%)	5 / 73 (6.85%)	2 / 69 (2.90%)
occurrences all number	4	1	5	2
Pruritus
subjects affected / exposed	4 / 38 (10.53%)	0 / 11 (0.00%)	5 / 73 (6.85%)	2 / 69 (2.90%)
occurrences all number	5	0	5	4
Erythema
subjects affected / exposed	5 / 38 (13.16%)	1 / 11 (9.09%)	2 / 73 (2.74%)	2 / 69 (2.90%)
occurrences all number	6	1	2	4
Nail disorder
subjects affected / exposed	4 / 38 (10.53%)	3 / 11 (27.27%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	4	3	1	0
Onycholysis
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	2 / 73 (2.74%)	3 / 69 (4.35%)
occurrences all number	2	0	2	3
Skin lesion
subjects affected / exposed	6 / 38 (15.79%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	12	0	3	0
Skin exfoliation
subjects affected / exposed	4 / 38 (10.53%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	4	1	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	2 / 73 (2.74%)	0 / 69 (0.00%)
occurrences all number	1	1	2	0
Pruritus generalised
subjects affected / exposed	2 / 38 (5.26%)	1 / 11 (9.09%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	2	1	1	0
Rash macular
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences all number	2	0	4	1
Rash pruritic
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	3	0	1	0
Nail discolouration
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	2 / 73 (2.74%)	0 / 69 (0.00%)
occurrences all number	0	1	2	0
Rash erythematous
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	3	0	1	0
Dermatitis contact
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	1	1	0	0
Hyperhidrosis
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	3	0	0	0
Skin ulcer
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	10	0	0	0
Solar dermatitis
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	1 / 38 (2.63%)	2 / 11 (18.18%)	3 / 73 (4.11%)	5 / 69 (7.25%)
occurrences all number	1	2	3	5
Dysuria
subjects affected / exposed	2 / 38 (5.26%)	1 / 11 (9.09%)	4 / 73 (5.48%)	3 / 69 (4.35%)
occurrences all number	2	1	12	9
Pollakiuria
subjects affected / exposed	2 / 38 (5.26%)	1 / 11 (9.09%)	3 / 73 (4.11%)	1 / 69 (1.45%)
occurrences all number	2	1	3	1
Bladder spasm
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	2 / 73 (2.74%)	0 / 69 (0.00%)
occurrences all number	3	0	2	0
Acute kidney injury
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	2	0	0	0
Proteinuria
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	1	1	0	0
Renal failure
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	2	0	0	0
Cystitis noninfective
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Musculoskeletal and connective tissue disorders
Myalgia
subjects affected / exposed	10 / 38 (26.32%)	2 / 11 (18.18%)	9 / 73 (12.33%)	9 / 69 (13.04%)
occurrences all number	15	7	11	13
Arthralgia
subjects affected / exposed	11 / 38 (28.95%)	3 / 11 (27.27%)	7 / 73 (9.59%)	6 / 69 (8.70%)
occurrences all number	18	3	9	9
Pain in extremity
subjects affected / exposed	7 / 38 (18.42%)	1 / 11 (9.09%)	8 / 73 (10.96%)	5 / 69 (7.25%)
occurrences all number	14	1	9	6
Muscle spasms
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	4 / 73 (5.48%)	7 / 69 (10.14%)
occurrences all number	7	0	4	9
Back pain
subjects affected / exposed	5 / 38 (13.16%)	1 / 11 (9.09%)	4 / 73 (5.48%)	3 / 69 (4.35%)
occurrences all number	10	1	4	3
Musculoskeletal pain
subjects affected / exposed	2 / 38 (5.26%)	1 / 11 (9.09%)	3 / 73 (4.11%)	2 / 69 (2.90%)
occurrences all number	2	1	5	2
Neck pain
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	4 / 73 (5.48%)	1 / 69 (1.45%)
occurrences all number	4	0	5	1
Muscular weakness
subjects affected / exposed	6 / 38 (15.79%)	0 / 11 (0.00%)	0 / 73 (0.00%)	1 / 69 (1.45%)
occurrences all number	9	0	0	3
Flank pain
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	3 / 69 (4.35%)
occurrences all number	2	0	1	3
Bone pain
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	2 / 73 (2.74%)	1 / 69 (1.45%)
occurrences all number	2	0	4	1
Musculoskeletal chest pain
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	2	0	1	0
Pain in jaw
subjects affected / exposed	3 / 38 (7.89%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	8	0	0	0
Musculoskeletal discomfort
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	2	0	0	0
Infections and infestations
Urinary tract infection
subjects affected / exposed	11 / 38 (28.95%)	4 / 11 (36.36%)	11 / 73 (15.07%)	4 / 69 (5.80%)
occurrences all number	29	8	20	7
Upper respiratory tract infection
subjects affected / exposed	11 / 38 (28.95%)	4 / 11 (36.36%)	3 / 73 (4.11%)	4 / 69 (5.80%)
occurrences all number	24	4	4	5
Sinusitis
subjects affected / exposed	3 / 38 (7.89%)	3 / 11 (27.27%)	1 / 73 (1.37%)	2 / 69 (2.90%)
occurrences all number	10	3	1	2
Oral candidiasis
subjects affected / exposed	4 / 38 (10.53%)	0 / 11 (0.00%)	2 / 73 (2.74%)	1 / 69 (1.45%)
occurrences all number	4	0	2	1
Oral herpes
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	2 / 73 (2.74%)	2 / 69 (2.90%)
occurrences all number	4	0	2	2
Bronchitis
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	3 / 73 (4.11%)	0 / 69 (0.00%)
occurrences all number	2	0	3	0
Folliculitis
subjects affected / exposed	5 / 38 (13.16%)	0 / 11 (0.00%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	5	0	0	0
Candida infection
subjects affected / exposed	0 / 38 (0.00%)	0 / 11 (0.00%)	4 / 73 (5.48%)	0 / 69 (0.00%)
occurrences all number	0	0	6	0
Cellulitis
subjects affected / exposed	2 / 38 (5.26%)	0 / 11 (0.00%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences all number	5	0	1	1
Influenza
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	2 / 73 (2.74%)	1 / 69 (1.45%)
occurrences all number	0	1	2	1
Localised infection
subjects affected / exposed	3 / 38 (7.89%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	3	1	0	0
Pneumonia
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	1 / 73 (1.37%)	0 / 69 (0.00%)
occurrences all number	1	1	1	0
Viral upper respiratory tract infection
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	1	2	0	0
Catheter site cellulitis
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Skin candida
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	1	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	12 / 38 (31.58%)	2 / 11 (18.18%)	15 / 73 (20.55%)	8 / 69 (11.59%)
occurrences all number	17	2	18	11
Hypokalaemia
subjects affected / exposed	6 / 38 (15.79%)	4 / 11 (36.36%)	13 / 73 (17.81%)	4 / 69 (5.80%)
occurrences all number	8	5	27	5
Hypomagnesaemia
subjects affected / exposed	8 / 38 (21.05%)	3 / 11 (27.27%)	8 / 73 (10.96%)	7 / 69 (10.14%)
occurrences all number	16	3	9	8
Dehydration
subjects affected / exposed	7 / 38 (18.42%)	0 / 11 (0.00%)	8 / 73 (10.96%)	3 / 69 (4.35%)
occurrences all number	8	0	9	4
Hyperglycaemia
subjects affected / exposed	2 / 38 (5.26%)	1 / 11 (9.09%)	2 / 73 (2.74%)	2 / 69 (2.90%)
occurrences all number	3	3	2	3
Hyponatraemia
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	4 / 73 (5.48%)	1 / 69 (1.45%)
occurrences all number	1	1	4	1
Hypophosphataemia
subjects affected / exposed	2 / 38 (5.26%)	1 / 11 (9.09%)	3 / 73 (4.11%)	0 / 69 (0.00%)
occurrences all number	3	1	3	0
Hypocalcaemia
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	2 / 69 (2.90%)
occurrences all number	0	1	0	3
Hypoalbuminaemia
subjects affected / exposed	1 / 38 (2.63%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	1	1	0	0
Hypercalcaemia
subjects affected / exposed	0 / 38 (0.00%)	1 / 11 (9.09%)	0 / 73 (0.00%)	0 / 69 (0.00%)
occurrences all number	0	4	0	0
Hyperkalaemia
subjects affected / exposed	4 / 38 (10.53%)	0 / 11 (0.00%)	1 / 73 (1.37%)	1 / 69 (1.45%)
occurrences all number	4	0	2	1

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Were there any global substantial amendments to the protocol? Yes

15 Dec 2009

• Changed the study drug from the powder-in-capsule (PIC) to the enteric coated tablet (ECT) formulation • Modified the alisertib dosing schedule from consecutive daily dosing to intermittent dosing • Increase the sample size in phase 1 from 20 to 30, and to decrease the number of study centers in phase 2 from 50 to 30 • Increased the duration of the phase 1 portion from 18 to 22 months, including an increase in the duration of the enrollment period from 6 to 10 months

15 Nov 2010

• Specified that subjects in the phase 1 portion could be followed until 110 progression-free survival (PFS) events were achieved in phase 2 • Added antineoplastic therapy as a reason to discontinue treatment with alisertib, paclitaxel, or combination therapy (alisertib + paclitaxel) • Allowed continued protocol treatment up to 24 months

30 Nov 2010

• Allowed subjects that could have been maintained on study treatment after disease progression (PD) in selected circumstances and to define the criteria for withdrawing subjects from study treatment

27 Apr 2012

• Provided the RP2D for the combination arm in phase 2 as determined from the phase 1 portion of the study

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) for Alisertib in Combination with Paclitaxel

Primary: Phase 1: Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) for Alisertib in Combination with Paclitaxel

Primary: Phase 1: MTD and RP2D for Paclitaxel in Combination with Alisertib

Primary: Phase 1: MTD and RP2D for Paclitaxel in Combination with Alisertib

Primary: Phase 1: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Phase 1: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Primary: Phase 1: Number of Subjects with Clinically Significant Laboratory Values

Primary: Phase 1: Number of Subjects with Clinically Significant Laboratory Values

Primary: Phase 1: Number of Subjects with Clinically Significant Vital Sign Findings

Primary: Phase 1: Number of Subjects with Clinically Significant Vital Sign Findings

Primary: Phase 1: Number of Subjects with Hypersensitivity and Neurotoxicity

Primary: Phase 1: Number of Subjects with Hypersensitivity and Neurotoxicity

Primary: Phase 2: Progression-Free Survival (PFS)

Primary: Phase 2: Progression-Free Survival (PFS)

Secondary: Phase 1: Combined Best Overall Response Rate (ORR) in Subjects with Recurrent Ovarian Cancer or Breast Cancer

Secondary: Phase 1: Combined Best Overall Response Rate (ORR) in Subjects with Recurrent Ovarian Cancer or Breast Cancer

Secondary: Cmax: Maximum Observed Concentration for Alisertib in Phase 1

Secondary: Cmax: Maximum Observed Concentration for Alisertib in Phase 1

Secondary: Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1

Secondary: Tmax: Time to First Occurrence of Cmax for Alisertib in Phase 1

Secondary: AUC(tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1

Secondary: AUC(tau): Area Under the Concentration-Time Curve During a Dosing Interval for Alisertib in Phase 1

Secondary: AUClast: Area under the Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1

Secondary: AUClast: Area under the Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Alisertib in Phase 1

Secondary: Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1

Secondary: Cmax: Maximum Observed Concentration for Paclitaxel in Phase 1

Secondary: AUClast: Area under the Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1

Secondary: AUClast: Area under the Concentration-Time Curve from Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel in Phase 1

Secondary: AUC0-∞: Area under the Concentration-Time Curve from Time 0 to Infinity, Calculated using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1

Secondary: AUC0-∞: Area under the Concentration-Time Curve from Time 0 to Infinity, Calculated using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1

Secondary: t½: Terminal Half-Life for Paclitaxel in Phase 1

Secondary: t½: Terminal Half-Life for Paclitaxel in Phase 1

Secondary: CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1

Secondary: CL: Total Clearance After Intravenous Administration, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel in Phase 1

Secondary: Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1

Secondary: Vss: Volume of Distribution at Steady State for Paclitaxel in Phase 1

Secondary: Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1

Secondary: Vz: Volume of Distribution During the Terminal Disposition Phase for Paclitaxel in Phase 1

Secondary: Phase 2: Combined Best Overall Response Rate (ORR)

Secondary: Phase 2: Combined Best Overall Response Rate (ORR)

Secondary: Phase 2: Duration of Response (DOR)

Secondary: Phase 2: Duration of Response (DOR)

Secondary: Phase 2: Time to Disease Progression (TTP)

Secondary: Phase 2: Time to Disease Progression (TTP)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Overall Survival (OS)

Secondary: Phase 2: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Phase 2: Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs)

Secondary: Phase 2: Number of Subjects With Clinically Significant Laboratory Values

Secondary: Phase 2: Number of Subjects With Clinically Significant Laboratory Values

Secondary: Phase 2: Number of Subjects with Clinically Significant Vital Sign Findings

Secondary: Phase 2: Number of Subjects with Clinically Significant Vital Sign Findings

Other pre-specified: Banked Tumor Specimens for Candidate Markers of Response to Alisertib and Taxanes

Other pre-specified: Banked Tumor Specimens for Candidate Markers of Response to Alisertib and Taxanes

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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