Phase 2 Study of Alisertib (MLN8237) in Combination With Paclitaxel Versus Placebo in Combination With Paclitaxel as Second Line Therapy for Small Cell Lung Cancer (SCLC)

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02038647
• Collaborator: (none)
• Enrollment: 178
• Locations: 61
• Arms: 2
• Actual Duration (Months): 37.9
• Patients Per Site: 2.9
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This is a two-arm, randomized, double-blind, placebo-controlled, multicenter, phase 2 study designed to is to determine if the combination treatment can improve progression free survival (defined as the time from the date of randomization to the date of first documentation of disease progression or death, whichever occurs first) when compared with placebo + paclitaxel.

Condition or Disease	Intervention/Treatment	Phase
Small Cell Lung Cancer	Drug: Alisertib; Drug: Placebo; Drug: Paclitaxel	Phase 2

Detailed Description

The drug tested in this study is called alisertib. Alisertib is being tested to treat people who have Small Cell Lung Cancer (SCLC). This study determined the safety and efficacy for alisertib when given twice a day along with paclitaxel.

This open label study enrolled 178 patients. Participants were randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which remained undisclosed to the patient and study doctor during the study (unless there is an urgent medical need) and participants were stratified at baseline as to whether brain mets were present or not; whether they were sensitive to prior therapy or were relapsed/refractory to prior therapy; and by world region:

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

• Paclitaxel 80 mg/m^2 + Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient

All participants received treatment until their disease progressed or they experienced unacceptable alisertib-related toxicity.

This multi-center trial was conducted world-wide. The overall time to participate in this study was approximately up to 22 months. Participants made multiple visits to the clinic, and were contacted by telephone every month for 6 months after the end of treatment (EOT) for follow-up assessment of progression free survival and for overall survival every 2 months until death, study closure, or 14 months after randomization of the last participant.

Study Design

• Study Type: Interventional
• Actual Enrollment: 178 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Phase 2 Clinical Trial of Alisertib (MLN8237) in Combination With Paclitaxel Versus Placebo in Combination With Paclitaxel as Second Line Therapy for Small Cell Lung Cancer (SCLC).
• Actual Study Start Date: May 12, 2014
• Actual Primary Completion Date: Jan 3, 2016
• Actual Study Completion Date: Jul 10, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alisertib (MLN8237) + Paclitaxel Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day until disease progression (Up to 17 Cycles).	Drug: Alisertib; Alisertib tablets; Other Names: MLN8237 ; Drug: Paclitaxel; Paclitaxel intravenous injection
Placebo Comparator: Placebo + Paclitaxel Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).	Drug: Placebo; Placebo matching tablets; Drug: Paclitaxel; Paclitaxel intravenous injection

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) as Determined by Investigator, Analyzed Using FDA Guidelines [Every cycle for first 6 months and then every 2 months until disease progression or death or up to data cut-off: 03 January 2016 (approximately 22 months)]

   PFS is defined as time in days from start of study treatment to first documentation of objective tumor progression based on Investigator's assessment or up to death due to any cause, whichever occurs first based on Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Progressive disease (PD) was defined as ≥20% increase in sum longest diameter (LD) in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Secondary Outcome Measures

1. Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [From the first dose through 30 days after the last dose of study medication: data cut-off 03 January 2016 (Up to 10.8 months)]

   An Adverse Event (AE) is defined as any untoward medical occurrence in clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with treatment. An AE can be any unfavorable and unintended sign (eg, clinically significant abnormal laboratory finding), symptom, or disease temporally associated with use of drug, whether or not it is considered related to drug. A treatment-emergent adverse event (TEAE) is defined as an AE with an onset that occurs after receiving study drug. A Serious Adverse Event (SAE) is any experience that suggests 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 congenital anomaly/birth defect or is medically significant per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

2. Overall Survival (OS) [Contact every 2 months after EOT/disease progression until the sooner of death, study closure, or 14 months after the last participant was randomized up to data cut-off: 3 January 2016 (approximately 22 months)]

   OS was defined as the time in days from the date of randomization to the date of death due to any cause.

3. Overall Response Rate (ORR) [Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)]

   ORR is defined as the percentage of participants who achieved CR or partial response (PR) as best response based on Investigator's assessment according to RECIST v 1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as ≥ 30% decrease in sum of LD of target lesions in reference to Baseline sum LD.

4. Complete Response Rate (CRR) [Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)]

   CRR is defined as the percentage of participants who achieved CR as best response and based on Investigator's assessment according to RECIST v 1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.

5. Disease Control Rate (DCR) [Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)]

   DCR was defined as the percentage of participants who achieved CR, PR, or SD (when SD was a minimum of 8 weeks in duration). Duration of SD was defined as the time from the date of randomization to the date of first documentation of disease progression for participants who achieved SD as their best overall response. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as ≥ 30% decrease in sum of LD of target lesions in reference to Baseline sum LD. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

6. Duration of Response (DOR) [From first documented response until disease progression until data cut-off 03 January 2016 (approximately 9.8 months)]

   DOR was defined as the time from the date of first documentation of a PR or better to the date of first documentation of PD for responders. PR was defined as ≥ 30% decrease in sum of longest diameter (LD) of target lesions in reference to Baseline sum LD. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

7. Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5 [Baseline up to Cycle 5 (approximately 4.6 months)]

   European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 is 30-item questionnaire with 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (fatigue, nausea, vomiting and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions use 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions use 7-point scale (1=very poor - 7=Excellent). Total Score=0-100 scale; for 5 functional scales and global quality-of-life scale, a higher score=a better level of functioning. For symptoms scale, higher score= higher level of symptoms. EORTC QLQ-LC13 is considered as standard instrument to assess the quality of life (QL) of lung cancer participants. Total Score=0-100. Higher score=increase in level of symptomatology. The change between (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) score collected at Cycle 5 relative to baseline.

8. Percentage of Participants Experiencing Symptom Relief [Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)]

   Percentage of participants experiencing symptom relief, including coughing relief, dyspnea relief, and pain relief. Coughing relief is defined as a decrease from baseline ≥ 10 in QLQ-LC13 cough scale/item score. Dyspnea relief is defined as a decrease from baseline ≥ 10 in QLQ-C30 dyspnea scale/item score. Pain relief is defined as a decrease from baseline ≥ 10 in QLQ-C30 pain scale score. EORTC QLQ-C30 is 30-item questionnaire with 5 functional scales, 1 global health status scale, 3 symptom scales, 6 single items. Total Score=0-100 scale; for 5 functional scales and global quality-of-life scale, a higher score=a better level of functioning. For symptoms scale, higher score= higher level of symptoms. EORTC QLQ-LC13 is considered as standard instrument to assess the QL of lung cancer participants. Total Score=0-100. Higher score=increase in level of symptomatology.

9. Time to Symptom Relief [Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)]

   Time to symptom (coughing/dyspnea/pain) relief was defined as the time from the date of randomization to the date of first detection of coughing/dyspnea/pain relief, respectively.

10. Time to Symptom Progression [Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)]

    Time to coughing/dyspnea/pain progression was defined as time from the date of randomization to date of first detection of progression. Coughing progression was defined as increase from baseline ≥10 in QLQ-LC13 cough scale/item score. Dyspnea progression was defined as increase from baseline ≥10 in QLQ-C30 dyspnea scale/item score. Pain progression was defined as increase from baseline ≥10 in QLQ-C30 pain scale score. EORTC QLQ-C30 is 30-item questionnaire with 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (fatigue, nausea, vomiting and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The QLQ-LC13 is 13-item scale for assessing treatment-specific symptoms in lung cancer. Total Score= 0-100 scale; for 5 functional scales and global quality-of-life scale, higher score=better level of functioning. For symptoms scale, higher score=higher level of symptoms.

11. Observed Plasma Concentration for Alisertib [Day 1 pre-dose and 1, 2-4, 3-6, 10-11 hours post-dose; Day 8, 2 hours post-dose; Day 15, 6-9 hours (hrs) post-dose]

12. Observed Plasma Concentration for Paclitaxel [Day 1 pre-dose and 1, 2-4, 3-6, 10-11 hours post-dose; Day 8, 2 hours post-dose; Day 15, 6-9 hours post-dose]

Other Outcome Measures

1. Biomarker Correlative Studies Including Circulating Tumor Cells and Circulating DNA Assessments [Day 1 cycle 1 in a 28-day cycle]

2. Health Related Quality of Life (HRQOL ) [Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

Each participant must meet all the following inclusion criteria to be enrolled in the study:

1. Male or female participants ≥ 18 years old.

2. Have a pathologically (histology or cytology) confirmed diagnosis of SCLC.

3. Have received and progressed after a platinum-based standard chemotherapy regimen for first line treatment of SCLC, either limited stage (LS) or extensive stage (ES).

4. Have measurable disease within ≤ 2 weeks before randomization. Clear radiographic evidence of disease progression after initial therapy should have been documented.

5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 (PS 0-1).

6. Participants with treated brain metastases (surgery, whole or stereotactic brain radiation) are allowed provided the lesions have been stable for at least 2 weeks and the participant is off steroids or is on a stable dose of steroids. Participants should be without neurologic dysfunction that would confound the evaluation of neurological and/or other AEs.

Exclusion Criteria

Participants meeting any of the following exclusion criteria are not to be randomized to treatment:

1. Any prior therapy for second-line treatment of SCLC.

2. Participants who relapsed ≥ 180 days after their response to first-line treatment.

3. Prior treatment with an Aurora A specific-targeted or pan-Aurora-targeted agent, including alisertib, or any other investigational agent.

4. Prior treatment with paclitaxel or any other taxane agent.

5. Known hypersensitivity to Cremophor® EL, paclitaxel, or its components.

6. Any comorbid condition or unresolved toxicity that would preclude administration of alisertib or weekly paclitaxel.

7. Prior history of ≥ Grade 2 neurotoxicity that is not resolved to ≤ Grade 1.

8. Participants with symptomatic and/or progressive brain metastases or with carcinomatous meningitis.

9. Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of alisertib and during study conduct. Major prohibited enzyme inducers include: phenytoin, carbamazepine, phenobarbital, rifampin, rifabutin, rifapentine, and St. John's wort.

10. Inability to swallow alisertib or other orally administered medications.

11. Requirement for administration of proton pump inhibitor (PPI), H2 antagonist, or pancreatic enzymes.

12. Diagnosed with or treated for another malignancy within 2 years before the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease.

13. Other severe acute or chronic medical or psychiatric condition(s) per protocol.

14. History of myocardial infarction, unstable symptomatic ischemic heart disease, uncontrolled hypertension despite appropriate medical therapy, any ongoing cardiac arrhythmias of Grade > 2, thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), or any other cardiac condition (eg, pericardial effusion or restrictive cardiomyopathy) within 6 months before receiving the first dose of study drug.

15. Known history of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C.

16. Surgery within 3 weeks (or 2 weeks for a minor surgery) before study enrollment and not fully recovered to baseline or to a stable clinical status.

17. Participants who are pregnant, lactating, or do not agree to use effective methods of contraception during the study treatment period through 6 months after the last dose of study drug per protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Los Angeles	California	United States
2		Sacramento	California	United States
3		New Haven	Connecticut	United States
4		Washington	District of Columbia	United States
5		Boca Raton	Florida	United States
6		Hollywood	Florida	United States
7		Orlando	Florida	United States
8		Tampa	Florida	United States
9		Atlanta	Georgia	United States
10		Chicago	Illinois	United States
11		Boston	Massachusetts	United States
12		Ann Arbor	Michigan	United States
13		Detroit	Michigan	United States
14		Minneapolis	Minnesota	United States
15		Cleveland	Ohio	United States
16		Hershey	Pennsylvania	United States
17		Philadelphia	Pennsylvania	United States
18		Pittsburgh	Pennsylvania	United States
19		Nashville	Tennessee	United States
20		Houston	Texas	United States
21		Seattle	Washington	United States
22		Edegem		Belgium
23		Gent		Belgium
24		Kortrijk		Belgium
25		Leuven		Belgium
26		Mons		Belgium
27		Roeselare		Belgium
28		Edmonton	Alberta	Canada
29		Hamilton	Ontario	Canada
30		Greenfield Park		Canada
31		Olomouc		Czechia
32		Ostrava		Czechia
33		Praha		Czechia
34		Usti Nad Labem		Czechia
35		Grenoble		France
36		Lyon		France
37		Marseille		France
38		Paris		France
39		Pessac		France
40		Rennes		France
41		Berlin		Germany
42		Frankfurt		Germany
43		Freiburg		Germany
44		Luebeck		Germany
45		Budapest		Hungary
46		Farkasgyepu		Hungary
47		Szolnok		Hungary
48		Tatabanya		Hungary
49		Torokbalint		Hungary
50		Milano		Italy
51		Orbassano		Italy
52		Parma		Italy
53		Gdansk		Poland
54		Mrozy		Poland
55		Warszawa		Poland
56		Wodzislaw Slaski		Poland
57		A Coruna		Spain
58		Barcelona		Spain
59		Girona		Spain
60		Madrid		Spain
61		Sevilla		Spain

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Director Clinical Science, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT02038647
• Other Study ID Numbers: C14018; 2013-003713-18; U1111-1154-9805; DRKS00007849
• First Posted: Jan 16, 2014
• Last Update Posted: Dec 27, 2018
• Last Verified: Nov 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Millennium Pharmaceuticals, Inc.: Drug therapy
• Additional relevant MeSH terms: Lung Neoplasms; Small Cell Lung Carcinoma; Paclitaxel

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 54 investigative sites in the United States, Canada, European Union (Belgium, Czech Republic, France, Germany, Hungary, Italy, Poland and Spain) from 12 May 2014 to 10 July 2017. Data cutoff for the primary analysis was 3 January 2016.
Pre-assignment Detail	Participants with a diagnosis of Small Cell Lung Cancer (SCLC) were enrolled in 1 of 2 treatment groups: alisertib + paclitaxel or placebo + paclitaxel arm group.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Period Title: Overall Study
STARTED	89	89
COMPLETED	0	0
NOT COMPLETED	89	89

Baseline Characteristics

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel	Total
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).	Total of all reporting groups
Overall Participants	89	89	178
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.8 (8.55)	63.4 (8.56)	62.6 (8.57)
Sex: Female, Male (Count of Participants)
Female	38 42.7%	39 43.8%	77 43.3%
Male	51 57.3%	50 56.2%	101 56.7%
Race/Ethnicity, Customized (participants) [Number]
Hispanic or Latino	2 2.2%	3 3.4%	5 2.8%
Not Hispanic or Latino	81 91%	84 94.4%	165 92.7%
Unknown or Not Reported	6 6.7%	1 1.1%	7 3.9%
Missing	0 0%	1 1.1%	1 0.6%
Race/Ethnicity, Customized (participants) [Number]
White	83 93.3%	83 93.3%	166 93.3%
Black or African American	3 3.4%	2 2.2%	5 2.8%
Not reported	2 2.2%	2 2.2%	4 2.2%
Asian	1 1.1%	0 0%	1 0.6%
Other	0 0%	1 1.1%	1 0.6%
Missing	0 0%	1 1.1%	1 0.6%
Region of Enrollment (participants) [Number]
Belgium	8 9%	8 9%	16 9%
Czech Republic	6 6.7%	5 5.6%	11 6.2%
France	7 7.9%	5 5.6%	12 6.7%
Germany	2 2.2%	1 1.1%	3 1.7%
Hungary	16 18%	15 16.9%	31 17.4%
Italy	2 2.2%	0 0%	2 1.1%
Poland	1 1.1%	3 3.4%	4 2.2%
Spain	6 6.7%	11 12.4%	17 9.6%
Canada	6 6.7%	6 6.7%	12 6.7%
United States	35 39.3%	35 39.3%	70 39.3%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	169.5 (10.43)	168.8 (9.52)	169.2 (9.96)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	78.47 (20.561)	75.26 (17.602)	76.87 (19.153)
Body Surface Area (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.911 (0.2829)	1.872 (0.2433)	1.891 (0.2637)

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS) as Determined by Investigator, Analyzed Using FDA Guidelines
Description	PFS is defined as time in days from start of study treatment to first documentation of objective tumor progression based on Investigator's assessment or up to death due to any cause, whichever occurs first based on Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1. Progressive disease (PD) was defined as ≥20% increase in sum longest diameter (LD) in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time Frame	Every cycle for first 6 months and then every 2 months until disease progression or death or up to data cut-off: 03 January 2016 (approximately 22 months)

Outcome Measure Data

Analysis Population Description

The intent-to-treat (ITT) population was defined as all participants who were randomized to study treatment. For participants who have not progressed and is last known to be alive, PFS was censored at the last response assessment that is stable disease (SD) or better as determined by Investigator, and analyzed using FDA Guidelines.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Measure Participants	89	89
Median (95% Confidence Interval) [days]	101	66

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib + Paclitaxel, Placebo + Paclitaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.113
	Comments	P-value tests the hypothesis of equal event times in both treatment arms obtained using the Log-rank test stratified by disease subtype as sensitive versus resistant/refractory and the presence of brain metastases.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.557 to 1.067
	Parameter Dispersion	Type: Value:
	Estimation Comments	The stratification factors were: disease subtype as sensitive versus resistant/refractory and the presence of brain metastases (yes or no) with treatment (Alisertib + Paclitaxel vs Placebo + Paclitaxel) as a factor in the model.

2. Secondary Outcome

Title	Percentage of Participants Who Experience at Least One Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Description	An Adverse Event (AE) is defined as any untoward medical occurrence in clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with treatment. An AE can be any unfavorable and unintended sign (eg, clinically significant abnormal laboratory finding), symptom, or disease temporally associated with use of drug, whether or not it is considered related to drug. A treatment-emergent adverse event (TEAE) is defined as an AE with an onset that occurs after receiving study drug. A Serious Adverse Event (SAE) is any experience that suggests 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 congenital anomaly/birth defect or is medically significant per National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.
Time Frame	From the first dose through 30 days after the last dose of study medication: data cut-off 03 January 2016 (Up to 10.8 months)

Outcome Measure Data

Analysis Population Description

The safety population was defined as all participants who received at least 1 dose of any study drug.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Measure Participants	87	89
TEAEs	99 111.2%	96 107.9%
SAEs	44 49.4%	31 34.8%

3. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was defined as the time in days from the date of randomization to the date of death due to any cause.
Time Frame	Contact every 2 months after EOT/disease progression until the sooner of death, study closure, or 14 months after the last participant was randomized up to data cut-off: 3 January 2016 (approximately 22 months)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized to study treatment. Participants without documentation of death at the time of the analysis were censored at the date when they were last known to be alive.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Measure Participants	89	89
Median (95% Confidence Interval) [days]	186	165

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib + Paclitaxel, Placebo + Paclitaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.714
	Comments	P-value tests the hypothesis of equal event times in both treatment arms obtained using the Log-rank test stratified by disease subtype as sensitive versus resistant/refractory and the presence of brain metastases.
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.652 to 1.341
	Parameter Dispersion	Type: Value:
	Estimation Comments	The stratification factors were: disease subtype as sensitive versus resistant/refractory and the presence of brain metastases (yes or no) with treatment (Alisertib + Paclitaxel vs Placebo + Paclitaxel) as a factor in the model.

4. Secondary Outcome

Title	Overall Response Rate (ORR)
Description	ORR is defined as the percentage of participants who achieved CR or partial response (PR) as best response based on Investigator's assessment according to RECIST v 1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as ≥ 30% decrease in sum of LD of target lesions in reference to Baseline sum LD.
Time Frame	Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized to study treatment.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Measure Participants	89	89
Number (95% Confidence Interval) [percentage of participants]	22 24.7%	18 20.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib + Paclitaxel, Placebo + Paclitaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.406
	Comments	Stratification factors were disease subtypes (sensitive versus resistant/refractory), the presence of brain metastases and region.
	Method	Weighted Cochran-Mantel-Haenszel test
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.35 to 1.55
	Parameter Dispersion	Type: Value:
	Estimation Comments	Logistic regression using ORR as dependent variable, treatment arm as independent variable and disease subtype (sensitive vs resistant/refractory) and presence of brain metastases as stratification factors.

5. Secondary Outcome

Title	Complete Response Rate (CRR)
Description	CRR is defined as the percentage of participants who achieved CR as best response and based on Investigator's assessment according to RECIST v 1.1. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm.
Time Frame	Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized to study treatment.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Measure Participants	89	89
Number (95% Confidence Interval) [percentage of participants]	1 1.1%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib + Paclitaxel, Placebo + Paclitaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.283
	Comments	Stratification factors were disease subtypes (sensitive versus resistant/refractory), the presence of brain metastases and region.
	Method	Weighted Cochran-Mantel-Haenszel test
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; 0.01 to 9999.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Logistic regression using CRR as dependent variable, treatment arm as independent variable and disease subtype (sensitive vs resistant/refractory) and presence of brain metastases as stratification factors.

6. Secondary Outcome

Title	Disease Control Rate (DCR)
Description	DCR was defined as the percentage of participants who achieved CR, PR, or SD (when SD was a minimum of 8 weeks in duration). Duration of SD was defined as the time from the date of randomization to the date of first documentation of disease progression for participants who achieved SD as their best overall response. CR was defined as disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR was defined as ≥ 30% decrease in sum of LD of target lesions in reference to Baseline sum LD. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time Frame	Baseline until disease progression, death or EOT up to data cut-off: 03 January 2016 (approximately 9.8 months)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized to study treatment.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Measure Participants	89	89
Number (95% Confidence Interval) [percentage of participants]	58 65.2%	46 51.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Alisertib + Paclitaxel, Placebo + Paclitaxel
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.077
	Comments	Stratification factors were disease subtypes (sensitive versus resistant/refractory), the presence of brain metastases and region.
	Method	Weighted Cochran-Mantel-Haenszel test
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.32 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Logistic regression using DCR as dependent variable, treatment arm as independent variable and disease subtype (sensitive vs resistant/refractory) and presence of brain metastases as stratification factors.

7. Secondary Outcome

Title	Duration of Response (DOR)
Description	DOR was defined as the time from the date of first documentation of a PR or better to the date of first documentation of PD for responders. PR was defined as ≥ 30% decrease in sum of longest diameter (LD) of target lesions in reference to Baseline sum LD. PD was defined as ≥20% increase in sum LD in reference to the smallest on-study sum LD, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time Frame	From first documented response until disease progression until data cut-off 03 January 2016 (approximately 9.8 months)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized to study treatment. Responders were evaluated for this outcome measure. Responders without documentation of PD were censored at their date of last response assessment that was SD or better.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Measure Participants	20	16
Median (95% Confidence Interval) [days]	96	85

8. Secondary Outcome

Title	Change From Baseline in Symptom (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) Score at Cycle 5
Description	European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 is 30-item questionnaire with 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (fatigue, nausea, vomiting and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions use 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions use 7-point scale (1=very poor - 7=Excellent). Total Score=0-100 scale; for 5 functional scales and global quality-of-life scale, a higher score=a better level of functioning. For symptoms scale, higher score= higher level of symptoms. EORTC QLQ-LC13 is considered as standard instrument to assess the quality of life (QL) of lung cancer participants. Total Score=0-100. Higher score=increase in level of symptomatology. The change between (QLQ-LC13 Cough Scale, QLQ-C30 Dyspnea Scale, QLQ-C30 Pain Scale) score collected at Cycle 5 relative to baseline.
Time Frame	Baseline up to Cycle 5 (approximately 4.6 months)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized to study treatment. Here number of participants analyzed are participants evaluated in this outcome measure at the specific timepoint.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Measure Participants	20	15
Change at Cycle 5, QLQ-LC-13 Cough Scale	-10.94 (3.07)	8.07 (6.04)
Change at Cycle 5, QLQ-C30 Dyspnea Scale	-3.48 (4.25)	-1.09 (2.92)
Change at Cycle 5, QLQ-C30 Pain Scale	-4.82 (4.86)	-4.88 (5.16)

9. Secondary Outcome

Title	Percentage of Participants Experiencing Symptom Relief
Description	Percentage of participants experiencing symptom relief, including coughing relief, dyspnea relief, and pain relief. Coughing relief is defined as a decrease from baseline ≥ 10 in QLQ-LC13 cough scale/item score. Dyspnea relief is defined as a decrease from baseline ≥ 10 in QLQ-C30 dyspnea scale/item score. Pain relief is defined as a decrease from baseline ≥ 10 in QLQ-C30 pain scale score. EORTC QLQ-C30 is 30-item questionnaire with 5 functional scales, 1 global health status scale, 3 symptom scales, 6 single items. Total Score=0-100 scale; for 5 functional scales and global quality-of-life scale, a higher score=a better level of functioning. For symptoms scale, higher score= higher level of symptoms. EORTC QLQ-LC13 is considered as standard instrument to assess the QL of lung cancer participants. Total Score=0-100. Higher score=increase in level of symptomatology.
Time Frame	Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized to study treatment. Participants without coughing/dyspnea/pain relief were censored at their last assessment.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Measure Participants	89	89
Coughing Relief	28 31.5%	24 27%
Dyspnea Relief	31 34.8%	16 18%
Pain Relief	39 43.8%	36 40.4%

10. Secondary Outcome

Title	Time to Symptom Relief
Description	Time to symptom (coughing/dyspnea/pain) relief was defined as the time from the date of randomization to the date of first detection of coughing/dyspnea/pain relief, respectively.
Time Frame	Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized to study treatment. Participants without coughing/dyspnea/pain relief were censored at their last assessment.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Measure Participants	89	89
Time to Coughing Relief	NA	NA
Time to Dyspnea Relief	NA	NA
Time to Pain Relief	3.0	3.7

11. Secondary Outcome

Title	Time to Symptom Progression
Description	Time to coughing/dyspnea/pain progression was defined as time from the date of randomization to date of first detection of progression. Coughing progression was defined as increase from baseline ≥10 in QLQ-LC13 cough scale/item score. Dyspnea progression was defined as increase from baseline ≥10 in QLQ-C30 dyspnea scale/item score. Pain progression was defined as increase from baseline ≥10 in QLQ-C30 pain scale score. EORTC QLQ-C30 is 30-item questionnaire with 5 functional scales (physical, role, emotional, cognitive, and social), 1 global health status scale, 3 symptom scales (fatigue, nausea, vomiting and pain), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The QLQ-LC13 is 13-item scale for assessing treatment-specific symptoms in lung cancer. Total Score= 0-100 scale; for 5 functional scales and global quality-of-life scale, higher score=better level of functioning. For symptoms scale, higher score=higher level of symptoms.
Time Frame	Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)

Outcome Measure Data

Analysis Population Description

The ITT population was defined as all participants who were randomized to study treatment. Participant without coughing/dyspnea/pain progression were censored at their last assessment.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Measure Participants	89	89
Time to Coughing Progression	NA	2.8
Time to Dyspnea Progression	3.7	4.6
Time to Pain Progression	2.9	2.8

12. Secondary Outcome

Title	Observed Plasma Concentration for Alisertib
Time Frame	Day 1 pre-dose and 1, 2-4, 3-6, 10-11 hours post-dose; Day 8, 2 hours post-dose; Day 15, 6-9 hours (hrs) post-dose

Outcome Measure Data

Analysis Population Description

Safety population was defined as all participants who received at least 1 dose of any study drug. Number analyzed is the number of participants with evaluable data at the given time-point.

Arm/Group Title	Alisertib + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).
Measure Participants	87
Cycle 1, Day 1, Pre-Dose	0 (0)
Cycle 1, Day 1, 1 hr Post-Dose	495.37 (663.456)
Cycle 1, Day 1, 2-4 hrs Post-Dose	861.18 (616.951)
Cycle 1, Day 1, 3-6 hrs Post-Dose	1048.88 (716.447)
Cycle 1, Day 1, 10-11 hrs Post-Dose	539.15 (291.170)
Cycle 1, Day 8, 2 hrs Post-Dose	897.41 (816.387)
Cycle 1, Day 15, 6-9 hrs Post-Dose (1st Sample)	1102.93 (612.265)
Cycle 1, Day 15, 6-9 hrs Post-Dose (2nd Sample)	976.92 (572.090)

13. Secondary Outcome

Title	Observed Plasma Concentration for Paclitaxel
Time Frame	Day 1 pre-dose and 1, 2-4, 3-6, 10-11 hours post-dose; Day 8, 2 hours post-dose; Day 15, 6-9 hours post-dose

Outcome Measure Data

Analysis Population Description

Due to change in planned analysis, data was only collected and summarized for alisertib not for paclitaxel.

Arm/Group Title	Alisertib + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).
Measure Participants	0

14. Other Pre-specified Outcome

Title	Biomarker Correlative Studies Including Circulating Tumor Cells and Circulating DNA Assessments
Time Frame	Day 1 cycle 1 in a 28-day cycle

Outcome Measure Data

Analysis Population Description

This is an exploratory endpoint.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Measure Participants	0	0

15. Other Pre-specified Outcome

Title	Health Related Quality of Life (HRQOL )
Time Frame	Baseline up to Cycle 11, data cut-off: 03 January 2016 (approximately 9.8 months)

Outcome Measure Data

Analysis Population Description

This is an exploratory endpoint.

Arm/Group Title	Alisertib + Paclitaxel	Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).	Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
Measure Participants	0	0

Adverse Events

Time Frame	First dose of study drug through 30 days after the last dose of study drug (Up to 646 Days)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment. Safety Population included all participants who received at least dose of any study drug.
Arm/Group Title	Alisertib + Paclitaxel		Placebo + Paclitaxel
Arm/Group Description	Alisertib 40 mg, tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 60 mg/m^2 intravenously (IV) once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 17 Cycles).		Alisertib placebo-matching tablets, orally, twice a day, 3 days on/4 days off for 3 weeks on Days 1-3, 8-10, and 15-17 in a 28-day cycle along with paclitaxel 80 mg/m^2 IV once a week for 3 weeks on Days 1, 8, and 15 in a 28-day cycle until disease progression (Up to 22 Cycles).
All Cause Mortality
	Alisertib + Paclitaxel		Placebo + Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/87 (13.8%)		11/89 (12.4%)
Serious Adverse Events
	Alisertib + Paclitaxel		Placebo + Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	39/87 (44.8%)		30/89 (33.7%)
Blood and lymphatic system disorders
Febrile neutropenia	9/87 (10.3%)	12	0/89 (0%)	0
Neutropenia	5/87 (5.7%)	5	0/89 (0%)	0
Anaemia	2/87 (2.3%)	2	1/89 (1.1%)	1
Leukopenia	1/87 (1.1%)	1	0/89 (0%)	0
Pancytopenia	1/87 (1.1%)	1	0/89 (0%)	0
Cardiac disorders
Cardiac failure	1/87 (1.1%)	1	1/89 (1.1%)	1
Acute coronary syndrome	1/87 (1.1%)	1	0/89 (0%)	0
Angina pectoris	0/87 (0%)	0	1/89 (1.1%)	1
Pericardial effusion	0/87 (0%)	0	2/89 (2.2%)	2
Gastrointestinal disorders
Diarrhoea	5/87 (5.7%)	5	0/89 (0%)	0
Stomatitis	4/87 (4.6%)	5	1/89 (1.1%)	1
Abdominal pain	1/87 (1.1%)	1	1/89 (1.1%)	1
Vomiting	0/87 (0%)	0	2/89 (2.2%)	2
Constipation	1/87 (1.1%)	1	0/89 (0%)	0
General disorders
General physical health deterioration	3/87 (3.4%)	4	1/89 (1.1%)	1
Fatigue	0/87 (0%)	0	1/89 (1.1%)	1
Pyrexia	1/87 (1.1%)	1	0/89 (0%)	0
Systemic inflammatory response syndrome	1/87 (1.1%)	1	0/89 (0%)	0
Hepatobiliary disorders
Bile duct stenosis	1/87 (1.1%)	1	0/89 (0%)	0
Infections and infestations
Neutropenic sepsis	2/87 (2.3%)	3	0/89 (0%)	0
Bacteraemia	1/87 (1.1%)	1	0/89 (0%)	0
Sepsis	1/87 (1.1%)	1	0/89 (0%)	0
Septic shock	1/87 (1.1%)	1	0/89 (0%)	0
Pneumonia	3/87 (3.4%)	3	1/89 (1.1%)	3
Pneumocystis jirovecii infection	0/87 (0%)	0	1/89 (1.1%)	1
Pneumocystis jirovecii pneumonia	0/87 (0%)	0	1/89 (1.1%)	2
Fungal infection	1/87 (1.1%)	1	0/89 (0%)	0
Oral herpes	1/87 (1.1%)	1	0/89 (0%)	0
Respiratory tract infection	1/87 (1.1%)	1	1/89 (1.1%)	1
Influenza	1/87 (1.1%)	1	0/89 (0%)	0
Erysipelas	0/87 (0%)	0	1/89 (1.1%)	1
Injury, poisoning and procedural complications
Fall	0/87 (0%)	0	1/89 (1.1%)	1
Metabolism and nutrition disorders
Dehydration	1/87 (1.1%)	1	2/89 (2.2%)	2
Diabetic metabolic decompensation	1/87 (1.1%)	1	0/89 (0%)	0
Hypokalaemia	1/87 (1.1%)	1	0/89 (0%)	0
Hyponatraemia	0/87 (0%)	0	1/89 (1.1%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/87 (1.1%)	1	2/89 (2.2%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Small cell lung cancer	0/87 (0%)	0	6/89 (6.7%)	7
Metastases to meninges	1/87 (1.1%)	1	0/89 (0%)	0
Metastases to peritoneum	0/87 (0%)	0	1/89 (1.1%)	1
Lung neoplasm malignant	2/87 (2.3%)	3	0/89 (0%)	0
Glioblastoma	1/87 (1.1%)	1	0/89 (0%)	0
Tumour pain	1/87 (1.1%)	1	0/89 (0%)	0
Metastases to liver	0/87 (0%)	0	1/89 (1.1%)	1
Nervous system disorders
Epilepsy	0/87 (0%)	0	1/89 (1.1%)	1
Seizure	1/87 (1.1%)	1	0/89 (0%)	0
Ataxia	1/87 (1.1%)	1	0/89 (0%)	0
Cognitive disorder	0/87 (0%)	0	1/89 (1.1%)	1
Neuropathy peripheral	0/87 (0%)	0	1/89 (1.1%)	1
Paraplegia	1/87 (1.1%)	1	0/89 (0%)	0
Psychiatric disorders
Confusional state	1/87 (1.1%)	1	0/89 (0%)	0
Mental status changes	1/87 (1.1%)	1	0/89 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory failure	3/87 (3.4%)	3	0/89 (0%)	0
Acute respiratory failure	1/87 (1.1%)	2	1/89 (1.1%)	1
Pulmonary embolism	2/87 (2.3%)	2	1/89 (1.1%)	1
Dyspnoea	1/87 (1.1%)	1	0/89 (0%)	0
Hypoxia	0/87 (0%)	0	1/89 (1.1%)	1
Haemoptysis	0/87 (0%)	0	1/89 (1.1%)	1
Pneumonitis	0/87 (0%)	0	1/89 (1.1%)	1
Pulmonary oedema	1/87 (1.1%)	2	0/89 (0%)	0
Vascular disorders
Aortic thrombosis	1/87 (1.1%)	2	0/89 (0%)	0
Embolism	1/87 (1.1%)	1	0/89 (0%)	0
Other (Not Including Serious) Adverse Events
	Alisertib + Paclitaxel		Placebo + Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	85/87 (97.7%)		80/89 (89.9%)
Blood and lymphatic system disorders
Anaemia	38/87 (43.7%)	55	18/89 (20.2%)	23
Neutropenia	41/87 (47.1%)	89	7/89 (7.9%)	11
Leukopenia	12/87 (13.8%)	18	5/89 (5.6%)	8
Thrombocytopenia	7/87 (8%)	7	3/89 (3.4%)	3
Gastrointestinal disorders
Diarrhoea	48/87 (55.2%)	104	18/89 (20.2%)	32
Nausea	30/87 (34.5%)	43	30/89 (33.7%)	38
Vomiting	28/87 (32.2%)	45	19/89 (21.3%)	27
Stomatitis	27/87 (31%)	49	6/89 (6.7%)	7
Constipation	8/87 (9.2%)	11	21/89 (23.6%)	25
Abdominal pain	12/87 (13.8%)	13	3/89 (3.4%)	4
Abdominal pain upper	7/87 (8%)	9	6/89 (6.7%)	6
Dyspepsia	8/87 (9.2%)	9	4/89 (4.5%)	4
Gastrooesophageal reflux disease	5/87 (5.7%)	7	5/89 (5.6%)	5
Dysphagia	5/87 (5.7%)	5	3/89 (3.4%)	3
General disorders
Fatigue	38/87 (43.7%)	52	28/89 (31.5%)	35
Asthenia	14/87 (16.1%)	32	11/89 (12.4%)	16
Oedema peripheral	6/87 (6.9%)	7	10/89 (11.2%)	14
Pyrexia	8/87 (9.2%)	8	6/89 (6.7%)	7
Non-cardiac chest pain	4/87 (4.6%)	5	5/89 (5.6%)	5
Infections and infestations
Upper respiratory tract infection	2/87 (2.3%)	2	5/89 (5.6%)	5
Injury, poisoning and procedural complications
Fall	5/87 (5.7%)	5	3/89 (3.4%)	4
Investigations
Neutrophil count decreased	14/87 (16.1%)	28	4/89 (4.5%)	4
Weight decreased	13/87 (14.9%)	18	5/89 (5.6%)	7
White blood cell count decreased	12/87 (13.8%)	20	1/89 (1.1%)	4
Metabolism and nutrition disorders
Decreased appetite	29/87 (33.3%)	36	19/89 (21.3%)	26
Hypokalaemia	10/87 (11.5%)	12	6/89 (6.7%)	7
Dehydration	7/87 (8%)	8	4/89 (4.5%)	5
Hypomagnesaemia	5/87 (5.7%)	5	6/89 (6.7%)	10
Hypocalcaemia	7/87 (8%)	7	1/89 (1.1%)	1
Hyperglycaemia	5/87 (5.7%)	6	1/89 (1.1%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	9/87 (10.3%)	12	5/89 (5.6%)	10
Muscular weakness	6/87 (6.9%)	6	6/89 (6.7%)	11
Back pain	5/87 (5.7%)	8	6/89 (6.7%)	9
Musculoskeletal pain	4/87 (4.6%)	4	5/89 (5.6%)	5
Pain in extremity	3/87 (3.4%)	3	5/89 (5.6%)	7
Musculoskeletal chest pain	0/87 (0%)	0	6/89 (6.7%)	8
Nervous system disorders
Dizziness	15/87 (17.2%)	17	9/89 (10.1%)	14
Headache	9/87 (10.3%)	9	6/89 (6.7%)	7
Neuropathy peripheral	8/87 (9.2%)	10	7/89 (7.9%)	10
Paraesthesia	4/87 (4.6%)	5	6/89 (6.7%)	9
Hypoaesthesia	4/87 (4.6%)	5	5/89 (5.6%)	6
Somnolence	5/87 (5.7%)	6	3/89 (3.4%)	3
Dysgeusia	2/87 (2.3%)	2	5/89 (5.6%)	5
Psychiatric disorders
Insomnia	7/87 (8%)	7	7/89 (7.9%)	8
Confusional state	2/87 (2.3%)	2	5/89 (5.6%)	5
Respiratory, thoracic and mediastinal disorders
Dyspnoea	21/87 (24.1%)	23	19/89 (21.3%)	22
Cough	17/87 (19.5%)	19	17/89 (19.1%)	18
Productive cough	4/87 (4.6%)	4	9/89 (10.1%)	12
Epistaxis	3/87 (3.4%)	3	7/89 (7.9%)	10
Dysphonia	5/87 (5.7%)	5	3/89 (3.4%)	3
Skin and subcutaneous tissue disorders
Alopecia	14/87 (16.1%)	15	5/89 (5.6%)	5
Rash maculo-papular	0/87 (0%)	0	6/89 (6.7%)	10
Vascular disorders
Hypertension	5/87 (5.7%)	5	11/89 (12.4%)	13

Limitations/Caveats

[Not Specified]

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

In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.