A Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Participants With Advanced Solid Tumors

• Sponsor: Millennium Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00500903
• Collaborator: (none)
• Enrollment: 87
• Location: 1
• Arms: 3
• Actual Duration (Months): 45.3
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

To determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of MLN8237 when given by mouth (PO) for a minimum of 7 and a maximum of 21 consecutive days, followed by a 14-day recovery period.

Condition or Disease	Intervention/Treatment	Phase
Advanced Malignancies	Drug: Alisertib	Phase 1

Detailed Description

The drug tested in this study is called alisertib. Alisertib is being tested to treat people who have advanced malignancies. This study determined the dose-limiting toxicity, maximum tolerated dose, safety and pharmacokinetics (how the drug moves through the body) for alisertib when given once or twice a day for 7 to 21 days. This open label study enrolled 87 participants. Participants were enrolled in one of 3 treatment groups:

• Powder-in-Capsule (PIC) Dose Escalation (alisertib 5, 10, 20, 40, 80, 110 or 150 mg PIC , once daily (QD) for 7 days (D),or alisertib 25 mg, PIC, orally, QD 14D, or alisertib 25, 50 or 70 mg, PIC, orally, QD 21D, or alisertib 50 or 60 mg, PIC, orally, twice daily (BID) 7D, alisertib 40 mg, PIC, orally, BID 14D

• ECT Dose Escalation (alisertib 10 or 20 mg, Enteric-coated Tablets (ECT), orally, QD for 7 to 21 days

• Relative Bioavailability (alisertib 40 mg ECT or PIC, orally, BID 7D in cycle 1, followed by alisertib 40 mg in the opposite formulation (PIC or ECT) orally, BID 7D in cycle 2, followed by alisertib 50 mg PIC orally, BID 7D in each additional All participants received treatment until their disease progressed or they experienced unacceptable alisertib-related toxicity. This multi-center trial was conducted in the United States. The overall time to participate in this study was 1011 days. Participants made multiple visits to the clinic, including a final visit 30 days after receiving their last dose of alisertib for a follow-up assessment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 87 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Dose Escalation Phase 1 Study of MLN8237, a Novel Aurora A Kinase Inhibitor, in Patients With Advanced Solid Tumors
• Actual Study Start Date: May 15, 2007
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Feb 23, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: PIC Dose Escalation Alisertib 5, 10, 20, 40, 80, 110 or 150 mg, Powder-in-Capsule (PIC) formulation, orally, once daily (QD) for 7 to 21 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 51 cycles).	Drug: Alisertib; Alisertib (MLN8237) will be supplied in capsules of 5 or 25 mg and will be given on an empty stomach, with patients remaining nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose. Each dose will be given by mouth with 8 ounces of water for 7 to 21 consecutive days. A 14-day recovery period will follow each dosing period regardless of its duration.; Other Names: MLN8237
Experimental: ECT Dose Escalation Alisertib 10 or 20 mg, Enteric-coated Tablet (ECT) formulation, orally, once daily (QD) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 2 cycles).	Drug: Alisertib; Alisertib (MLN8237) will be supplied in capsules of 5 or 25 mg and will be given on an empty stomach, with patients remaining nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose. Each dose will be given by mouth with 8 ounces of water for 7 to 21 consecutive days. A 14-day recovery period will follow each dosing period regardless of its duration.; Other Names: MLN8237
Experimental: Relative Bioavailability Alisertib 40 mg ECT or PIC formulation, orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 1, followed by alisertib 40 mg in the opposite formulation (PIC or ECT) orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 2, followed by alisertib 50 mg PIC formulation orally, twice daily (BID) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 9 cycles).	Drug: Alisertib; Alisertib (MLN8237) will be supplied in capsules of 5 or 25 mg and will be given on an empty stomach, with patients remaining nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose. Each dose will be given by mouth with 8 ounces of water for 7 to 21 consecutive days. A 14-day recovery period will follow each dosing period regardless of its duration.; Other Names: MLN8237

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose-Limiting Toxicity (DLT) [Cycle 1 Day 1 up to Day 35 (alisertib daily for 7 to 21 days followed by a 14-day recovery period)]

   DLT was evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and was defined as any of the following events related to therapy with alisertib: Grade 4 neutropenia lasting ≥7 consecutive days Grade 4 neutropenia with fever and/or infection Platelet count <25,000/mm^3 Grade 3 or greater nausea and/or emesis despite use of optimal antiemetic prophylaxis Grade 3 or greater diarrhea despite maximal supportive therapy with loperamide Any other Grade 3 or greater nonhematologic toxicity, with the following exceptions: Grade 3 arthralgia/myalgias, Any grade of alopecia, Brief (<1 week) Grade 3 fatigue Treatment delay of >1 week due to failure of adequate hematologic or nonhematologic recovery from previous cycle of treatment Other alisertib-related nonhematologic toxicities ≥Grade 2 that, in the opinion of the investigator, required a dose reduction or discontinuation of therapy with alisertib.

2. Maximum Tolerated Dose (MTD) of Alisertib [From first dose of study drug to 30 days after the last dose (up to 1011 days)]

   MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 patients.

3. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [From first dose of study drug to 30 days after the last dose (up to 1011 days)]

   An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant 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.

Secondary Outcome Measures

1. Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose]

2. Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose]

3. AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose]

4. Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose]

5. Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose]

6. Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose]

7. CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose]

8. Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose]

9. CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose]

10. Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose]

11. Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose]

12. AUCt: Area Under the Concentration--Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose]

13. Terminal Half-Life for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [Cycle 1 Day 14 predose and at multiple time-points (up to 10 hours) postdose]

14. Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose]

15. Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose]

16. CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose]

17. Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose]

18. CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose]

19. Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose]

20. Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose]

21. AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose]

22. Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [Cycle 1 Day 21 predose and at multiple time points (up to 10 hours) postdose]

23. Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [Cycle 1 Days 14 and 21 predose and at multiple timepoints (up to 10 hours) postdose]

24. Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [Cycle 1 Days 14 and 21 predose and at multiple timepoints up to 10 hours postdose]

25. CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [Cycle 1 Days 14 and 21 predose and at multiple timepoints up to 10 hours postdose]

26. Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [Cycle 1 Day 1 predose and at multiple time points (up to 24 hours) postdose]

27. CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [Cycle 1 Day 1 predose and at multiple time points (up to 24 hours) postdose]

28. Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose]

29. Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose]

30. AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose]

31. Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [Cycle 1 Day 8]

32. Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose]

33. Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose]

34. CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose]

35. Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose]

36. CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose]

37. Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing [Cycle 1 Days 1 and 7 predose and at multiple time-points (up to 10 hours) postdose]

38. Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing [Cycle 1 Days 1 and 7 predose and at multiple time-points (up to 10 hours) postdose]

39. AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing [Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose]

40. AUCt: Area Under the Concentration-time Curve From Time 0 to Time t as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7 [Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose]

41. Cmax: Maximum Observed Concentration as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7 [Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose]

42. Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing [Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose]

    Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.

43. Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing [Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose]

    Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.

44. Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 14 Days (QD14D) Dosing [Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose]

    Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.

45. Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 14 Days (QD14D) Dosing [Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose]

    Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.

46. Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) Dosing [Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Days 7 and 21, 6 hours postdose]

    Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.

47. Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing [Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Days 7 and 21, 6 hours postdose]

    Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.

48. Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing [Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Day 7, 6 hours postdose]

    Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.

49. Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing [Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Day 7, 6 hours postdose]

    Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.

50. Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 14 Days (BID14D) Dosing [Baseline and Cycle 1 Day 7, 6 hours postdose]

    Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.

51. Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 14 Days (BID14D) Dosing [Baseline and Cycle 1 Day 7, 6 hours postdose]

    Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.

52. Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 [Cycle 1 Day 1 predose]

    One peripheral blood sample (approximately 4 mL) was to be obtained on Day 1 of Cycle 1 prior to the first dose of alisertib to genotype patients for polymorphisms in UGT1A1 because UGT1A1 is one of the enzymes responsible for glucuronidation of alisertib, which is expected to contribute to the clearance of alisertib. wt=wild type *28=polymorphism in the promoter region of a UGT1A1 allele resulting in reduced UGT1A1 expression.

53. Best Overall Response Based on Investigator Assessment [Beginning at the end of Cycle 2, every 2 cycles until progressive disease (PD); Participants who discontinue study drug before PD: Follow-Up (FU) every 8-12 weeks until PD or as per institutional practice (Up to 33.2 months)]

    Best overall response is defined as the percentage of participants with Complete Response (CR) + Partial Response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1. According to RECIST: CR is defined as disappearance of all target and nontarget lesions and normalization of tumor marker level (if applicable); PR is defined as ≥30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, persistence of 1 or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits.

54. Duration Of Response (DOR) [Beginning at the end of Cycle 2, every 2 cycles until progressive disease (PD); Participants who discontinue study drug before PD: Follow-Up (FU) every 8-12 weeks until PD or as per institutional practice (Up to 33.2 months)]

    DOR is defined as the time from the date of first documentation of a confirmed response to the date of first documented PD. PD is defined as 20% increase in the sum of the longest diameter of target lesions.

55. Effect of Food on the Pharmacokinetics (PK) of Alisertib [Up to 6 months]

    The effects of food on the PK of alisertib were to be evaluated using the preferred alisertib regimen (unit dose and formulation) based on the results from the relative bioavailability study.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically or cytologically confirmed metastatic and/or advanced solid tumors (including lymphomas) for which no effective standard treatment is available

• Aged 18 years or more

• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

• Expected survival longer than 3 months from enrollment in the study

• Radiographically or clinically evaluable tumor; however, measurable disease as defined by (RECIST) criteria is not required for participation in this study

• Suitable venous access for the conduct of blood sampling for MLN8237 PK

• Recovered from the reversible effects of prior antineoplastic therapy (with the exception of alopecia and grade 1 neuropathy) with at least 4 weeks elapsed since the last exposure to cytotoxic chemotherapy or to radiotherapy and at least 6 weeks elapsed since exposure to nitrosoureas or mitomycin C. Participants treated with fully human monoclonal antibodies must not have received treatment with such antibodies for at least 6 weeks, and those treated with chimeric monoclonal antibodies must not have received treatment with such antibodies for at least 4 weeks. Participants treated with noncytotoxic small molecule drugs (eg, tyrosine kinase inhibitors, such as Tarceva®, and hormonal agents, such as Femara®) must not have received treatment with these drugs for at least 2 weeks before the first dose of MLN8237 is given.

• Male participants must use an appropriate method of barrier contraception (eg, condoms) and inform any sexual partners that they must also use a reliable method of contraception (eg, birth control pills) from the time of informed consent until 3 months after the last dose of study treatment.

• Female participants must be postmenopausal, surgically sterilized, or willing to use reliable methods of birth control (eg, a hormonal contraceptive, an intrauterine device, diaphragm with spermicide, or abstinence) and inform male sexual partners that they must also use a reliable method of contraception (eg, condoms) from the time of informed consent until 3 months after the last dose of study treatment.

• Willing and able to give written informed consent before the conduct of any study related procedure that is not part of normal medical care, and willing to comply with the protocol

Exclusion Criteria:

• Pregnant or lactating

• Major surgery or serious infection within the 28 days preceding the first dose of study treatment

• Life-threatening illness or uncontrolled medical illness unrelated to cancer

• Ongoing nausea or vomiting of any severity

• Grade 1 diarrhea

• Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of MLN8237. Examples include but are not limited to partial gastrectomy, history of small intestine surgery, and celiac disease.

• History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.

• Difficulty swallowing capsules

• Inability to take nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose of MLN8237

• Received more than 4 previous cytotoxic chemotherapeutic regimens including regimens used as adjuvant or neo-adjuvant therapies. There is no limit on the number of noncytotoxic therapies (eg, hormonal and immunologic) that participants may have received. Tyrosine kinase inhibitors (eg, Tarceva and Iressa®) are considered noncytotoxic compounds.

• Prior treatment with high-dose chemotherapy, defined as chemotherapy requiring the use of peripheral blood or bone marrow stem cell support for hematopoietic reconstitution

• Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone marrow

• Clinical and/or radiographic evidence of cerebral metastases. However, participants who have a history of central nervous system (CNS) metastasis but who have no radiographic or clinical evidence of residual tumor (eg, following complete surgical resection or stereotactic radiosurgery) are not excluded from participation in this study

• Absolute neutrophil count <1500/mm^{3; platelet count <100,000/mm}3

• Serum creatinine >1.6 mg/dl or a measured or estimated creatinine clearance <40 mL/minute

• Bilirubin >1.5 times the upper limit of the normal range (ULN); aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >2.5 times the ULN, and alkaline phosphatase (ALP) >2.5 times the ULN. Both the AST and ALP may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of metastatic disease to liver and/or to bone; however, the ALT must in all circumstances be <2.5 times the ULN

• Abnormalities on 12-lead electrocardiogram (ECG) considered by the investigator to be clinically significant or baseline prolongation of the rate-corrected QT interval (eg, repeated demonstration of QTc interval > 450 milliseconds)

• Left ventricular ejection fraction (LVEF) < 50%

• Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection. Testing for these agents is not required in the absence of clinical findings or suspicion.

• Less than 4 weeks between the last dose of an investigational agent and the first dose of MLN8237

• Admission or evidence of benzodiazepine dependence or abuse and/or alcohol abuse or an inability to restrict consumption of alcohol to no more than 1 standard unit of alcohol per day during the study and for 30 days from the last dose of study treatment. A standard unit of alcohol is defined as one 12-oz (150mL) beer, 1.5 oz (45mL) of 80-proof alcohol, or one 6-oz (175mL) glass of wine.

• Lactose intolerant, for the food effect cohort only.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sarah Cannon Research Institute (SCRI)	Nashville	Tennessee	United States	37203

Sponsors and Collaborators

• Millennium Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor, Millennium Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Millennium Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT00500903
• Other Study ID Numbers: C14001; U1111-1187-1087
• First Posted: Jul 13, 2007
• Last Update Posted: Mar 14, 2019
• 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: Neoplasms

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 3 investigative sites in the United States from 15 May 2007 to 23 February 2011.
Pre-assignment Detail	Participants with a diagnosis of advanced malignancies were enrolled in 1 of 3 treatment groups, alisertib 5 to 150 mg Powder-in-Capsule (PIC) dose escalation cohort, alisertib 10 or 20 mg Enteric-coated Tablet (ECT) dose escalation cohort, or alisertib 40 mg PIC/ECT in a crossover design followed by alisertib 50 mg relative bioavailability cohort.

Arm/Group Title	PIC Dose Escalation	ECT Dose Escalation	Relative Bioavailability
Arm/Group Description	Alisertib 5, 10, 20, 40, 80, 110 or 150 mg, PIC, orally, once daily (QD) for 7 days, followed by a 14-day recovery period or alisertib 25 mg, PIC, orally, QD for 14 days, followed by a 14-day recovery period or alisertib 25, 50 or 70 mg, PIC, orally, QD for 21 days followed by a 14-day recovery period or alisertib 50 or 60 mg, PIC, orally, twice daily (BID) for 7 days followed by a 14-day recovery period or alisertib 40 mg, PIC, orally, BID for 14 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).	Alisertib 10 or 20 mg, Enteric-coated Tablet (ECT) formulation, orally, once daily (QD) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 2 cycles).	Alisertib 40 mg ECT or PIC formulation, orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 1, followed by alisertib 40 mg in the opposite formulation (PIC or ECT) orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 2, followed by alisertib 50 mg PIC formulation orally, twice daily (BID) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 9 cycles).
Period Title: Overall Study
STARTED	65	2	20
COMPLETED	0	0	0
NOT COMPLETED	65	2	20

Baseline Characteristics

Arm/Group Title	PIC Dose Escalation	ECT Dose Escalation	Relative Bioavailability	Total
Arm/Group Description	Alisertib 5, 10, 20, 40, 80, 110 or 150 mg, PIC, orally, once daily (QD) for 7 days, followed by a 14-day recovery period or alisertib 25 mg, PIC, orally, QD for 14 days, followed by a 14-day recovery period or alisertib 25, 50 or 70 mg, PIC, orally, QD for 21 days followed by a 14-day recovery period or alisertib 50 or 60 mg, PIC, orally, twice daily (BID) for 7 days followed by a 14-day recovery period or alisertib 40 mg, PIC, orally, BID for 14 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).	Alisertib 10 or 20 mg, Enteric-coated Tablet (ECT) formulation, orally, once daily (QD) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 2 cycles).	Alisertib 40 mg ECT or PIC formulation, orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 1, followed by alisertib 40 mg in the opposite formulation (PIC or ECT) orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 2, followed by alisertib 50 mg PIC formulation orally, twice daily (BID) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 9 cycles).	Total of all reporting groups
Overall Participants	65	2	20	87
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.6 (10.44)	57.0 (15.56)	56.9 (11.71)	60.4 (10.88)
Sex: Female, Male (Count of Participants)
Female	33 50.8%	1 50%	9 45%	43 49.4%
Male	32 49.2%	1 50%	11 55%	44 50.6%
Race/Ethnicity, Customized (participants) [Number]
Not Hispanic or Latino	56 86.2%	2 100%	20 100%	78 89.7%
Not Reported	7 10.8%	0 0%	0 0%	7 8%
Hispanic or Latino	2 3.1%	0 0%	0 0%	2 2.3%
Race/Ethnicity, Customized (participants) [Number]
White	55 84.6%	2 100%	18 90%	75 86.2%
Black or African American	9 13.8%	0 0%	2 10%	11 12.6%
Other	1 1.5%	0 0%	0 0%	1 1.1%
Region of Enrollment (participants) [Number]
United States	65 100%	2 100%	20 100%	87 100%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	169.3 (10.06)	165.1 (0.00)	171.5 (12.51)	169.7 (10.55)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	78.24 (18.130)	67.36 (11.226)	83.97 (21.706)	79.33 (18.976)
Body Surface Area (BSA) (m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [m^2]	1.91 (0.263)	1.75 (0.147)	1.99 (0.294)	1.92 (0.270)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose-Limiting Toxicity (DLT)
Description	DLT was evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and was defined as any of the following events related to therapy with alisertib: Grade 4 neutropenia lasting ≥7 consecutive days Grade 4 neutropenia with fever and/or infection Platelet count <25,000/mm^3 Grade 3 or greater nausea and/or emesis despite use of optimal antiemetic prophylaxis Grade 3 or greater diarrhea despite maximal supportive therapy with loperamide Any other Grade 3 or greater nonhematologic toxicity, with the following exceptions: Grade 3 arthralgia/myalgias, Any grade of alopecia, Brief (<1 week) Grade 3 fatigue Treatment delay of >1 week due to failure of adequate hematologic or nonhematologic recovery from previous cycle of treatment Other alisertib-related nonhematologic toxicities ≥Grade 2 that, in the opinion of the investigator, required a dose reduction or discontinuation of therapy with alisertib.
Time Frame	Cycle 1 Day 1 up to Day 35 (alisertib daily for 7 to 21 days followed by a 14-day recovery period)

Outcome Measure Data

Analysis Population Description

DLT-Evaluable Population included all participants who received at least 75% of their planned alisertib doses for their first cycle of treatment (unless interrupted by DLT) and had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.

Arm/Group Title	Alisertib 5 mg PIC QD 7D	Alisertib 10 mg PIC QD 7D	Alisertib 20 mg PIC QD 7D	Alisertib 40 mg PIC QD 7D	Alisertib 80 mg PIC QD 7D	Alisertib 110 mg PIC QD 7D	Alisertib 150 mg PIC QD 7D	Alisertib 25 mg PIC QD 14D	Alisertib 25 mg PIC QD 21D	Alisertib 50 mg PIC QD 21D	Alisertib 70 mg PIC QD 21D	Alisertib 50 mg PIC BID 7D	Alisertib 60 mg PIC BID 7D	Alisertib 40 mg PIC BID 14D	Alisertib 10 mg ECT QD7	Alisertib 20 mg ECT QD7
Arm/Group Description	Alisertib 5 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 10 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).	Alisertib 20 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 31 cycles).	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).	Alisertib 80 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles).	Alisertib 110 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 150 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 7 cycles).	Alisertib 70 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 60 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 35 cycles).	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).	Alisertib 10 mg, Enteric-coated Tablet (ECT) formulation, orally, once daily (QD) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 2 cycles).	Alisertib 20 mg, Enteric-coated Tablet (ECT) formulation, orally, once daily (QD) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 2 cycles).
Measure Participants	3	3	3	3	3	6	6	3	3	6	7	11	6	2	1	1
Number [participants]	0 0%	0 0%	0 0%	0 0%	0 NaN	1 NaN	3 NaN	0 NaN	0 NaN	0 NaN	1 NaN	2 NaN	2 NaN	2 NaN	0 NaN	0 NaN

2. Primary Outcome

Title	Maximum Tolerated Dose (MTD) of Alisertib
Description	MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 patients.
Time Frame	From first dose of study drug to 30 days after the last dose (up to 1011 days)

Outcome Measure Data

Analysis Population Description

DLT-Evaluable Population included all participants who received at least 75% of their planned alisertib doses for their first cycle of treatment (unless interrupted by DLT) and had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.

Arm/Group Title	Alisertib
Arm/Group Description	Alisertib 5, 10, 20, 40, 80, 110 or 150 mg, PIC, orally, once daily (QD) for 7 days, followed by a 14-day recovery period or alisertib 25 mg, PIC, orally, QD for 14 days, followed by a 14-day recovery period or alisertib 25, 50 or 70 mg, PIC, orally, QD for 21 days followed by a 14-day recovery period or alisertib 50 or 60 mg, PIC, orally, twice daily (BID) for 7 days followed by a 14-day recovery period or alisertib 40 mg, PIC, orally, BID for 14 days followed by a 14-day recovery period or alisertib 10 or 20 mg ECT, orally QD for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	65
Number [mg BID for 7 Days]	50

3. Primary Outcome

Title	Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant 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.
Time Frame	From first dose of study drug to 30 days after the last dose (up to 1011 days)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received any amount of study drug.

Arm/Group Title	PIC Dose Escalation	ECT Dose Escalation	Relative Bioavailability
Arm/Group Description	Alisertib 5, 10, 20, 40, 80, 110 or 150 mg, PIC, orally, once daily (QD) for 7 days, followed by a 14-day recovery period or alisertib 25 mg, PIC, orally, QD for 14 days, followed by a 14-day recovery period or alisertib 25, 50 or 70 mg, PIC, orally, QD for 21 days followed by a 14-day recovery period or alisertib 50 or 60 mg, PIC, orally, twice daily (BID) for 7 days followed by a 14-day recovery period or alisertib 40 mg, PIC, orally, BID for 14 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).	Alisertib 10 or 20 mg, Enteric-coated Tablet (ECT) formulation, orally, once daily (QD) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 2 cycles).	Alisertib 40 mg ECT or PIC formulation, orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 1, followed by alisertib 40 mg in the opposite formulation (PIC or ECT) orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 2, followed by alisertib 50 mg PIC formulation orally, twice daily (BID) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 9 cycles).
Measure Participants	65	2	20
AEs	65 100%	2 100%	20 100%
SAEs	26 40%	0 0%	1 5%

4. Secondary Outcome

Title	Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 5 mg PIC QD 7D	Alisertib 10 mg PIC QD 7D	Alisertib 20 mg PIC QD 7D	Alisertib 40 mg PIC QD 7D	Alisertib 80 mg PIC QD 7D	Alisertib 110 mg PIC QD 7D	Alisertib 150 mg PIC QD 7D
Arm/Group Description	Alisertib 5 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 10 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).	Alisertib 20 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 31 cycles).	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).	Alisertib 80 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles).	Alisertib 110 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 150 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	3	3	3	3	3	6	6
Day 1	208.4 (27.96)	279.1 (46.20)	759.3 (11.82)	1245.4 (20.60)	1661.3 (45.20)	2717.8 (44.62)	4260.3 (42.62)
Day 7	285.7 (32.74)	931.5 (81.68)	1114.1 (36.96)	1681.6 (64.62)	2376.3 (51.06)	3586.4 (48.28)	4467.8 (24.58)

5. Secondary Outcome

Title	Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 5 mg PIC QD 7D	Alisertib 10 mg PIC QD 7D	Alisertib 20 mg PIC QD 7D	Alisertib 40 mg PIC QD 7D	Alisertib 80 mg PIC QD 7D	Alisertib 110 mg PIC QD 7D	Alisertib 150 mg PIC QD 7D
Arm/Group Description	Alisertib 5 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 10 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).	Alisertib 20 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 31 cycles).	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).	Alisertib 80 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles).	Alisertib 110 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 150 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	3	3	3	3	3	6	6
Day 1	2.000	2.000	1.500	2.000	2.000	2.000	2.000
Day 7	1.500	3.750	1.500	2.000	2.000	3.710	2.000

6. Secondary Outcome

Title	AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 5 mg PIC QD 7D	Alisertib 10 mg PIC QD 7D	Alisertib 20 mg PIC QD 7D	Alisertib 40 mg PIC QD 7D	Alisertib 80 mg PIC QD 7D	Alisertib 110 mg PIC QD 7D	Alisertib 150 mg PIC QD 7D
Arm/Group Description	Alisertib 5 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 10 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).	Alisertib 20 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 31 cycles).	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).	Alisertib 80 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles).	Alisertib 110 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 150 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	3	3	3	3	3	6	6
Day 1	1682.4 (31.06)	2525.8 (21.87)	5772.1 (10.68)	12045.4 (57.01)	20958.1 (38.92)	29460.7 (39.43)	38582.1 (45.95)
Day 7	2919.5 (32.31)	10602.9 (107.87)	10927.5 (45.27)	21976.0 (96.64)	27825.5 (53.59)	46271.1 (33.38)	53031.9 (26.22)

7. Secondary Outcome

Title	Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time Frame	Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given timepoint.

Arm/Group Title	Alisertib 5 mg PIC QD 7D	Alisertib 10 mg PIC QD 7D	Alisertib 20 mg PIC QD 7D	Alisertib 40 mg PIC QD 7D	Alisertib 80 mg PIC QD 7D	Alisertib 110 mg PIC QD 7D	Alisertib 150 mg PIC QD 7D
Arm/Group Description	Alisertib 5 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 10 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).	Alisertib 20 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 31 cycles).	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).	Alisertib 80 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles).	Alisertib 110 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 150 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	2	2	3	2	3	6	5
Mean (Standard Deviation) [h]	24.950 (20.4354)	35.150 (23.4052)	26.400 (19.7684)	18.155 (12.5087)	39.333 (18.8006)	13.427 (4.3465)	16.766 (9.7804)

8. Secondary Outcome

Title	Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time Frame	Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given timepoint.

Arm/Group Title	Alisertib 5 mg PIC QD 7D	Alisertib 10 mg PIC QD 7D	Alisertib 20 mg PIC QD 7D	Alisertib 40 mg PIC QD 7D	Alisertib 80 mg PIC QD 7D	Alisertib 110 mg PIC QD 7D	Alisertib 150 mg PIC QD 7D
Arm/Group Description	Alisertib 5 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 10 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).	Alisertib 20 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 31 cycles).	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).	Alisertib 80 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles).	Alisertib 110 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 150 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	3	2	3	3	2	6	5
Mean (Standard Deviation) [ratio]	1.753 (0.2754)	6.350 (7.2408)	2.037 (0.9708)	1.997 (0.9393)	1.535 (0.3323)	1.677 (0.6788)	1.588 (0.4129)

9. Secondary Outcome

Title	Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time Frame	Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given timepoint.

Arm/Group Title	Alisertib 5 mg PIC QD 7D	Alisertib 10 mg PIC QD 7D	Alisertib 20 mg PIC QD 7D	Alisertib 40 mg PIC QD 7D	Alisertib 80 mg PIC QD 7D	Alisertib 110 mg PIC QD 7D	Alisertib 150 mg PIC QD 7D
Arm/Group Description	Alisertib 5 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 10 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).	Alisertib 20 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 31 cycles).	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).	Alisertib 80 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles).	Alisertib 110 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 150 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	3	2	3	3	3	6	5
Mean (Standard Deviation) [ratio]	4.107 (0.8460)	5.195 (3.9527)	5.430 (2.4856)	3.907 (2.3944)	3.850 (2.0612)	4.922 (2.5890)	4.610 (0.5314)

10. Secondary Outcome

Title	CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time Frame	Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given timepoint.

Arm/Group Title	Alisertib 5 mg PIC QD 7D	Alisertib 10 mg PIC QD 7D	Alisertib 20 mg PIC QD 7D	Alisertib 40 mg PIC QD 7D	Alisertib 80 mg PIC QD 7D	Alisertib 110 mg PIC QD 7D	Alisertib 150 mg PIC QD 7D
Arm/Group Description	Alisertib 5 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 10 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).	Alisertib 20 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 31 cycles).	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).	Alisertib 80 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles).	Alisertib 110 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 150 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	3	2	3	3	3	6	5
Geometric Mean (Geometric Coefficient of Variation) [liters (L)/h]	3.302 (35.8915)	1.817 (107.8347)	3.525 (49.1267)	3.511 (72.1346)	5.545 (41.0258)	4.348 (61.5266)	5.450 (37.3021)

11. Secondary Outcome

Title	Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 5 mg PIC QD 7D	Alisertib 10 mg PIC QD 7D	Alisertib 20 mg PIC QD 7D	Alisertib 40 mg PIC QD 7D	Alisertib 80 mg PIC QD 7D	Alisertib 110 mg PIC QD 7D	Alisertib 150 mg PIC QD 7D
Arm/Group Description	Alisertib 5 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 10 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).	Alisertib 20 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 31 cycles).	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).	Alisertib 80 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles).	Alisertib 110 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 150 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	3	3	3	3	2	6	6
Mean (Standard Deviation) [ng]	0.0 (0.00)	0.0 (0.00)	0.0 (0.00)	4806.7 (8325.39)	18815.0 (1675.84)	13813.3 (16387.22)	14473.3 (15603.71)

12. Secondary Outcome

Title	CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 40 mg PIC QD 7D	Alisertib 80 mg PIC QD 7D	Alisertib 110 mg PIC QD 7D	Alisertib 150 mg PIC QD 7D
Arm/Group Description	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).	Alisertib 80 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles).	Alisertib 110 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 150 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	1	1	5	5
Mean (Standard Deviation) [L/h]	0.0012630 (NA)	0.0013860 (NA)	0.0009414 (0.00063956)	0.0006710 (0.00060091)

13. Secondary Outcome

Title	Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 25 mg PIC QD 14D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).
Measure Participants	3
Day 1	778.7 (24.28)
Day 7	995.5 (43.21)
Day 14	808.9 (37.96)

14. Secondary Outcome

Title	Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 25 mg PIC QD 14D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).
Measure Participants	3
Day 1	4.000
Day 7	2.000
Day 14	2.000

15. Secondary Outcome

Title	AUCt: Area Under the Concentration--Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 25 mg PIC QD 14D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).
Measure Participants	3
Day 1	8061.6 (17.30)
Day 7	8634.0 (42.70)
Day 14	8978.0 (20.15)

16. Secondary Outcome

Title	Terminal Half-Life for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time Frame	Cycle 1 Day 14 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 25 mg PIC QD 14D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).
Measure Participants	3
Mean (Standard Deviation) [h]	65.67 (43.859)

17. Secondary Outcome

Title	Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time Frame	Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 25 mg PIC QD 14D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).
Measure Participants	3
Day 7	1.203 (0.6964)
Day 14	1.133 (0.2303)

18. Secondary Outcome

Title	Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time Frame	Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 25 mg PIC QD 14D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).
Measure Participants	3
Day 7	6.877 (1.1151)
Day 14	5.073 (2.2113)

19. Secondary Outcome

Title	CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time Frame	Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 25 mg PIC QD 14D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).
Measure Participants	3
Day 7	6.030 (2.9963)
Day 14	5.433 (0.9808)

20. Secondary Outcome

Title	Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 25 mg PIC QD 14D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).
Measure Participants	3
Mean (Standard Deviation) [ng]	800.0 (1385.64)

21. Secondary Outcome

Title	CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 25 mg PIC QD 14D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).
Measure Participants	1
Mean (Standard Deviation) [L/h]	0.0004930 (NA)

22. Secondary Outcome

Title	Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 25 mg PIC QD 21D	Alisertib 50 mg PIC QD 21D	Alisertib 70 mg PIC QD 21D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 7 cycles).	Alisertib 70 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	3	6	7
Day 1	898.2 (86.35)	1725.9 (54.70)	2237.0 (54.18)
Day 14	1343.3 (60.32)	1722.0 (38.82)	2598.3 (12.49)
Day 21	1104.7 (45.15)	1564.2 (38.80)	1974.5 (59.49)

23. Secondary Outcome

Title	Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 25 mg PIC QD 21D	Alisertib 50 mg PIC QD 21D	Alisertib 70 mg PIC QD 21D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 7 cycles).	Alisertib 70 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	3	6	7
Day 1	2.020	2.285	2.000
Day 14	2.000	2.000	2.000
Day 21	2.000	2.000	2.000

24. Secondary Outcome

Title	AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 25 mg PIC QD 21D	Alisertib 50 mg PIC QD 21D	Alisertib 70 mg PIC QD 21D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 7 cycles).	Alisertib 70 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	3	6	7
Day 1	10058.0 (66.85)	14686.6 (44.04)	22114.8 (68.66)
Day 14	15131.7 (49.89)	17168.2 (32.09)	23197.2 (17.75)
Day 21	13199.3 (70.05)	19336.3 (26.85)	23499.8 (65.64)

25. Secondary Outcome

Title	Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time Frame	Cycle 1 Day 21 predose and at multiple time points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.

Arm/Group Title	Alisertib 25 mg PIC QD 21D	Alisertib 50 mg PIC QD 21D	Alisertib 70 mg PIC QD 21D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 7 cycles).	Alisertib 70 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	3	6	5
Mean (Standard Deviation) [h]	31.667 (6.7122)	23.650 (16.9487)	22.378 (19.8802)

26. Secondary Outcome

Title	Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time Frame	Cycle 1 Days 14 and 21 predose and at multiple timepoints (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 25 mg PIC QD 21D	Alisertib 50 mg PIC QD 21D	Alisertib 70 mg PIC QD 21D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 7 cycles).	Alisertib 70 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	3	6	7
Day 14	1.560 (0.5543)	1.230 (0.4193)	1.440 (0.1493)
Day 21	1.560 (1.0516)	1.373 (0.4474)	1.335 (0.4749)

27. Secondary Outcome

Title	Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time Frame	Cycle 1 Days 14 and 21 predose and at multiple timepoints up to 10 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 25 mg PIC QD 21D	Alisertib 50 mg PIC QD 21D	Alisertib 70 mg PIC QD 21D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 7 cycles).	Alisertib 70 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	3	6	7
Day 14	4.773 (0.9001)	7.543 (5.4982)	6.392 (2.0824)
Day 21	3.637 (1.8675)	4.157 (2.1051)	5.570 (2.5772)

28. Secondary Outcome

Title	CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time Frame	Cycle 1 Days 14 and 21 predose and at multiple timepoints up to 10 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 25 mg PIC QD 21D	Alisertib 50 mg PIC QD 21D	Alisertib 70 mg PIC QD 21D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 7 cycles).	Alisertib 70 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	3	6	7
Day 14	3.181 (42.5706)	5.612 (28.6881)	5.825 (17.7291)
Day 21	3.656 (89.5750)	4.984 (25.6945)	5.745 (42.3818)

29. Secondary Outcome

Title	Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time points (up to 24 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 25 mg PIC QD 21D	Alisertib 50 mg PIC QD 21D	Alisertib 70 mg PIC QD 21D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 7 cycles).	Alisertib 70 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	3	6	7
Mean (Standard Deviation) [ng]	3047.7 (5278.71)	5766.7 (7971.95)	9391.4 (11410.18)

30. Secondary Outcome

Title	CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time points (up to 24 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 25 mg PIC QD 21D	Alisertib 50 mg PIC QD 21D	Alisertib 70 mg PIC QD 21D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 7 cycles).	Alisertib 70 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	1	3	4
Mean (Standard Deviation) [L/h]	0.0008640 (NA)	0.0012323 (0.00111840)	0.0007865 (0.00042447)

31. Secondary Outcome

Title	Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 50 mg PIC BID 7D	Alisertib 60 mg PIC BID 7D
Arm/Group Description	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 60 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 35 cycles).
Measure Participants	11	6
Day 1	1581.1 (37.34)	1867.1 (29.03)
Day 7	3376.4 (41.74)	3080.8 (38.79)

32. Secondary Outcome

Title	Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 50 mg PIC BID 7D	Alisertib 60 mg PIC BID 7D
Arm/Group Description	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 60 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 35 cycles).
Measure Participants	11	6
Day 1	2.000	2.000
Day 7	2.015	2.000

33. Secondary Outcome

Title	AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 50 mg PIC BID 7D	Alisertib 60 mg PIC BID 7D
Arm/Group Description	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 60 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 35 cycles).
Measure Participants	11	6
Day 1	11166.3 (37.45)	13200.4 (26.70)
Day 7	32291.5 (40.82)	27386.1 (37.43)

34. Secondary Outcome

Title	Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time Frame	Cycle 1 Day 8

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.

Arm/Group Title	Alisertib 50 mg PIC BID 7D	Alisertib 60 mg PIC BID 7D
Arm/Group Description	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 60 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 35 cycles).
Measure Participants	10	6
Mean (Standard Deviation) [h]	20.215 (15.5083)	18.200 (3.2212)

35. Secondary Outcome

Title	Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time Frame	Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.

Arm/Group Title	Alisertib 50 mg PIC BID 7D	Alisertib 60 mg PIC BID 7D
Arm/Group Description	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 60 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 35 cycles).
Measure Participants	5	3
Mean (Standard Deviation) [ratio]	2.474 (1.0467)	2.543 (0.1950)

36. Secondary Outcome

Title	Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time Frame	Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.

Arm/Group Title	Alisertib 50 mg PIC BID 7D	Alisertib 60 mg PIC BID 7D
Arm/Group Description	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 60 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 35 cycles).
Measure Participants	6	4
Mean (Standard Deviation) [ratio]	2.193 (1.1346)	1.890 (0.2012)

37. Secondary Outcome

Title	CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time Frame	Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.

Arm/Group Title	Alisertib 50 mg PIC BID 7D	Alisertib 60 mg PIC BID 7D
Arm/Group Description	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 60 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 35 cycles).
Measure Participants	5	4
Geometric Mean (Geometric Coefficient of Variation) [L/h]	2.984 (43.8719)	4.220 (47.9681)

38. Secondary Outcome

Title	Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 50 mg PIC BID 7D	Alisertib 60 mg PIC BID 7D
Arm/Group Description	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 60 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 35 cycles).
Measure Participants	10	5
Mean (Standard Deviation) [ng]	13775.0 (7937.14)	8498.3 (6866.09)

39. Secondary Outcome

Title	CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 50 mg PIC BID 7D	Alisertib 60 mg PIC BID 7D
Arm/Group Description	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 60 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 35 cycles).
Measure Participants	10	5
Mean (Standard Deviation) [ng]	0.001 (0.0011)	0.001 (0.0004)

40. Secondary Outcome

Title	Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing
Time Frame	Cycle 1 Days 1 and 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 40 mg PIC BID 14D
Arm/Group Description	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	2
Day 1	1236.6 (37.29)
Day 7	2060.0 (NA)

41. Secondary Outcome

Title	Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing
Time Frame	Cycle 1 Days 1 and 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 40 mg PIC BID 14D
Arm/Group Description	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	2
Day 1	3.00
Day 7	1.70

42. Secondary Outcome

Title	AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing
Time Frame	Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 40 mg PIC BID 14D
Arm/Group Description	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	2
Geometric Mean (Geometric Coefficient of Variation) [nM*h]	9684.8 (71.50)

43. Secondary Outcome

Title	AUCt: Area Under the Concentration-time Curve From Time 0 to Time t as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7
Time Frame	Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 40 mg ECT BID 7D	Alisertib 40 mg PIC BID 7D
Arm/Group Description	Alisertib 40 mg, Enteric-coated tablet (ECT), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period for 1 cycle.	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period for 1 cycle.
Measure Participants	14	14
Mean (Standard Deviation) [nM*h]	12700.0 (6557.58)	14190.7 (7097.72)

44. Secondary Outcome

Title	Cmax: Maximum Observed Concentration as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7
Time Frame	Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.

Arm/Group Title	Alisertib 40 mg ECT BID 7D	Alisertib 40 mg PIC BID 7D
Arm/Group Description	Alisertib 40 mg, Enteric-coated tablet (ECT), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period for 1 cycle.	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period for 1 cycle.
Measure Participants	14	14
Mean (Standard Deviation) [nM]	1666.1 (765.28)	2027.9 (928.96)

45. Secondary Outcome

Title	Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing
Description	Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time Frame	Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-points.

Arm/Group Title	Alisertib 5 mg PIC QD 7D	Alisertib 10 mg PIC QD 7D	Alisertib 20 mg PIC QD 7D	Alisertib 40 mg PIC QD 7D	Alisertib 80 mg PIC QD 7D	Alisertib 110 mg PIC QD 7D	Alisertib 150 mg PIC QD 7D
Arm/Group Description	Alisertib 5 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 10 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).	Alisertib 20 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 31 cycles).	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).	Alisertib 80 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles).	Alisertib 110 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 150 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	3	2	3	3	3	5	6
Day 1, Hour 6	0.405 (0.2701)	0.614 (0.5437)	0.263 (0.1461)	0.168 (0.5146)	0.488 (1.0215)	0.261 (0.4597)	0.865 (0.9420)
Day 1, Hour 24	0.019 (0.1914)	-0.103 (0.0186)	0.005 (0.0709)	0.141 (0.3852)	0.108 (0.4081)	1.764 (2.6380)	0.239 (0.6992)

46. Secondary Outcome

Title	Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing
Description	Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.
Time Frame	Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-points.

Arm/Group Title	Alisertib 5 mg PIC QD 7D	Alisertib 10 mg PIC QD 7D	Alisertib 20 mg PIC QD 7D	Alisertib 40 mg PIC QD 7D	Alisertib 80 mg PIC QD 7D	Alisertib 110 mg PIC QD 7D	Alisertib 150 mg PIC QD 7D
Arm/Group Description	Alisertib 5 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 10 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).	Alisertib 20 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 31 cycles).	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).	Alisertib 80 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles).	Alisertib 110 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 150 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	3	2	3	3	3	5	6
Day 1, Hour 6	0.010 (0.1175)	-0.090 (0.1278)	0.042 (0.0731)	0.040 (0.0701)	0.121 (0.1317)	0.036 (0.0530)	-0.042 (0.1262)
Day 1, Hour 24	0.009 (0.1164)	0.065 (0.1404)	0.000 (0.0000)	0.037 (0.0634)	0.074 (0.1286)	0.151 (0.1721)	0.139 (0.2069)

47. Secondary Outcome

Title	Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 14 Days (QD14D) Dosing
Description	Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time Frame	Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-points.

Arm/Group Title	Alisertib 25 mg PIC QD 14D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).
Measure Participants	3
Day 1, Hour 6	0.134 (0.1723)
Day 1, Hour 24	0.047 (0.0589)

48. Secondary Outcome

Title	Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 14 Days (QD14D) Dosing
Description	Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.
Time Frame	Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-points.

Arm/Group Title	Alisertib 25 mg PIC QD 14D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 5 cycles).
Measure Participants	3
Day 1, Hour 6	0.000 (0.0000)
Day 1, Hour 24	0.000 (0.0000)

49. Secondary Outcome

Title	Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) Dosing
Description	Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time Frame	Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Days 7 and 21, 6 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 25 mg PIC QD 21D	Alisertib 50 mg PIC QD 21D	Alisertib 70 mg PIC QD 21D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 7 cycles).	Alisertib 70 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	3	6	7
Day 1, Hour 6	0.380 (0.4165)	0.405 (0.4690)	0.510 (NA)
Day 1, Hour 24	0.021 (0.1081)	0.082 (0.1796)	0.289 (0.5746)
Day 7, Hour 6	0.479 (0.3040)
Day 21, Hour 6	0.045 (NA)	0.742 (0.5782)

50. Secondary Outcome

Title	Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing
Description	Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.
Time Frame	Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Days 7 and 21, 6 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 25 mg PIC QD 21D	Alisertib 50 mg PIC QD 21D	Alisertib 70 mg PIC QD 21D
Arm/Group Description	Alisertib 25 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 7 cycles).	Alisertib 70 mg, Powder-in-Capsule (PIC), orally, once daily (QD) for 21 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	3	6	7
Day 1, Hour 6	0.122 (0.2117)	0.000 (0.0000)	0.000 (NA)
Day 1, Hour 24	0.042 (0.0722)	0.042 (0.0719)	0.000 (0.0000)
Day 7, Hour 6	0.000 (0.0000)
Day 21, Hour 6	0.099 (NA)	0.032 (0.0552)

51. Secondary Outcome

Title	Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing
Description	Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time Frame	Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Day 7, 6 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 50 mg PIC BID 7D	Alisertib 60 mg PIC BID 7D
Arm/Group Description	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 60 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 35 cycles).
Measure Participants	11	6
Day 1, Hour 6	0.054 (0.3022)	0.364 (0.2574)
Day 1, Hour 24	2.578 (2.2875)	1.435 (0.8329)
Day 7, Hour 6	5.486 (5.8688)

52. Secondary Outcome

Title	Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing
Description	Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.
Time Frame	Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Day 7, 6 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.

Arm/Group Title	Alisertib 50 mg PIC BID 7D	Alisertib 60 mg PIC BID 7D
Arm/Group Description	Alisertib 50 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles).	Alisertib 60 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 35 cycles).
Measure Participants	11	6
Day 1, Hour 6	-0.016 (0.0494)	0.020 (0.0491)
Day 1, Hour 24	0.055 (0.1691)	0.080 (0.1958)
Day 7, Hour 6	2.142 (3.2510)

53. Secondary Outcome

Title	Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 14 Days (BID14D) Dosing
Description	Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time Frame	Baseline and Cycle 1 Day 7, 6 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.

Arm/Group Title	Alisertib 40 mg PIC BID 14D
Arm/Group Description	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	1
Mean (Standard Deviation) [mitotic cells/millimeter of BEL]	1.507 (NA)

54. Secondary Outcome

Title	Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 14 Days (BID14D) Dosing
Description	Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.
Time Frame	Baseline and Cycle 1 Day 7, 6 hours postdose

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.

Arm/Group Title	Alisertib 40 mg PIC BID 14D
Arm/Group Description	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 14 days (D) followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
Measure Participants	1
Mean (Standard Deviation) [apoptotic cells/millimeter of BEL]	2.837 (NA)

55. Secondary Outcome

Title	Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1
Description	One peripheral blood sample (approximately 4 mL) was to be obtained on Day 1 of Cycle 1 prior to the first dose of alisertib to genotype patients for polymorphisms in UGT1A1 because UGT1A1 is one of the enzymes responsible for glucuronidation of alisertib, which is expected to contribute to the clearance of alisertib. wt=wild type *28=polymorphism in the promoter region of a UGT1A1 allele resulting in reduced UGT1A1 expression.
Time Frame	Cycle 1 Day 1 predose

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received any amount of study drug.

Arm/Group Title	Alisertib
Arm/Group Description	Alisertib 5, 10, 20, 40, 80, 110 or 150 mg, PIC, orally, once daily (QD) for 7 days, followed by a 14-day recovery period or alisertib 25 mg, PIC, orally, QD for 14 days, followed by a 14-day recovery period or alisertib 25, 50 or 70 mg, PIC, orally, QD for 21 days followed by a 14-day recovery period or alisertib 50 or 60 mg, PIC, orally, twice daily (BID) for 7 days followed by a 14-day recovery period or alisertib 40 mg, PIC, orally, BID for 14 days followed by a 14-day recovery period or alisertib 10 or 20 mg ECT, orally QD for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	87
wt/wt	38 58.5%
wt/*28	30 46.2%
*28/*28	9 13.8%
*28/other	4 6.2%
other/other	2 3.1%
Not Determined	1 1.5%
Missing	3 4.6%

56. Secondary Outcome

Title	Best Overall Response Based on Investigator Assessment
Description	Best overall response is defined as the percentage of participants with Complete Response (CR) + Partial Response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1. According to RECIST: CR is defined as disappearance of all target and nontarget lesions and normalization of tumor marker level (if applicable); PR is defined as ≥30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, persistence of 1 or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits.
Time Frame	Beginning at the end of Cycle 2, every 2 cycles until progressive disease (PD); Participants who discontinue study drug before PD: Follow-Up (FU) every 8-12 weeks until PD or as per institutional practice (Up to 33.2 months)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received any amount of study drug.

Arm/Group Title	Alisertib
Arm/Group Description	Alisertib 5, 10, 20, 40, 80, 110 or 150 mg, PIC, orally, once daily (QD) for 7 days, followed by a 14-day recovery period or alisertib 25 mg, PIC, orally, QD for 14 days, followed by a 14-day recovery period or alisertib 25, 50 or 70 mg, PIC, orally, QD for 21 days followed by a 14-day recovery period or alisertib 50 or 60 mg, PIC, orally, twice daily (BID) for 7 days followed by a 14-day recovery period or alisertib 40 mg, PIC, orally, BID for 14 days followed by a 14-day recovery period or alisertib 10 or 20 mg ECT, orally QD for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	87
Number [percentage of participants]	1 1.5%

57. Secondary Outcome

Title	Duration Of Response (DOR)
Description	DOR is defined as the time from the date of first documentation of a confirmed response to the date of first documented PD. PD is defined as 20% increase in the sum of the longest diameter of target lesions.
Time Frame	Beginning at the end of Cycle 2, every 2 cycles until progressive disease (PD); Participants who discontinue study drug before PD: Follow-Up (FU) every 8-12 weeks until PD or as per institutional practice (Up to 33.2 months)

Outcome Measure Data

Analysis Population Description

Safety Population included all participants who received any amount of study drug.

Arm/Group Title	Alisertib
Arm/Group Description	Alisertib 5, 10, 20, 40, 80, 110 or 150 mg, PIC, orally, once daily (QD) for 7 days, followed by a 14-day recovery period or alisertib 25 mg, PIC, orally, QD for 14 days, followed by a 14-day recovery period or alisertib 25, 50 or 70 mg, PIC, orally, QD for 21 days followed by a 14-day recovery period or alisertib 50 or 60 mg, PIC, orally, twice daily (BID) for 7 days followed by a 14-day recovery period or alisertib 40 mg, PIC, orally, BID for 14 days followed by a 14-day recovery period or alisertib 10 or 20 mg ECT, orally QD for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).
Measure Participants	1
Number [days]	470

58. Secondary Outcome

Title	Effect of Food on the Pharmacokinetics (PK) of Alisertib
Description	The effects of food on the PK of alisertib were to be evaluated using the preferred alisertib regimen (unit dose and formulation) based on the results from the relative bioavailability study.
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

The effects of food on the PK of alisertib was not conducted. As the development of alisertib was transitioned from the PIC to the ECT formulation and the clinical dose of alisertib ECT had not been determined yet, it was decided that the effect of food would be evaluated in a different study at the appropriate clinical dose, administered as ECT.

Arm/Group Title	Alisertib 40 mg ECT BID 7D	Alisertib 40 mg PIC BID 7D
Arm/Group Description	Alisertib 40 mg, Enteric-coated tablet (ECT), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period for 1 cycle.	Alisertib 40 mg, Powder-in-Capsule (PIC), orally, twice daily (BID) for 7 days (D) followed by a 14--day recovery period for 1 cycle.
Measure Participants	0	0

Adverse Events

Time Frame	From first dose of study drug to 30 days after the last dose (up to 1011 days)
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	PIC Dose Escalation		ECT Dose Escalation		Relative Bioavailability
Arm/Group Description	Alisertib 5, 10, 20, 40, 80, 110 or 150 mg, PIC, orally, once daily (QD) for 7 days, followed by a 14-day recovery period or alisertib 25 mg, PIC, orally, QD for 14 days, followed by a 14-day recovery period or alisertib 25, 50 or 70 mg, PIC, orally, QD for 21 days followed by a 14-day recovery period or alisertib 50 or 60 mg, PIC, orally, twice daily (BID) for 7 days followed by a 14-day recovery period or alisertib 40 mg, PIC, orally, BID for 14 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles).		Alisertib 10 or 20 mg, Enteric-coated Tablet (ECT) formulation, orally, once daily (QD) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 2 cycles).		Alisertib 40 mg ECT or PIC formulation, orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 1, followed by alisertib 40 mg in the opposite formulation (PIC or ECT) orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 2, followed by alisertib 50 mg PIC formulation orally, twice daily (BID) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 9 cycles).
All Cause Mortality
	PIC Dose Escalation		ECT Dose Escalation		Relative Bioavailability
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	PIC Dose Escalation		ECT Dose Escalation		Relative Bioavailability
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/65 (40%)		0/2 (0%)		1/20 (5%)
Blood and lymphatic system disorders
Febrile neutropenia	5/65 (7.7%)		0/2 (0%)		1/20 (5%)
Neutropenia	3/65 (4.6%)		0/2 (0%)		0/20 (0%)
Anaemia	4/65 (6.2%)		0/2 (0%)		0/20 (0%)
Thrombocytopenia	4/65 (6.2%)		0/2 (0%)		0/20 (0%)
Cardiac disorders
Restrictive cardiomyopathy	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Ventricular dysfunction	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Arrhythmia supraventricular	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Atrial fibrillation	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Gastrointestinal disorders
Diarrhoea	3/65 (4.6%)		0/2 (0%)		0/20 (0%)
Nausea	3/65 (4.6%)		0/2 (0%)		0/20 (0%)
Vomiting	2/65 (3.1%)		0/2 (0%)		0/20 (0%)
Intestinal obstruction	2/65 (3.1%)		0/2 (0%)		0/20 (0%)
Small intestinal obstruction	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Abdominal pain	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Gastrointestinal haemorrhage	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Stomatitis	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
General disorders
Asthenia	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Fatigue	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Disease progression	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Jaundice cholestatic	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Bile duct obstruction	0/65 (0%)		0/2 (0%)		1/20 (5%)
Bile duct stenosis	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Infections and infestations
Klebsiella bacteraemia	1/65 (1.5%)		0/2 (0%)		1/20 (5%)
Urinary tract infection	2/65 (3.1%)		0/2 (0%)		0/20 (0%)
Enterococcal bacteraemia	0/65 (0%)		0/2 (0%)		1/20 (5%)
Pneumonia	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Staphylococcal infection	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Bacteraemia	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Injury, poisoning and procedural complications
Radius fracture	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/65 (0%)		0/2 (0%)		1/20 (5%)
Neck pain	0/65 (0%)		0/2 (0%)		1/20 (5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to central nervous system	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Pancreatic carcinoma metastatic	0/65 (0%)		0/2 (0%)		1/20 (5%)
Nervous system disorders
Syncope	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Headache	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Mental impairment	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Psychiatric disorders
Hallucination, visual	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Renal and urinary disorders
Renal failure acute	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Reproductive system and breast disorders
Vaginal haemorrhage	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/65 (3.1%)		0/2 (0%)		0/20 (0%)
Pulmonary embolism	1/65 (1.5%)		0/2 (0%)		0/20 (0%)
Vascular disorders
Deep vein thrombosis	0/65 (0%)		0/2 (0%)		1/20 (5%)
Other (Not Including Serious) Adverse Events
	PIC Dose Escalation		ECT Dose Escalation		Relative Bioavailability
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	65/65 (100%)		2/2 (100%)		20/20 (100%)
Blood and lymphatic system disorders
Neutropenia	28/65 (43.1%)		0/2 (0%)		7/20 (35%)
Anaemia	24/65 (36.9%)		2/2 (100%)		6/20 (30%)
Thrombocytopenia	8/65 (12.3%)		0/2 (0%)		0/20 (0%)
Leukopenia	2/65 (3.1%)		0/2 (0%)		4/20 (20%)
Lymphopenia	1/65 (1.5%)		0/2 (0%)		3/20 (15%)
Cardiac disorders
Atrial flutter	0/65 (0%)		0/2 (0%)		1/20 (5%)
Ear and labyrinth disorders
Ear pain	1/65 (1.5%)		0/2 (0%)		1/20 (5%)
Endocrine disorders
Hypothyroidism	0/65 (0%)		0/2 (0%)		1/20 (5%)
Eye disorders
Vision blurred	4/65 (6.2%)		0/2 (0%)		0/20 (0%)
Eye swelling	0/65 (0%)		0/2 (0%)		1/20 (5%)
Visual disturbance	0/65 (0%)		0/2 (0%)		1/20 (5%)
Gastrointestinal disorders
Nausea	39/65 (60%)		1/2 (50%)		6/20 (30%)
Diarrhoea	34/65 (52.3%)		1/2 (50%)		6/20 (30%)
Vomiting	24/65 (36.9%)		1/2 (50%)		2/20 (10%)
Stomatitis	15/65 (23.1%)		1/2 (50%)		5/20 (25%)
Constipation	12/65 (18.5%)		0/2 (0%)		4/20 (20%)
Abdominal pain	13/65 (20%)		0/2 (0%)		2/20 (10%)
Flatulence	5/65 (7.7%)		0/2 (0%)		1/20 (5%)
Abdominal distension	5/65 (7.7%)		0/2 (0%)		0/20 (0%)
Ascites	4/65 (6.2%)		0/2 (0%)		0/20 (0%)
Oral pain	3/65 (4.6%)		1/2 (50%)		0/20 (0%)
Abdominal pain lower	1/65 (1.5%)		0/2 (0%)		2/20 (10%)
Dyspepsia	1/65 (1.5%)		0/2 (0%)		1/20 (5%)
Abdominal discomfort	0/65 (0%)		0/2 (0%)		1/20 (5%)
Frequent bowel movements	0/65 (0%)		0/2 (0%)		1/20 (5%)
Gastrooesophageal reflux disease	0/65 (0%)		0/2 (0%)		1/20 (5%)
Gingival pain	0/65 (0%)		0/2 (0%)		1/20 (5%)
General disorders
Fatigue	32/65 (49.2%)		2/2 (100%)		12/20 (60%)
Oedema peripheral	13/65 (20%)		0/2 (0%)		4/20 (20%)
Pyrexia	12/65 (18.5%)		0/2 (0%)		5/20 (25%)
Asthenia	11/65 (16.9%)		1/2 (50%)		1/20 (5%)
Chills	4/65 (6.2%)		0/2 (0%)		2/20 (10%)
Gait disturbance	3/65 (4.6%)		0/2 (0%)		1/20 (5%)
Chest discomfort	2/65 (3.1%)		0/2 (0%)		1/20 (5%)
Pain	1/65 (1.5%)		1/2 (50%)		1/20 (5%)
Malaise	1/65 (1.5%)		0/2 (0%)		1/20 (5%)
Non-cardiac chest pain	1/65 (1.5%)		0/2 (0%)		1/20 (5%)
Catheter site inflammation	0/65 (0%)		0/2 (0%)		1/20 (5%)
Irritability	0/65 (0%)		0/2 (0%)		1/20 (5%)
Hepatobiliary disorders
Hepatobiliary disorders	4/65 (6.2%)		0/2 (0%)		0/20 (0%)
Infections and infestations
Urinary tract infection	6/65 (9.2%)		0/2 (0%)		0/20 (0%)
Escherichia infection	0/65 (0%)		0/2 (0%)		1/20 (5%)
Folliculitis	0/65 (0%)		0/2 (0%)		1/20 (5%)
Investigations
White blood cell count decreased	21/65 (32.3%)		0/2 (0%)		3/20 (15%)
Blood alkaline phosphatase increased	6/65 (9.2%)		0/2 (0%)		1/20 (5%)
Blood creatinine increased	5/65 (7.7%)		0/2 (0%)		1/20 (5%)
Weight decreased	6/65 (9.2%)		0/2 (0%)		0/20 (0%)
Alanine aminotransferase increased	4/65 (6.2%)		0/2 (0%)		1/20 (5%)
Aspartate aminotransferase increased	4/65 (6.2%)		0/2 (0%)		1/20 (5%)
Platelet count decreased	3/65 (4.6%)		0/2 (0%)		1/20 (5%)
Weight increased	3/65 (4.6%)		0/2 (0%)		1/20 (5%)
Blood bilirubin increased	2/65 (3.1%)		0/2 (0%)		1/20 (5%)
Neutrophil count decreased	1/65 (1.5%)		0/2 (0%)		1/20 (5%)
Activated partial thromboplastin time prolonged	0/65 (0%)		0/2 (0%)		1/20 (5%)
Blood sodium decreased	0/65 (0%)		0/2 (0%)		1/20 (5%)
Metabolism and nutrition disorders
Anorexia	30/65 (46.2%)		1/2 (50%)		3/20 (15%)
Dehydration	9/65 (13.8%)		0/2 (0%)		1/20 (5%)
Hypokalaemia	8/65 (12.3%)		0/2 (0%)		1/20 (5%)
Hyperglycaemia	7/65 (10.8%)		0/2 (0%)		0/20 (0%)
Hypocalcaemia	7/65 (10.8%)		0/2 (0%)		0/20 (0%)
Hyponatraemia	7/65 (10.8%)		0/2 (0%)		0/20 (0%)
Hyperkalaemia	6/65 (9.2%)		0/2 (0%)		0/20 (0%)
Hypernatraemia	1/65 (1.5%)		0/2 (0%)		1/20 (5%)
Hypomagnesaemia	1/65 (1.5%)		0/2 (0%)		1/20 (5%)
Musculoskeletal and connective tissue disorders
Muscle spasms	6/65 (9.2%)		0/2 (0%)		2/20 (10%)
Back pain	5/65 (7.7%)		0/2 (0%)		2/20 (10%)
Arthralgia	4/65 (6.2%)		0/2 (0%)		2/20 (10%)
Myalgia	4/65 (6.2%)		1/2 (50%)		1/20 (5%)
Shoulder pain	5/65 (7.7%)		0/2 (0%)		1/20 (5%)
Neck pain	3/65 (4.6%)		0/2 (0%)		2/20 (10%)
Pain in extremity	1/65 (1.5%)		0/2 (0%)		3/20 (15%)
Chest wall pain	2/65 (3.1%)		0/2 (0%)		1/20 (5%)
Joint swelling	0/65 (0%)		0/2 (0%)		1/20 (5%)
Groin pain	1/65 (1.5%)		0/2 (0%)		1/20 (5%)
Nervous system disorders
Somnolence	27/65 (41.5%)		0/2 (0%)		6/20 (30%)
Dizziness	13/65 (20%)		0/2 (0%)		3/20 (15%)
Headache	9/65 (13.8%)		0/2 (0%)		0/20 (0%)
Paraesthesia	6/65 (9.2%)		0/2 (0%)		1/20 (5%)
Peripheral sensory neuropathy	4/65 (6.2%)		0/2 (0%)		0/20 (0%)
Grand mal convulsion	0/65 (0%)		0/2 (0%)		1/20 (5%)
Psychiatric disorders
Insomnia	7/65 (10.8%)		0/2 (0%)		0/20 (0%)
Anxiety	1/65 (1.5%)		0/2 (0%)		3/20 (15%)
Confusional state	3/65 (4.6%)		0/2 (0%)		1/20 (5%)
Depression	1/65 (1.5%)		0/2 (0%)		1/20 (5%)
Agitation	0/65 (0%)		0/2 (0%)		1/20 (5%)
Mood altered	0/65 (0%)		0/2 (0%)		1/20 (5%)
Renal and urinary disorders
Pollakiuria	1/65 (1.5%)		0/2 (0%)		2/20 (10%)
Reproductive system and breast disorders
Vaginal haemorrhage	4/65 (6.2%)		0/2 (0%)		1/20 (5%)
Erectile dysfunction	0/65 (0%)		0/2 (0%)		1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Cough	10/65 (15.4%)		0/2 (0%)		1/20 (5%)
Dyspnoea	9/65 (13.8%)		0/2 (0%)		0/20 (0%)
Dyspnoea exertional	5/65 (7.7%)		1/2 (50%)		1/20 (5%)
Rhinorrhoea	3/65 (4.6%)		0/2 (0%)		1/20 (5%)
Pharyngolaryngeal pain	1/65 (1.5%)		0/2 (0%)		1/20 (5%)
Skin and subcutaneous tissue disorders
Alopecia	25/65 (38.5%)		1/2 (50%)		10/20 (50%)
Rash	5/65 (7.7%)		0/2 (0%)		1/20 (5%)
Pruritus	5/65 (7.7%)		0/2 (0%)		0/20 (0%)
Dermatitis acneiform	0/65 (0%)		0/2 (0%)		1/20 (5%)
Hyperhidrosis	0/65 (0%)		0/2 (0%)		1/20 (5%)
Onychorrhexis	0/65 (0%)		0/2 (0%)		1/20 (5%)
Swelling face	0/65 (0%)		0/2 (0%)		1/20 (5%)
Urticaria	0/65 (0%)		0/2 (0%)		1/20 (5%)
Vascular disorders
Hot flush	1/65 (1.5%)		0/2 (0%)		1/20 (5%)
Hypotension	1/65 (1.5%)		0/2 (0%)		1/20 (5%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

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.