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

Sponsor
Millennium Pharmaceuticals, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT00651664
Collaborator
(none)
59
Enrollment
2
Locations
10
Arms
41.4
Actual Duration (Months)
29.5
Patients Per Site
0.7
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a multicenter, dose escalation, phase 1 study of MLN8237 in adult participants with advanced malignancies (excluding those with primary bone marrow involvement, such as leukemias and multiple myeloma).

Condition or Disease Intervention/Treatment Phase
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 59 patients. Participants were enrolled in one of 10 dose escalation arms:

  • Alisertib 5 mg once daily (QD) for 7 Days (D)

  • Alisertib 80 mg QD 7D

  • Alisertib 150 mg QD 7D

  • Alisertib 50 mg twice daily (BID) 7D

  • Alisertib 60 mg BID 7D

  • Alisertib 75 mg BID 7D

  • Alisertib 100 mg BID 7D

  • Alisertib 50 mg QD 14D

  • Alisertib 50 mg QD 21D

  • Alisertib 70 mg QD 21D

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

This multi-center trial was conducted in Spain. The overall time to participate in this study was 730 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 :
59 participants
Allocation:
Non-Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase I Clinical and Pharmacodynamic Study of MLN8237, A Novel Aurora A Kinase Inhibitor, in Patients With Advanced Malignancies
Actual Study Start Date :
Oct 22, 2007
Actual Primary Completion Date :
Sep 1, 2010
Actual Study Completion Date :
Apr 5, 2011

Arms and Interventions

Arm Intervention/Treatment
Experimental: Alisertib 5 mg QD 7D

Alisertib 5 mg, capsules, 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 3 cycles).

Drug: alisertib
Alisertib (MLN8237) capsules
Other Names:
  • MLN8237

    		•
    Experimental: Alisertib 80 mg QD 7D

    Alisertib 80 mg, capsules, 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 4 cycles).

    Drug: alisertib
    Alisertib (MLN8237) capsules
    Other Names:
  • MLN8237

    		•
    Experimental: Alisertib 150 mg QD 7D

    Alisertib 150 mg, capsules, 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 6 cycles).

    Drug: alisertib
    Alisertib (MLN8237) capsules
    Other Names:
  • MLN8237

    		•
    Experimental: Alisertib 50 mg BID 7D

    Alisertib 50 mg, capsules, 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 29 cycles).

    Drug: alisertib
    Alisertib (MLN8237) capsules
    Other Names:
  • MLN8237

    		•
    Experimental: Alisertib 60 mg BID 7D

    Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles).

    Drug: alisertib
    Alisertib (MLN8237) capsules
    Other Names:
  • MLN8237

    		•
    Experimental: Alisertib 75 mg BID 7D

    Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles).

    Drug: alisertib
    Alisertib (MLN8237) capsules
    Other Names:
  • MLN8237

    		•
    Experimental: Alisertib 100 mg BID 7D

    Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).

    Drug: alisertib
    Alisertib (MLN8237) capsules
    Other Names:
  • MLN8237

    		•
    Experimental: Alisertib 50 mg QD 14D

    Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).

    Drug: alisertib
    Alisertib (MLN8237) capsules
    Other Names:
  • MLN8237

    		•
    Experimental: Alisertib 50 mg QD 21D

    Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles).

    Drug: alisertib
    Alisertib (MLN8237) capsules
    Other Names:
  • MLN8237

    		•
    Experimental: Alisertib 70 mg QD 21D

    Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).

    Drug: alisertib
    Alisertib (MLN8237) capsules
    Other Names:
  • MLN8237

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Number of Participants With Dose-Limiting Toxicity (DLT) [First dose through 30 days following the last dose of study drug (up to 730 days)]

      DLT was evaluated using the National Cancer Institutes Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0; defined as any of the following events related to alisertib therapy: Grade 4 neutropenia lasting for ≥7 consecutive days during recovery Grade 4 neutropenia with fever and/or infection Confirmed platelet count <25,000/mm^3 ≥Grade 3 nausea and/or emesis despite the use of an antiemetic prophylaxis ≥Grade 3 diarrhea that occurred despite 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 because of a failure of adequate hematologic or nonhematologic recovery from the 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 [Signing of the Informed Consent through 30 days following the last dose of study drug (up to 730 days)]

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

    Secondary Outcome Measures

    1. Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7]

    2. Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7]

    3. AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing [Cycle1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7]

    4. Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7 or 8 (BID arms)]

    5. Accumulation Ratio (Rac) for Alisertib 7 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7]

      Rac for Day 7=AUCt Day 7/AUCt Day 1.

    6. Peak/Trough Ratio for Aliserib 7 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7]

    7. CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7]

    8. Cmax: Maximum Observed Concentration for Alisertib 14 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14]

    9. Tmax: Time of First Occurrence of Cmax for Alisertib 14 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14]

    10. AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 14 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14]

    11. Terminal Half-Life (t1/2) for Alisertib 14 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14]

    12. Accumulation Ratio (Rac) for Alisertib 14 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14]

      Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1.

    13. Peak/Trough Ratio for Aliserib 14 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14]

    14. CLss/F: Apparent Oral Clearance at Steady State 14 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14]

    15. Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21]

    16. Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21]

    17. AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21]

    18. Terminal Half-Life (t1/2) for Alisertib 21 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 21]

    19. Accumulation Ratio (Rac) for Alisertib 21 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21]

      Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1. Rac for Day 21=AUCt Day 21/AUCt Day 1.

    20. Peak/Trough Ratio for Aliserib 21 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21]

    21. CLss/F: Apparent Oral Clearance at Steady State 21 Day Dosing [Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21]

    22. Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing [Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Day 7, 6 and 24 hours post-dose.]

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

    23. Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing [Cycle 1: Pre-dose (Baseline) and Day 1 and 7, 6 hours post-dose; Day 14, 6 and 24 hours post-dose]

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

    24. Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing [Cycle 1: Pre-dose (Baseline) and Day 7, 14 and 21, 6 hours post-dose]

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

    25. Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing [Cycle 1: Day 1, 6 hours post-dose; Days 7 6 and 24 hours post-dose; Day 21: 6 hours post-dose]

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

    26. Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing [Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose]

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

    27. Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing [Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose; Day 21: 6 hours post-dose]

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

    28. Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing [Cycle 1: Pre-dose (Baseline) and Days 1 and 7, 6 hours post-dose]

      Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.

    29. Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 14 Day Dosing [Cycle 1: Pre-dose (Baseline) and Day 7, 6 hours post-dose]

      Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.

    30. Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing [Cycle 1: Pre-dose (Baseline) and Days 7 and 21, 6 hours post-dose]

      Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.

    Other Outcome Measures

    1. Percentage of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 [Cycle 1: Pre-dose]

      A blood sample was collected prior to alisertib dosing for the purpose of genotyping for polymorphisms in UGT1A1. The percentage of participants in the polymorphism categories: wt/wt, wt/*28, *28/*28, *28/wt, *28/other and other/other is reported. wt=wild type. *28 polymorphism in the promoter region of a UGT1A1 allele resulting in reduced UGT1A1 expression.

    Eligibility Criteria

    Criteria

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

    1. Have a histologically or cytologically confirmed metastatic and/or advanced malignancy (including lymphomas but excluding malignancies with extensive bone marrow involvement such as leukemias and multiple myeloma) for which standard treatment does not offer curative or life-prolonging potential.

    2. Aged 18 years or more.

    3. Eastern Cooperative Oncology Group performance status 0 or 1.

    4. Have an expected survival longer than 3 months from enrollment in the study.

    5. Radiographically or clinically evaluable tumor.

    6. Suitable venous access for the conduct of blood sampling.

    7. 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® [erlotinib], and hormonal agents, such as Femara® [letrozole]) must not have received treatment with these drugs for at least 2 weeks before the first dose of alisertib was given.

    8. Male participants must use an appropriate method of barrier contraception and inform any sexual partners that they must also use a reliable method of contraception from the time of informed consent until 3 months after the last dose of study treatment.

    9. Female participants must be postmenopausal at least 1 year, OR surgically sterile, OR if of childbearing potential, agree to 2 effective methods of nonhormonal contraception, or agree to completely abstain from heterosexual intercourse.

    10. Able to give written consent.

    Exclusion Criteria:

    1. Pregnant or lactating.

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

    3. Life-threatening or uncontrolled medical illness unrelated to cancer.

    4. Ongoing nausea or vomiting of any severity.

    5. Grade 1 diarrhea. Participants who require ongoing therapy with an antimotility agent to control diarrhea to a Grade 1 or lower level are not allowed to participate in this trial.

    6. Known gastrointestinal disease or gastrointestinal procedures that could interfere with the oral absorption or tolerance of MLN8237.

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

    8. Difficulty swallowing capsules.

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

    10. Received more than 4 previous cytotoxic chemotherapeutic regimens, including regimens used as adjuvant or neo-adjuvant therapies (in participants with metastatic breast cancer, a total of 5 previous cytotoxic chemotherapeutic regimens is permitted).

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

    12. Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone marrow for the distribution of active bone marrow in adults).

    13. Clinical and/or radiographic evidence of cerebral metastases. However, participants who have a history of central nervous system 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.

    14. Absolute neutrophil count(ANC) < 1500/mm3; platelet count< 100,000/mm3.

    15. Serum creatinine >1.6 mg/dL or a measured or estimated (Cockcroft-Gault formula) creatinine clearance <40 mL/min

    16. 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 could be elevated up to 5 times the ULN if their elevation could be reasonably ascribed to the presence of metastatic disease to liver and/or to bone; however, the ALT in all circumstances must have been <2.5 times the ULN.

    17. Abnormalities on 12-lead electrocardiogram 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).

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

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

    20. 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.

    21. Activated partial thromboplastin time (aPTT) and/or prothrombin time (PT) exceeding the upper limit of the normal range.

    22. Known bleeding diathesis or history of abnormal bleeding.

    23. Ongoing therapy with an anticoagulant (e.g., aspirin, plavix, coumadin).

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Ciutat Sanitaria Vall d'Hebron - Servicio de Oncologia Barcelona Spain 08035
    2 H. Clínico Universitario de Valencia Valencia Spain

    Sponsors and Collaborators

    • Millennium Pharmaceuticals, Inc.

    Investigators

    • Study Director: Medical Director Clinical Science, Takeda

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Millennium Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT00651664
    Other Study ID Numbers:
    • C14002
    • 2006-006048-68
    • U1111-1187-1151
    First Posted:
    Apr 3, 2008
    Last Update Posted:
    Mar 15, 2019
    Last Verified:
    Nov 1, 2018
    Additional relevant MeSH terms:
    Neoplasms

    Study Results

    Participant Flow

    Recruitment Details Participants took part in the study at 2 investigative sites in Spain from 22 October 2007 to 05 April 2011.
    Pre-assignment Detail Participants with a diagnosis of advanced malignancies were enrolled in a dose escalation study, alisertib 5, 80 150 mg once daily (QD) for 7 days; 50, 60, 75, 100 mg twice daily for 7 days; 50 mg QD for 14 days; 50, 70 mg QD for 21 days.
    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles). Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles). Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    Period Title: Overall Study
    STARTED 3 3 3 14 6 3 6 7 7 7
    COMPLETED 0 0 0 0 0 0 0 0 0 0
    NOT COMPLETED 3 3 3 14 6 3 6 7 7 7

    Baseline Characteristics

    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D Total
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles). Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles). Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles). Total of all reporting groups
    Overall Participants 3 3 3 14 6 3 6 7 7 7 59
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    52.7
    (9.07)
    62.3
    (13.80)
    55.7
    (20.79)
    62.5
    (11.67)
    59.2
    (18.74)
    48.3
    (14.84)
    58.7
    (8.69)
    58.0
    (13.83)
    53.0
    (11.08)
    64.7
    (5.53)
    58.8
    (12.46)
    Sex: Female, Male (Count of Participants)
    Female
    0
    0%
    1
    33.3%
    2
    66.7%
    6
    42.9%
    4
    66.7%
    0
    0%
    2
    33.3%
    2
    28.6%
    3
    42.9%
    2
    28.6%
    22
    37.3%
    Male
    3
    100%
    2
    66.7%
    1
    33.3%
    8
    57.1%
    2
    33.3%
    3
    100%
    4
    66.7%
    5
    71.4%
    4
    57.1%
    5
    71.4%
    37
    62.7%
    Race/Ethnicity, Customized (participants) [Number]
    Hispanic/Latino
    3
    100%
    3
    100%
    3
    100%
    14
    100%
    6
    100%
    3
    100%
    6
    100%
    7
    100%
    6
    85.7%
    5
    71.4%
    56
    94.9%
    Not Hispanic/Latino
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    1
    14.3%
    2
    28.6%
    3
    5.1%
    Race/Ethnicity, Customized (participants) [Number]
    Number [participants]
    3
    100%
    3
    100%
    3
    100%
    14
    100%
    6
    100%
    3
    100%
    6
    100%
    7
    100%
    7
    100%
    7
    100%
    59
    100%
    Region of Enrollment (participants) [Number]
    Spain
    3
    100%
    3
    100%
    3
    100%
    14
    100%
    6
    100%
    3
    100%
    6
    100%
    7
    100%
    7
    100%
    7
    100%
    59
    100%
    Height (cm) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [cm]
    164.0
    (7.21)
    164.3
    (10.79)
    167.3
    (1.53)
    165.8
    (9.26)
    160.5
    (4.76)
    171.3
    (10.26)
    165.2
    (10.21)
    169.9
    (10.92)
    160.4
    (11.57)
    167.6
    (8.40)
    165.4
    (9.15)
    Weight (kg) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [kg]
    83.7
    (32.13)
    75.2
    (10.56)
    70.3
    (4.24)
    74.4
    (16.48)
    64.8
    (6.83)
    90.5
    (7.74)
    69.6
    (16.22)
    76.7
    (15.06)
    69.1
    (14.78)
    77.9
    (11.91)
    74.0
    (14.95)
    Body Surface Area (BSA) (m^2) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [m^2]
    1.93
    (0.393)
    1.85
    (0.191)
    1.81
    (0.047)
    1.85
    (0.225)
    1.70
    (0.102)
    2.07
    (0.098)
    1.78
    (0.244)
    1.87
    (0.204)
    1.75
    (0.231)
    1.90
    (0.145)
    1.84
    (0.208)

    Outcome Measures

    1. Primary Outcome
    Title Number of Participants With Dose-Limiting Toxicity (DLT)
    Description DLT was evaluated using the National Cancer Institutes Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0; defined as any of the following events related to alisertib therapy: Grade 4 neutropenia lasting for ≥7 consecutive days during recovery Grade 4 neutropenia with fever and/or infection Confirmed platelet count <25,000/mm^3 ≥Grade 3 nausea and/or emesis despite the use of an antiemetic prophylaxis ≥Grade 3 diarrhea that occurred despite 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 because of a failure of adequate hematologic or nonhematologic recovery from the 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 First dose through 30 days following the last dose of study drug (up to 730 days)

    Outcome Measure Data

    Analysis Population Description
    DLT Evaluable Population was defined as all participants who received at least 75% of their planned alisertib doses for their first cycle of treatment (unless interrupted by DLT) and had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.
    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles). Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles). Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    Measure Participants 3 3 3 12 6 2 6 6 7 6
    Number [participants]
    0
    0%
    0
    0%
    0
    0%
    0
    0%
    2
    33.3%
    2
    66.7%
    3
    50%
    1
    14.3%
    1
    14.3%
    3
    42.9%
    2. Primary Outcome
    Title Maximum Tolerated Dose (MTD) of Alisertib
    Description The MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 participants.
    Time Frame Signing of the Informed Consent through 30 days following the last dose of study drug (up to 730 days)

    Outcome Measure Data

    Analysis Population Description
    DLT Evaluable Population was defined as all participants who received at least 75% of their planned alisertib doses for their first cycle of treatment (unless interrupted by DLT) and had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.
    Arm/Group Title Alisertib
    Arm/Group Description Alisertib 5, 80 or 150 mg, capsules, orally, once daily (QD) for 7 days, followed by a 14-day recovery period or alisertib 50, 60, 75 or 100 mg, capsules, orally, twice daily (BID) for 7 days, followed by a 14-day recovery period or alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period or alisertib 50 or 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
    Measure Participants 54
    Number [mg BID for 7 Days]
    50
    3. Secondary Outcome
    Title Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
    Measure Participants 3 3 3 14 6 3 6
    Day 1
    123.15
    (6.554)
    1774.12
    (36.496)
    2014.81
    (22.038)
    1035.3
    (75.70)
    1536.1
    (44.70)
    1266.6
    (45.69)
    3196.4
    (51.11)
    Day 7
    109.13
    (34.458)
    1502.89
    (32.818)
    4136.24
    (26.253)
    1964.4
    (46.26)
    3412.5
    (27.06)
    5710.4
    (23.89)
    4694.2
    (38.86)
    4. Secondary Outcome
    Title Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7

    Outcome Measure Data

    Analysis Population Description
    PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
    Measure Participants 3 3 3 14 6 3 6
    Day 1
    1.920
    2.730
    4.000
    2.040
    2.000
    2.000
    3.835
    Day 7
    1.670
    1.580
    1.550
    2.000
    2.000
    4.170
    1.580
    5. Secondary Outcome
    Title AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing
    Description
    Time Frame Cycle1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7

    Outcome Measure Data

    Analysis Population Description
    PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
    Measure Participants 3 3 3 14 6 3 6
    Day 1
    975.0
    (NA)
    18204.2
    (36.19)
    27262.7
    (38.0)
    6314.1
    (82.32)
    9771.5
    (53.77)
    6895.3
    (9.21)
    16541.5
    (65.99)
    Day 7
    658.5
    (35.64)
    16101.6
    (38.81)
    48421.8
    (36.53)
    17795.6
    (43.87)
    25853.3
    (41.44)
    51684.4
    (24.87)
    40166.7
    (51.90)
    6. Secondary Outcome
    Title Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7 or 8 (BID arms)

    Outcome Measure Data

    Analysis Population Description
    Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for t1/2 analysis.
    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
    Measure Participants 0 2 3 9 6 3 6
    Mean (Standard Deviation) [hr]
    18.25
    (8.697)
    19.80
    (6.129)
    15.913
    (6.4766)
    19.475
    (15.5019)
    18.500
    (7.6295)
    13.637
    (6.8712)
    7. Secondary Outcome
    Title Accumulation Ratio (Rac) for Alisertib 7 Day Dosing
    Description Rac for Day 7=AUCt Day 7/AUCt Day 1.
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7

    Outcome Measure Data

    Analysis Population Description
    Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis Rac.
    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
    Measure Participants 1 3 3 8 4 2 4
    Mean (Standard Deviation) [ratio]
    0.874
    (0)
    0.892
    (0.1331)
    1.954
    (0.9092)
    2.295
    (0.9846)
    2.583
    (0.8959)
    7.765
    (1.9163)
    2.350
    (1.4926)
    8. Secondary Outcome
    Title Peak/Trough Ratio for Aliserib 7 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7

    Outcome Measure Data

    Analysis Population Description
    Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis.
    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
    Measure Participants 2 3 3 9 6 3 5
    Mean (Standard Deviation) [ratio]
    5.950
    (0.3253)
    4.650
    (0.2163)
    4.507
    (0.3029)
    3.083
    (2.2296)
    3.050
    (1.4056)
    1.867
    (0.6009)
    2.256
    (1.2013)
    9. Secondary Outcome
    Title CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7

    Outcome Measure Data

    Analysis Population Description
    Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for CLss/F analysis.
    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
    Measure Participants 3 3 3 9 6 3 5
    Geometric Mean (Geometric Coefficient of Variation) [liter(L)/hr]
    14.055
    (27.6995)
    9.604
    (35.5110)
    5.967
    (31.2592)
    5.414
    (57.9221)
    4.182
    (51.2761)
    2.795
    (23.5794)
    4.798
    (49.4182)
    10. Secondary Outcome
    Title Cmax: Maximum Observed Concentration for Alisertib 14 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14

    Outcome Measure Data

    Analysis Population Description
    PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 14D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
    Measure Participants 7
    Day 1
    1145.4
    (53.09)
    Day 7
    1418.1
    (70.96)
    Day 14
    1671.1
    (51.66)
    11. Secondary Outcome
    Title Tmax: Time of First Occurrence of Cmax for Alisertib 14 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14

    Outcome Measure Data

    Analysis Population Description
    PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 14D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
    Measure Participants 7
    Day 1
    2.030
    Day 7
    2.000
    Day 14
    2.000
    12. Secondary Outcome
    Title AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 14 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 14D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
    Measure Participants 7
    Day 1
    15363.0
    (24.82)
    Day 7
    17918.8
    (78.55)
    Day 14
    16449.8
    (59.87)
    13. Secondary Outcome
    Title Terminal Half-Life (t1/2) for Alisertib 14 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14

    Outcome Measure Data

    Analysis Population Description
    Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data for analysis of t1/2. No data was available for analysis at Day 7.
    Arm/Group Title Alisertib 50 mg QD 14D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
    Measure Participants 5
    Mean (Standard Deviation) [hr]
    26.62
    (13.611)
    14. Secondary Outcome
    Title Accumulation Ratio (Rac) for Alisertib 14 Day Dosing
    Description Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1.
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14

    Outcome Measure Data

    Analysis Population Description
    Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis Rac. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 14D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
    Measure Participants 7
    Day 7
    1.671
    (0.8242)
    Day 14
    1.813
    (0.5001)
    15. Secondary Outcome
    Title Peak/Trough Ratio for Aliserib 14 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14

    Outcome Measure Data

    Analysis Population Description
    Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 14D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
    Measure Participants 7
    Day 7
    4.415
    (2.5016)
    Day 14
    7.412
    (4.2472)
    16. Secondary Outcome
    Title CLss/F: Apparent Oral Clearance at Steady State 14 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14

    Outcome Measure Data

    Analysis Population Description
    Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for CLss/F analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 14D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
    Measure Participants 7
    Day 7
    5.381
    (92.8272)
    Day 14
    5.856
    (98.2758)
    17. Secondary Outcome
    Title Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21

    Outcome Measure Data

    Analysis Population Description
    PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    Measure Participants 7 7
    Day 1
    1112.3
    (42.99)
    2220.3
    (47.57)
    Day 14
    1524.1
    (64.25)
    2595.0
    (42.98)
    Day 21
    1651.7
    (30.70)
    2093.7
    (11.68)
    18. Secondary Outcome
    Title Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21

    Outcome Measure Data

    Analysis Population Description
    PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    Measure Participants 7 7
    Day 1
    4.000
    2.000
    Day 14
    2.070
    2.130
    Day 21
    2.100
    2.125
    19. Secondary Outcome
    Title AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21

    Outcome Measure Data

    Analysis Population Description
    Pharmacokinetic (PK) Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    Measure Participants 7 7
    Day 1
    11701.0
    (49.78)
    18953.4
    (56.89)
    Day 14
    20262.8
    (71.34)
    30918.3
    (55.68)
    Day 21
    18264.9
    (28.67)
    24515.6
    (23.80)
    20. Secondary Outcome
    Title Terminal Half-Life (t1/2) for Alisertib 21 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 21

    Outcome Measure Data

    Analysis Population Description
    Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for t1/2 analysis.
    Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    Measure Participants 6 3
    Mean (Standard Deviation) [hr]
    20.13
    (6.326)
    26.13
    (9.780)
    21. Secondary Outcome
    Title Accumulation Ratio (Rac) for Alisertib 21 Day Dosing
    Description Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1. Rac for Day 21=AUCt Day 21/AUCt Day 1.
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21

    Outcome Measure Data

    Analysis Population Description
    Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis Rac. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    Measure Participants 7 7
    Day 14
    2.482
    (2.7166)
    2.103
    (0.3861)
    Day 21
    1.678
    (0.7587)
    1.933
    (1.1104)
    22. Secondary Outcome
    Title Peak/Trough Ratio for Aliserib 21 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21

    Outcome Measure Data

    Analysis Population Description
    Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    Measure Participants 7 7
    Day 14
    4.070
    (2.4751)
    3.628
    (0.4864)
    Day 21
    4.792
    (2.5652)
    4.658
    (2.1825)
    23. Secondary Outcome
    Title CLss/F: Apparent Oral Clearance at Steady State 21 Day Dosing
    Description
    Time Frame Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21

    Outcome Measure Data

    Analysis Population Description
    Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for CLss/F analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    Measure Participants 7 7
    Day 14
    4.753
    (70.5636)
    4.364
    (47.3164)
    Day 21
    5.276
    (28.1356)
    5.593
    (21.8384)
    24. Secondary Outcome
    Title Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing
    Description Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
    Time Frame Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Day 7, 6 and 24 hours post-dose.

    Outcome Measure Data

    Analysis Population Description
    Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
    Measure Participants 3 3 3 13 6 3 6
    Day 1, 6 Hours Post-Dose
    0.187
    (0.0709)
    0.107
    (0.0777)
    0.197
    (0.0814)
    0.310
    (0.2087)
    0.378
    (0.4107)
    0.175
    (0.2333)
    0.850
    (1.0741)
    Day 7, 6 Hours Post-Dose
    0.193
    (0.1650)
    0.617
    (0.7514)
    2.703
    (0.7112)
    3.489
    (2.6893)
    6.220
    (5.7549)
    8.757
    (4.0493)
    9.150
    (8.9050)
    Day 7, 24 Hours Post-Dose
    0.140
    (0.1179)
    0.397
    (0.2159)
    5.270
    (3.8325)
    3.184
    (4.4984)
    1.250
    (0.0000)
    25.190
    (1.7678)
    17.123
    (9.4877)
    25. Secondary Outcome
    Title Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing
    Description Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
    Time Frame Cycle 1: Pre-dose (Baseline) and Day 1 and 7, 6 hours post-dose; Day 14, 6 and 24 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 14D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
    Measure Participants 7
    Day 1, 6 Hours Post-Dose
    1.180
    (0.0000)
    Day 7, 6 Hours Post-Dose
    0.950
    (0.9963)
    Day 14, 6 Hours Post-Dose
    1.146
    (1.6239)
    Day 7, 24 Hours Post-Dose
    0.368
    (0.4464)
    26. Secondary Outcome
    Title Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day 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 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
    Time Frame Cycle 1: Pre-dose (Baseline) and Day 7, 14 and 21, 6 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    Measure Participants 7 7
    Day 7, 6 Hours Post-Dose
    1.534
    (1.9201)
    1.900
    (2.2774)
    Day 14, 6 Hours Post-Dose
    0.341
    (0.3182)
    1.168
    (0.7587)
    Day 21, 6 Hours Post-Dose
    0.250
    (1.453)
    0.565
    (0.5565)
    27. Secondary Outcome
    Title Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing
    Description Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
    Time Frame Cycle 1: Day 1, 6 hours post-dose; Days 7 6 and 24 hours post-dose; Day 21: 6 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
    Measure Participants 3 3 3 13 6 3 6
    Day 1, 6 hour post-dose
    0.080
    (0.0693)
    0.000
    (0.0000)
    0.097
    (0.0850)
    0.040
    (0.0634)
    0.000
    (0.0000)
    0.055
    (0.0778)
    0.242
    (0.2566)
    Day 7, 6 hour post-dose
    0.040
    (0.0693)
    0.560
    (0.9699)
    1.303
    (0.5950)
    1.525
    (2.2399)
    3.173
    (4.3170)
    6.040
    (1.9928)
    5.162
    (2.2801)
    Day 7, 24 hour post-dose
    0.040
    (0.0693)
    0.343
    (0.4944)
    2.145
    (1.6476)
    1.050
    (1.749)
    0.830
    (0.00)
    7.715
    (0.1202)
    4.713
    (1.1924)
    28. Secondary Outcome
    Title Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing
    Description Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
    Time Frame Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 14D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
    Measure Participants 7
    Day 1, 6 hours post-dose
    0.000
    (0.000)
    Day 7, 6 hours post-dose
    0.390
    (0.8721)
    Day 14, 6 hours post-dose
    0.484
    (0.7869)
    Day 14, 24 hours post-dose
    0.260
    (0.3834)
    29. Secondary Outcome
    Title Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing
    Description Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
    Time Frame Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose; Day 21: 6 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    Measure Participants 7 7
    Day 7, 6 hours post-dose
    0.606
    (0.9954)
    0.379
    (0.6276)
    Day 14, 6 hours post-dose
    0.146
    (0.2355)
    0.404
    (0.4334)
    Day 21, 6 hours post-dose
    0.134
    (0.1698)
    0.230
    (0.1283)
    30. Secondary Outcome
    Title Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing
    Description Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
    Time Frame Cycle 1: Pre-dose (Baseline) and Days 1 and 7, 6 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles).
    Measure Participants 3 3 3 13 6 3 6
    Day 1, 6 hours post-dose
    0.125
    (0.1061)
    0.610
    (0.0000)
    6.460
    (9.1075)
    1.464
    (1.3294)
    1.080
    (0.3394)
    0.090
    (0.0000)
    2.907
    (2.0284)
    Day 7, 6 hours post-dose
    1.145
    (0.0354)
    0.590
    (0.0000)
    15.500
    (13.5623)
    2.020
    (2.9567)
    3.115
    (3.1608)
    5.840
    (0.0000)
    3.527
    (2.1258)
    31. Secondary Outcome
    Title Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 14 Day Dosing
    Description Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
    Time Frame Cycle 1: Pre-dose (Baseline) and Day 7, 6 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacodynamics Evaluable Population was defined as all participants who received at least the first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment.
    Arm/Group Title Alisertib 50 mg QD 14D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles).
    Measure Participants 7
    Mean (Standard Deviation) [percentage of cells]
    0.008
    (0.0000)
    32. Secondary Outcome
    Title Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing
    Description Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
    Time Frame Cycle 1: Pre-dose (Baseline) and Days 7 and 21, 6 hours post-dose

    Outcome Measure Data

    Analysis Population Description
    Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
    Arm/Group Title Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Arm/Group Description Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    Measure Participants 7 7
    Day 7, 6 hours post-dose
    0.027
    (0.0171)
    0.050
    (0.0243)
    Day 21, 6 hours post-dose
    0.014
    (0.0072)
    0.054
    (0.0038)
    33. Other Pre-specified Outcome
    Title Percentage of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1
    Description A blood sample was collected prior to alisertib dosing for the purpose of genotyping for polymorphisms in UGT1A1. The percentage of participants in the polymorphism categories: wt/wt, wt/*28, *28/*28, *28/wt, *28/other and other/other is reported. wt=wild type. *28 polymorphism in the promoter region of a UGT1A1 allele resulting in reduced UGT1A1 expression.
    Time Frame Cycle 1: Pre-dose

    Outcome Measure Data

    Analysis Population Description
    Safety population was defined as all participants who received any amount of study drug. A blood sample was not evaluable for 3 participants and was missing for 5 participants. Data is presented for one arm because the data was collected prior to the participant receiving their assigned treatment.
    Arm/Group Title Alisertib
    Arm/Group Description Alisertib 5, 80 or 150 mg, capsules, orally, once daily (QD) for 7 days, followed by a 14-day recovery period or alisertib 50, 60, 75 or 100 mg, capsules, orally, twice daily (BID) for 7 days, followed by a 14-day recovery period or alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period or alisertib 50 or 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles).
    Measure Participants 59
    wt/wt
    34
    1133.3%
    wt/*28
    44
    1466.7%
    *28/*28
    7
    233.3%
    *28/wt
    0
    0%
    *28/other
    0
    0%
    other/other
    2
    66.7%

    Adverse Events

    Time Frame Signing of the Informed Consent through 30 days following the last dose of study drug (up to 730 days)
    Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
    Arm/Group Title Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Arm/Group Description Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles). Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles). Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles).
    All Cause Mortality
    Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN) / (NaN)
    Serious Adverse Events
    Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/3 (33.3%) 1/3 (33.3%) 1/3 (33.3%) 6/14 (42.9%) 3/6 (50%) 1/3 (33.3%) 5/6 (83.3%) 1/7 (14.3%) 3/7 (42.9%) 4/7 (57.1%)
    Blood and lymphatic system disorders
    Neutropenia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 1/6 (16.7%) 1 0/3 (0%) 0 2/6 (33.3%) 2 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Febrile neutropenia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Lymphadenopathy 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Gastrointestinal disorders
    Diarrhoea 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 1/6 (16.7%) 1 0/3 (0%) 0 2/6 (33.3%) 2 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Stomatitis 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 3/6 (50%) 3 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Enteritis 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Lower gastrointestinal haemorrhage 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Vomiting 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    General disorders
    Pyrexia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 1/6 (16.7%) 1 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Infections and infestations
    Escherichia urinary tract infection 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Pneumonia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0
    Respiratory tract infection 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0
    Injury, poisoning and procedural complications
    Accidental overdose 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Incorrect dose administered 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Metabolism and nutrition disorders
    Hypomagnesaemia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0
    Metastases to central nervous system 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Metastases to meninges 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Nervous system disorders
    Headache 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Somnolence 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Spinal cord compression 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Psychiatric disorders
    Bradyphrenia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Renal and urinary disorders
    Renal failure 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Other (Not Including Serious) Adverse Events
    Alisertib 5 mg QD 7D Alisertib 80 mg QD 7D Alisertib 150 mg QD 7D Alisertib 50 mg BID 7D Alisertib 60 mg BID 7D Alisertib 75 mg BID 7D Alisertib 100 mg BID 7D Alisertib 50 mg QD 14D Alisertib 50 mg QD 21D Alisertib 70 mg QD 21D
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 3/39 (7.7%) 3/30 (10%) 3/101 (3%) 14/142 (9.9%) 6/68 (8.8%) 3/68 (4.4%) 6/194 (3.1%) 7/119 (5.9%) 7/67 (10.4%) 7/68 (10.3%)
    Blood and lymphatic system disorders
    Anaemia 2/3 (66.7%) 2 2/3 (66.7%) 3 2/3 (66.7%) 3 8/14 (57.1%) 11 4/6 (66.7%) 4 3/3 (100%) 4 5/6 (83.3%) 6 5/7 (71.4%) 6 4/7 (57.1%) 4 1/7 (14.3%) 1
    Leukopenia 0/3 (0%) 0 1/3 (33.3%) 2 2/3 (66.7%) 8 8/14 (57.1%) 11 3/6 (50%) 3 2/3 (66.7%) 7 6/6 (100%) 9 2/7 (28.6%) 3 1/7 (14.3%) 1 4/7 (57.1%) 4
    Neutropenia 0/3 (0%) 0 1/3 (33.3%) 1 3/3 (100%) 9 4/14 (28.6%) 5 4/6 (66.7%) 6 2/3 (66.7%) 7 3/6 (50%) 8 2/7 (28.6%) 2 3/7 (42.9%) 4 2/7 (28.6%) 2
    Lymphopenia 0/3 (0%) 0 0/3 (0%) 0 2/3 (66.7%) 4 9/14 (64.3%) 11 2/6 (33.3%) 2 1/3 (33.3%) 1 0/6 (0%) 0 6/7 (85.7%) 10 2/7 (28.6%) 2 0/7 (0%) 0
    Thrombocytopenia 0/3 (0%) 0 1/3 (33.3%) 1 2/3 (66.7%) 5 5/14 (35.7%) 8 2/6 (33.3%) 4 1/3 (33.3%) 3 5/6 (83.3%) 6 2/7 (28.6%) 4 0/7 (0%) 0 1/7 (14.3%) 1
    Febrile neutropenia 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 3 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Leukocytosis 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Cardiac disorders
    Palpitations 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Ear and labyrinth disorders
    Ear pain 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Eye disorders
    Keratitis 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 1/6 (16.7%) 1 2/3 (66.7%) 3 2/6 (33.3%) 12 0/7 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0
    Dry eye 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Vision blurred 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Gastrointestinal disorders
    Nausea 1/3 (33.3%) 3 0/3 (0%) 0 2/3 (66.7%) 8 1/14 (7.1%) 1 2/6 (33.3%) 2 1/3 (33.3%) 1 4/6 (66.7%) 9 2/7 (28.6%) 2 3/7 (42.9%) 6 5/7 (71.4%) 5
    Stomatitis 0/3 (0%) 0 1/3 (33.3%) 1 2/3 (66.7%) 6 3/14 (21.4%) 3 2/6 (33.3%) 2 2/3 (66.7%) 7 3/6 (50%) 6 0/7 (0%) 0 3/7 (42.9%) 3 1/7 (14.3%) 1
    Diarrhoea 1/3 (33.3%) 4 0/3 (0%) 0 1/3 (33.3%) 2 2/14 (14.3%) 2 3/6 (50%) 3 2/3 (66.7%) 4 2/6 (33.3%) 9 1/7 (14.3%) 3 2/7 (28.6%) 4 2/7 (28.6%) 3
    Vomiting 1/3 (33.3%) 5 0/3 (0%) 0 1/3 (33.3%) 4 0/14 (0%) 0 2/6 (33.3%) 3 1/3 (33.3%) 1 3/6 (50%) 3 3/7 (42.9%) 4 2/7 (28.6%) 7 3/7 (42.9%) 3
    Abdominal pain 0/3 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 1/14 (7.1%) 2 2/6 (33.3%) 2 0/3 (0%) 0 2/6 (33.3%) 3 3/7 (42.9%) 3 0/7 (0%) 0 0/7 (0%) 0
    Dyspepsia 1/3 (33.3%) 1 0/3 (0%) 0 1/3 (33.3%) 2 0/14 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 1
    Abdominal pain upper 2/3 (66.7%) 2 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 1/6 (16.7%) 3 0/3 (0%) 0 0/6 (0%) 0 2/7 (28.6%) 2 0/7 (0%) 0 0/7 (0%) 0
    Constipation 1/3 (33.3%) 1 0/3 (0%) 0 1/3 (33.3%) 2 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 3/7 (42.9%) 3
    Enteritis 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 3/14 (21.4%) 3 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/7 (28.6%) 4 0/7 (0%) 0 0/7 (0%) 0
    Dry mouth 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 2 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Proctalgia 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 3/6 (50%) 4 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Rectal tenesmus 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 2 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 5 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Rectal haemorrhage 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 3 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Anal fissure 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 2 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Haematochezia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Abdominal distension 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Aphthous stomatitis 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Ascites 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Colonic haemorrhage 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Dysphagia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Flatulence 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Haemorrhoids 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Odynophagia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Oral pain 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Perianal erythema 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    General disorders
    Asthenia 3/3 (100%) 3 0/3 (0%) 0 2/3 (66.7%) 9 3/14 (21.4%) 3 3/6 (50%) 3 2/3 (66.7%) 2 5/6 (83.3%) 10 3/7 (42.9%) 3 6/7 (85.7%) 6 4/7 (57.1%) 4
    Pyrexia 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 4 1/14 (7.1%) 1 1/6 (16.7%) 1 1/3 (33.3%) 1 5/6 (83.3%) 8 4/7 (57.1%) 5 1/7 (14.3%) 1 2/7 (28.6%) 2
    Oedema peripheral 1/3 (33.3%) 1 0/3 (0%) 0 1/3 (33.3%) 1 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 1/7 (14.3%) 1
    Chills 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 2 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Chest pain 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Feeling jittery 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Gait disturbance 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Red man syndrome 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Hepatobiliary disorders
    Hepatic pain 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/14 (14.3%) 2 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Hyperbilirubinaemia 0/3 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 2
    Jaundice 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Infections and infestations
    Nasopharyngitis 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 1/6 (16.7%) 1 2/3 (66.7%) 2 3/6 (50%) 3 2/7 (28.6%) 2 1/7 (14.3%) 2 0/7 (0%) 0
    Oral candidiasis 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Respiratory tract infection 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 1/7 (14.3%) 2 0/7 (0%) 0
    Bronchitis 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Catheter related infection 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Gastroenteritis escherichia coli 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Herpes simplex 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Nail infection 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Urinary tract infection 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Injury, poisoning and procedural complications
    Accidental overdose 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Incorrect dose administered 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Upper limb fracture 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0
    Investigations
    Blood alkaline phosphatase increased 1/3 (33.3%) 1 1/3 (33.3%) 1 0/3 (0%) 0 5/14 (35.7%) 6 0/6 (0%) 0 1/3 (33.3%) 1 4/6 (66.7%) 4 3/7 (42.9%) 3 0/7 (0%) 0 2/7 (28.6%) 2
    Alanine aminotransferase increased 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 7/14 (50%) 8 1/6 (16.7%) 1 1/3 (33.3%) 1 1/6 (16.7%) 1 3/7 (42.9%) 5 1/7 (14.3%) 1 1/7 (14.3%) 1
    Aspartate aminotransferase increased 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 4/14 (28.6%) 6 2/6 (33.3%) 2 0/3 (0%) 0 0/6 (0%) 0 2/7 (28.6%) 3 1/7 (14.3%) 1 2/7 (28.6%) 2
    Gamma-glutamyltransferase increased 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 4/14 (28.6%) 4 0/6 (0%) 0 1/3 (33.3%) 1 3/6 (50%) 3 2/7 (28.6%) 3 0/7 (0%) 0 1/7 (14.3%) 1
    Blood creatinine increased 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 2/14 (14.3%) 2 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/7 (14.3%) 1 0/7 (0%) 0 1/7 (14.3%) 1
    Blood bilirubin increased 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Blood urea increased 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/14 (14.3%) 2 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Activated partial thromboplastin time prolonged 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Platelet count decreased 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0
    Blood creatinine decreased 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Red blood cell count decreased 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Transaminases increased 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Weight decreased 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Metabolism and nutrition disorders
    Anorexia 2/3 (66.7%) 2 0/3 (0%) 0 2/3 (66.7%) 5 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 8 1/7 (14.3%) 1 4/7 (57.1%) 4 2/7 (28.6%) 3
    Hyperkalaemia 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 3/14 (21.4%) 4 1/6 (16.7%) 1 0/3 (0%) 0 2/6 (33.3%) 2 2/7 (28.6%) 4 0/7 (0%) 0 1/7 (14.3%) 1
    Hyperglycaemia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 5/14 (35.7%) 5 1/6 (16.7%) 1 0/3 (0%) 0 0/6 (0%) 0 2/7 (28.6%) 2 0/7 (0%) 0 0/7 (0%) 0
    Hyponatraemia 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 3/14 (21.4%) 6 1/6 (16.7%) 1 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 1 1/7 (14.3%) 1
    Hypercholesterolaemia 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 3/14 (21.4%) 3 2/6 (33.3%) 2 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Hypocalcaemia 0/3 (0%) 0 1/3 (33.3%) 2 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 3/7 (42.9%) 5 0/7 (0%) 0 0/7 (0%) 0
    Hypoalbuminaemia 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 2 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Hyperproteinaemia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/7 (28.6%) 2 0/7 (0%) 0 0/7 (0%) 0
    Hypertriglyceridaemia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/14 (14.3%) 4 1/6 (16.7%) 1 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Hyperuricaemia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/14 (14.3%) 3 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Hypokalaemia 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Hyperchloraemia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/7 (28.6%) 3 0/7 (0%) 0 0/7 (0%) 0
    Hypermagnesaemia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 2/14 (14.3%) 2 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Hypoproteinaemia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 2 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Dehydration 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Fluid intake reduced 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Hypercalcaemia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Hyperphosphataemia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Hypochloraemia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Hypomagnesaemia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Musculoskeletal and connective tissue disorders
    Back pain 0/3 (0%) 0 1/3 (33.3%) 1 1/3 (33.3%) 1 0/14 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/6 (0%) 0 2/7 (28.6%) 2 1/7 (14.3%) 1 1/7 (14.3%) 1
    Arthralgia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Pain in extremity 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 2 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Bone pain 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Myalgia 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Osteoarthritis 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Shoulder pain 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 2/3 (66.7%) 2 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 2/7 (28.6%) 2 0/7 (0%) 0
    Synovial sarcoma 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0
    Tumour haemorrhage 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 3 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Nervous system disorders
    Somnolence 1/3 (33.3%) 1 2/3 (66.7%) 2 2/3 (66.7%) 8 4/14 (28.6%) 4 2/6 (33.3%) 3 1/3 (33.3%) 6 3/6 (50%) 10 0/7 (0%) 0 1/7 (14.3%) 1 5/7 (71.4%) 5
    Headache 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/7 (14.3%) 1 1/7 (14.3%) 1 2/7 (28.6%) 2
    Cerebral ataxia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 2/7 (28.6%) 2
    Dizziness 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 1/6 (16.7%) 2 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Aphonia 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Dysaesthesia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Dysgeusia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Neuropathic pain 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Paraesthesia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0
    Psychiatric disorders
    Insomnia 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/14 (0%) 0 1/6 (16.7%) 1 2/3 (66.7%) 4 3/6 (50%) 4 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Confusional state 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 2 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Affect lability 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Anxiety 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Bradyphrenia 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Nervousness 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Renal and urinary disorders
    Haematuria 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 1 0/7 (0%) 0
    Dysuria 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Oliguria 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Pollakiuria 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 1/3 (33.3%) 1 1/3 (33.3%) 1 1/3 (33.3%) 1 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1 1/7 (14.3%) 1
    Rhinorrhoea 0/3 (0%) 0 2/3 (66.7%) 2 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 2/7 (28.6%) 2 0/7 (0%) 0 0/7 (0%) 0
    Cough 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 1
    Dysphonia 0/3 (0%) 0 1/3 (33.3%) 1 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Epistaxis 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Haemoptysis 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 1/7 (14.3%) 2 0/7 (0%) 0
    Pharyngolaryngeal pain 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Productive cough 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Skin and subcutaneous tissue disorders
    Alopecia 0/3 (0%) 0 2/3 (66.7%) 2 3/3 (100%) 3 1/14 (7.1%) 1 4/6 (66.7%) 4 2/3 (66.7%) 2 4/6 (66.7%) 4 1/7 (14.3%) 1 3/7 (42.9%) 3 5/7 (71.4%) 5
    Dry skin 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 2/6 (33.3%) 2 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Exfoliative rash 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 1/6 (16.7%) 1 1/3 (33.3%) 2 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Palmar-plantar erythrodysaesthesia syndrome 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 1/3 (33.3%) 1 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Rash 1/3 (33.3%) 1 0/3 (0%) 0 0/3 (0%) 0 1/14 (7.1%) 1 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Blister 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Nail disorder 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Onycholysis 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Pruritus 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Rash pruritic 0/3 (0%) 0 0/3 (0%) 0 1/3 (33.3%) 1 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Toxic skin eruption 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Vascular disorders
    Hypotension 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 1/7 (14.3%) 1 0/7 (0%) 0 0/7 (0%) 0
    Haematoma 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 1/6 (16.7%) 1 0/3 (0%) 0 0/6 (0%) 0 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0
    Phlebitis 0/3 (0%) 0 0/3 (0%) 0 0/3 (0%) 0 0/14 (0%) 0 0/6 (0%) 0 0/3 (0%) 0 1/6 (16.7%) 1 0/7 (0%) 0 0/7 (0%) 0 0/7 (0%) 0

    Limitations/Caveats

    [Not Specified]

    More Information

    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.

    Results Point of Contact

    Name/Title Medical Director
    Organization Takeda
    Phone +1-877-825-3327
    Email trialdisclosures@takeda.com
    Responsible Party:
    Millennium Pharmaceuticals, Inc.
    ClinicalTrials.gov Identifier:
    NCT00651664
    Other Study ID Numbers:
    • C14002
    • 2006-006048-68
    • U1111-1187-1151
    First Posted:
    Apr 3, 2008
    Last Update Posted:
    Mar 15, 2019
    Last Verified:
    Nov 1, 2018