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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00500903
Recruitment Status : Completed
First Posted : July 13, 2007
Results First Posted : March 14, 2019
Last Update Posted : March 14, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

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

Condition or disease Intervention/treatment Phase
Advanced Malignancies Drug: Alisertib Phase 1

Detailed Description:

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

  • Powder-in-Capsule (PIC) Dose Escalation (alisertib 5, 10, 20, 40, 80, 110 or 150 mg PIC , once daily (QD) for 7 days (D),or alisertib 25 mg, PIC, orally, QD 14D, or alisertib 25, 50 or 70 mg, PIC, orally, QD 21D, or alisertib 50 or 60 mg, PIC, orally, twice daily (BID) 7D, alisertib 40 mg, PIC, orally, BID 14D
  • ECT Dose Escalation (alisertib 10 or 20 mg, Enteric-coated Tablets (ECT), orally, QD for 7 to 21 days
  • Relative Bioavailability (alisertib 40 mg ECT or PIC, orally, BID 7D in cycle 1, followed by alisertib 40 mg in the opposite formulation (PIC or ECT) orally, BID 7D in cycle 2, followed by alisertib 50 mg PIC orally, BID 7D in each additional All participants received treatment until their disease progressed or they experienced unacceptable alisertib-related toxicity. This multi-center trial was conducted in the United States. The overall time to participate in this study was 1011 days. Participants made multiple visits to the clinic, including a final visit 30 days after receiving their last dose of alisertib for a follow-up assessment.

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

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

Experimental: ECT Dose Escalation
Alisertib 10 or 20 mg, Enteric-coated Tablet (ECT) formulation, orally, once daily (QD) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 2 cycles).
Drug: Alisertib
Alisertib (MLN8237) will be supplied in capsules of 5 or 25 mg and will be given on an empty stomach, with patients remaining nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose. Each dose will be given by mouth with 8 ounces of water for 7 to 21 consecutive days. A 14-day recovery period will follow each dosing period regardless of its duration.
Other Name: MLN8237

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




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

    DLT was evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and was defined as any of the following events related to therapy with alisertib:

    1. Grade 4 neutropenia lasting ≥7 consecutive days
    2. Grade 4 neutropenia with fever and/or infection
    3. Platelet count <25,000/mm^3
    4. Grade 3 or greater nausea and/or emesis despite use of optimal antiemetic prophylaxis
    5. Grade 3 or greater diarrhea despite maximal supportive therapy with loperamide
    6. Any other Grade 3 or greater nonhematologic toxicity, with the following exceptions: Grade 3 arthralgia/myalgias, Any grade of alopecia, Brief (<1 week) Grade 3 fatigue
    7. Treatment delay of >1 week due to failure of adequate hematologic or nonhematologic recovery from previous cycle of treatment
    8. Other alisertib-related nonhematologic toxicities ≥Grade 2 that, in the opinion of the investigator, required a dose reduction or discontinuation of therapy with alisertib.

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

  3. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From first dose of study drug to 30 days after the last dose (up to 1011 days) ]
    An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.


Secondary Outcome Measures :
  1. Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  2. Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  3. AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  4. Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [ Time Frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  5. Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [ Time Frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  6. Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [ Time Frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  7. CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [ Time Frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  8. Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose ]
  9. CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose ]
  10. Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  11. Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  12. AUCt: Area Under the Concentration--Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  13. Terminal Half-Life for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [ Time Frame: Cycle 1 Day 14 predose and at multiple time-points (up to 10 hours) postdose ]
  14. Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [ Time Frame: Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose ]
  15. Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [ Time Frame: Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose ]
  16. CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [ Time Frame: Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose ]
  17. Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose ]
  18. CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose ]
  19. Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose ]
  20. Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose ]
  21. AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose ]
  22. Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [ Time Frame: Cycle 1 Day 21 predose and at multiple time points (up to 10 hours) postdose ]
  23. Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [ Time Frame: Cycle 1 Days 14 and 21 predose and at multiple timepoints (up to 10 hours) postdose ]
  24. Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [ Time Frame: Cycle 1 Days 14 and 21 predose and at multiple timepoints up to 10 hours postdose ]
  25. CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [ Time Frame: Cycle 1 Days 14 and 21 predose and at multiple timepoints up to 10 hours postdose ]
  26. Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time points (up to 24 hours) postdose ]
  27. CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time points (up to 24 hours) postdose ]
  28. Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  29. Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  30. AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  31. Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [ Time Frame: Cycle 1 Day 8 ]
  32. Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [ Time Frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  33. Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [ Time Frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  34. CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [ Time Frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  35. Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose ]
  36. CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose ]
  37. Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing [ Time Frame: Cycle 1 Days 1 and 7 predose and at multiple time-points (up to 10 hours) postdose ]
  38. Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing [ Time Frame: Cycle 1 Days 1 and 7 predose and at multiple time-points (up to 10 hours) postdose ]
  39. AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing [ Time Frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose ]
  40. AUCt: Area Under the Concentration-time Curve From Time 0 to Time t as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7 [ Time Frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  41. Cmax: Maximum Observed Concentration as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7 [ Time Frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose ]
  42. Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing [ Time Frame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose ]
    Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers—serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.

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

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

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

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

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

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

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

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

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

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

    One peripheral blood sample (approximately 4 mL) was to be obtained on Day 1 of Cycle 1 prior to the first dose of alisertib to genotype patients for polymorphisms in UGT1A1 because UGT1A1 is one of the enzymes responsible for glucuronidation of alisertib, which is expected to contribute to the clearance of alisertib.

    wt=wild type

    *28=polymorphism in the promoter region of a UGT1A1 allele resulting in reduced UGT1A1 expression.


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

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

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



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically or cytologically confirmed metastatic and/or advanced solid tumors (including lymphomas) for which no effective standard treatment is available
  • Aged 18 years or more
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Expected survival longer than 3 months from enrollment in the study
  • Radiographically or clinically evaluable tumor; however, measurable disease as defined by (RECIST) criteria is not required for participation in this study
  • Suitable venous access for the conduct of blood sampling for MLN8237 PK
  • Recovered from the reversible effects of prior antineoplastic therapy (with the exception of alopecia and grade 1 neuropathy) with at least 4 weeks elapsed since the last exposure to cytotoxic chemotherapy or to radiotherapy and at least 6 weeks elapsed since exposure to nitrosoureas or mitomycin C. Participants treated with fully human monoclonal antibodies must not have received treatment with such antibodies for at least 6 weeks, and those treated with chimeric monoclonal antibodies must not have received treatment with such antibodies for at least 4 weeks. Participants treated with noncytotoxic small molecule drugs (eg, tyrosine kinase inhibitors, such as Tarceva®, and hormonal agents, such as Femara®) must not have received treatment with these drugs for at least 2 weeks before the first dose of MLN8237 is given.
  • Male participants must use an appropriate method of barrier contraception (eg, condoms) and inform any sexual partners that they must also use a reliable method of contraception (eg, birth control pills) from the time of informed consent until 3 months after the last dose of study treatment.
  • Female participants must be postmenopausal, surgically sterilized, or willing to use reliable methods of birth control (eg, a hormonal contraceptive, an intrauterine device, diaphragm with spermicide, or abstinence) and inform male sexual partners that they must also use a reliable method of contraception (eg, condoms) from the time of informed consent until 3 months after the last dose of study treatment.
  • Willing and able to give written informed consent before the conduct of any study related procedure that is not part of normal medical care, and willing to comply with the protocol

Exclusion Criteria:

  • Pregnant or lactating
  • Major surgery or serious infection within the 28 days preceding the first dose of study treatment
  • Life-threatening illness or uncontrolled medical illness unrelated to cancer
  • Ongoing nausea or vomiting of any severity
  • > Grade 1 diarrhea
  • Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of MLN8237. Examples include but are not limited to partial gastrectomy, history of small intestine surgery, and celiac disease.
  • History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.
  • Difficulty swallowing capsules
  • Inability to take nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose of MLN8237
  • Received more than 4 previous cytotoxic chemotherapeutic regimens including regimens used as adjuvant or neo-adjuvant therapies. There is no limit on the number of noncytotoxic therapies (eg, hormonal and immunologic) that participants may have received. Tyrosine kinase inhibitors (eg, Tarceva and Iressa®) are considered noncytotoxic compounds.
  • Prior treatment with high-dose chemotherapy, defined as chemotherapy requiring the use of peripheral blood or bone marrow stem cell support for hematopoietic reconstitution
  • Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone marrow
  • Clinical and/or radiographic evidence of cerebral metastases. However, participants who have a history of central nervous system (CNS) metastasis but who have no radiographic or clinical evidence of residual tumor (eg, following complete surgical resection or stereotactic radiosurgery) are not excluded from participation in this study
  • Absolute neutrophil count <1500/mm^3; platelet count <100,000/mm^3
  • Serum creatinine >1.6 mg/dl or a measured or estimated creatinine clearance <40 mL/minute
  • Bilirubin >1.5 times the upper limit of the normal range (ULN); aspartate aminotransferase (AST)/alanine aminotransferase (ALT) >2.5 times the ULN, and alkaline phosphatase (ALP) >2.5 times the ULN. Both the AST and ALP may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of metastatic disease to liver and/or to bone; however, the ALT must in all circumstances be <2.5 times the ULN
  • Abnormalities on 12-lead electrocardiogram (ECG) considered by the investigator to be clinically significant or baseline prolongation of the rate-corrected QT interval (eg, repeated demonstration of QTc interval > 450 milliseconds)
  • Left ventricular ejection fraction (LVEF) < 50%
  • Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection. Testing for these agents is not required in the absence of clinical findings or suspicion.
  • Less than 4 weeks between the last dose of an investigational agent and the first dose of MLN8237
  • Admission or evidence of benzodiazepine dependence or abuse and/or alcohol abuse or an inability to restrict consumption of alcohol to no more than 1 standard unit of alcohol per day during the study and for 30 days from the last dose of study treatment. A standard unit of alcohol is defined as one 12-oz (150mL) beer, 1.5 oz (45mL) of 80-proof alcohol, or one 6-oz (175mL) glass of wine.
  • Lactose intolerant, for the food effect cohort only.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00500903


Locations
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United States, Tennessee
Sarah Cannon Research Institute (SCRI)
Nashville, Tennessee, United States, 37203
Sponsors and Collaborators
Millennium Pharmaceuticals, Inc.
Investigators
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Study Director: Medical Monitor Millennium Pharmaceuticals, Inc.

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Responsible Party: Millennium Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT00500903     History of Changes
Other Study ID Numbers: C14001
U1111-1187-1087 ( Registry Identifier: WHO )
First Posted: July 13, 2007    Key Record Dates
Results First Posted: March 14, 2019
Last Update Posted: March 14, 2019
Last Verified: November 2018

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda ( Millennium Pharmaceuticals, Inc. ):
Drug therapy