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Pharmacokinetics of Alisertib in Adults With Advanced Solid Tumors or Relapsed/Refractory Lymphoma With Varying Degrees of Hepatic Function

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ClinicalTrials.gov Identifier: NCT02214147
Recruitment Status : Completed
First Posted : August 12, 2014
Results First Posted : November 15, 2018
Last Update Posted : November 15, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda ( Millennium Pharmaceuticals, Inc. )

Tracking Information
First Submitted Date  ICMJE July 30, 2014
First Posted Date  ICMJE August 12, 2014
Results First Submitted Date  ICMJE April 9, 2018
Results First Posted Date  ICMJE November 15, 2018
Last Update Posted Date November 15, 2018
Actual Study Start Date  ICMJE August 21, 2014
Actual Primary Completion Date April 5, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
  • Unbound Cmax: Maximum Observed Plasma Concentration for Alisertib [ Time Frame: Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose ]
  • Unbound AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib [ Time Frame: Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose ]
  • Unbound AUC0-∞: Area Under the Concentration-Time Curve From Time 0 to Infinity for Alisertib [ Time Frame: Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose ]
Original Primary Outcome Measures  ICMJE
 (submitted: August 8, 2014)
  • Maximum observed plasma concentration (Cmax) of alisertib [ Time Frame: Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose ]
    Maximum observed plasma concentration (Cmax) is the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve.
  • Area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-last) of alisertib [ Time Frame: Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose ]
    Area under the plasma concentration versus time curve from zero to the time of the last quantifiable concentration.
  • Area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞) of alisertib [ Time Frame: Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose ]
    Area under the plasma concentration-time curve from time 0 to infinity
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 9, 2018)
  • Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event [ Time Frame: Baseline to 30 days after last dose (Up to 312 Days) ]
    An adverse event is any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event is defined as an adverse event with an onset that occurs after receiving study drug.
  • Percentage of Participants Who Experienced at Least 1 Serious Adverse Event [ Time Frame: Baseline to 30 days after last dose (Up to 312 Days) ]
    A serious adverse event is any untoward medical occurrence or effect that at any dose of a drug results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically important due to other reasons than the above mentioned criteria.
  • Percentage of Participants With Clinically Significant Laboratory Values [ Time Frame: Baseline to the end of the study (Up to 312 Days) ]
    Laboratory assessments include serum chemistry and hematology. An abnormal laboratory value was assessed as an AE if that value led to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline.
  • Percentage of Participants With Clinically Significant Vital Signs [ Time Frame: Baseline to the end of the study (Up to 312 days) ]
    Vital signs include measurements of sitting diastolic and systolic blood pressure, heart rate, and temperature. Any vital signs determined by the investigator to be clinically significant were recorded as AEs.
  • Cmax: Maximum Observed Plasma Concentration for Alisertib Metabolites M1 and M2 [ Time Frame: Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose ]
  • Tmax: Time of First Occurrence of Cmax for Alisertib Metabolites M1 and M2 [ Time Frame: Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose ]
  • AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib Metabolites M1 and M2 [ Time Frame: Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose ]
    The area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-last) of the alisertib metabolites M1 and M2 was determined from the concentration-time curve of each participant using non-compartmental methods.
  • Dose-normalized Trough Concentration of Alisertib on Cycle 1 Day 14 [ Time Frame: Pre-dose on Day 14 of Cycle 1 ]
    A single blood sample will be collected pre-dose on Cycle 1 Day 14. The concentration of alisertib was determined in the plasma sample and dose-normalized.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 8, 2014)
  • Percentage of participants who experience at least 1 treatment-emergent adverse event [ Time Frame: Baseline to 30 days after last dose ]
    An adverse event is any unfavorable and unintended sign (eg, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A treatment-emergent adverse event is defined as an adverse event with an onset that occurs after receiving study drug.
  • Percentage of participants who experience at least 1 serious adverse event [ Time Frame: Baseline to 30 days after last dose ]
    A serious adverse event is any untoward medical occurrence or effect that at any dose of a drug results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is medically important due to other reasons than the above mentioned criteria.
  • Percentage of participants with clinically significant laboratory values or vital signs [ Time Frame: Baseline to the end of the study (up to 12 months) ]
    Laboratory assessments include serum chemistry and hematology. Vital signs include measurements of sitting diastolic and systolic blood pressure, heart rate, and temperature.
  • Maximum observed plasma concentration (Cmax) of the alisertib metabolites M1 and M2 [ Time Frame: Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose ]
    The maximum observed plasma concentration (Cmax) of the alisertib metabolites M1 and M2 will be determined from the concentration-time curve of each participant using non-compartmental methods.
  • Time to reach the maximum plasma concentration (Tmax) of the alisertib metabolites M1 and M2 [ Time Frame: Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose ]
    The time to reach the maximum plasma concentration (Tmax) of the alisertib metabolites M1 and M2 will be determined from the concentration-time curve of each participant using non-compartmental methods.
  • Area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-last) of the alisertib metabolites M1 and M2 [ Time Frame: Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose ]
    The area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-last) of the alisertib metabolites M1 and M2 will be determined from the concentration-time curve of each participant using non-compartmental methods.
  • Dose-normalized Trough Concentration of Alisertib on Cycle 1 Day 14 [ Time Frame: Pre-dose on Day 14 of Cycle 1 ]
    A single blood sample will be collected pre-dose on Cycle 1 Day 14. The concentration of alisertib will be determined in the plasma sample and dose-normalized.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Pharmacokinetics of Alisertib in Adults With Advanced Solid Tumors or Relapsed/Refractory Lymphoma With Varying Degrees of Hepatic Function
Official Title  ICMJE Pharmacokinetics of Oral Alisertib (MLN8237) in Adult Patients With Advanced Solid Tumors or Relapsed/Refractory Lymphoma With Varying Degrees of Hepatic Function
Brief Summary The purpose of this study is to evaluate the effect of moderate or severe hepatic impairment on the single-dose pharmacokinetics of alisertib in adult participants with cancer.
Detailed Description

The drug being tested in this study is called alisertib. Alisertib was tested to assess how it was processed by the body in participants with advanced solid tumors or relapsed/refractory lymphoma with varying degrees of liver function. This study also assessed laboratory results and safety.

The study enrolled 36 participants. Participants were assigned to 1 of the 3 treatment groups based on the status of their liver function: Normal hepatic function (Total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN), moderate hepatic impairment (Total bilirubin > 1.5-3 x ULN and ALT level = Any), or severe hepatic impairment (Total bilirubin > 3 x ULN and ALT level = Any). All participants were administered one 50 mg dose of alisertib on Day 1, Cycle 1. Alisertib was administered again on Days 8 through 14 of Cycle 1, followed by a 14-day rest period. Doses administered on Days 8-14 were 50, 30, or 20 mg of alisertib, depending on hepatic function. Alisertib was then continued at the same dose as in Cycle 1, Days 8-14 in 21-day cycles (7 days of alisertib followed by a 14-day rest period) for up to 1 year (approximately 16 cycles).

This multicenter trial was conducted in USA only. The overall time to participate in this study was up to 312 Days. Participants made multiple visits to the clinic including an end-of-study visit 30 days after the last dose of study drug for a follow-up assessment.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Advanced Solid Tumors
  • Relapsed/Refractory Lymphoma
Intervention  ICMJE Drug: Alisertib
Alisertib will be supplied as enteric coated tablets.
Other Name: MLN8237
Study Arms  ICMJE
  • Experimental: Alisertib: Normal Hepatic Function
    Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 50 mg, orally, twice daily (BID) for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 50 mg, BID for 7 days, followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Normal hepatic function includes participants with total bilirubin ≤ upper limit of the normal range [ULN] and alanine aminotransferase [ALT] level ≤ ULN.
    Intervention: Drug: Alisertib
  • Experimental: Alisertib: Moderate Hepatic Impairment
    Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by alisertib 30 mg, BID for 7 days (Cycle 1 Day 8 to 14), followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 30 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Moderate hepatic impairment includes participants with total bilirubin > 1.5-3 x ULN and any ALT level.
    Intervention: Drug: Alisertib
  • Experimental: Alisertib: Severe Hepatic Impairment
    Alisertib 50 mg, orally, once, on Cycle 1 Day 1, followed by, alisertib 20 mg, BID for 7 days (Cycle 1 Day 8 to 14) followed by a 14-day rest period. Starting at Cycle 2 Day 1, alisertib 20 mg, BID for 7 days followed by a 14-day rest period unless a dose reduction is indicated. Participants may continue to receive alisertib until they experience progressive disease or unacceptable alisertib-related toxicities for up to 12 months (approximately 16 cycles), unless it is determined by the investigator, with agreement by the sponsor, that a participant would derive clinical benefit from continued treatment beyond 12 months. Severe hepatic impairment includes participants with total bilirubin > 3 x ULN and any ALT level.
    Intervention: Drug: Alisertib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 26, 2016)
36
Original Estimated Enrollment  ICMJE
 (submitted: August 8, 2014)
48
Actual Study Completion Date  ICMJE July 18, 2016
Actual Primary Completion Date April 5, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male or female participants 18 years of age or older.
  2. Histologically or cytologically confirmed metastatic and/or advanced solid tumors or lymphomas for which standard curative or life-prolonging treatment does not exist or is no longer effective or tolerable.
  3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
  4. Female participants who:

    • Are post-menopausal for at least 1 year before the screening visit, OR
    • Are surgically sterile, OR
    • If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant (periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception).
  5. Male participants, even if surgically sterilized (ie, status postvasectomy), who:

    • Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
    • Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant (periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception).
  6. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
  7. Suitable venous access for the study-required blood sampling, including pharmacokinetics.
  8. Ability to swallow tablets.
  9. Participants with biliary obstruction for which a stent had been placed are eligible provided that the stent has been in place for more than 14 days before the first dose of alisertib and liver function has stabilized.
  10. Recovered from the reversible effects of prior antineoplastic therapy (ie, ≤ Grade 1 toxicity or baseline).
  11. Clinical laboratory values as specified below:

    • Absolute neutrophil count (ANC) ≥ 1500/μL and platelet count ≥ 75,000/μL.

      • Participants with normal hepatic function: Total bilirubin and alanine aminotransferase (ALT) must be ≤ upper limit of the normal range (ULN).
      • Participants with moderate hepatic impairment: total bilirubin must be > 1.5 to 3 x ULN with any ALT level.
      • Participants with severe hepatic impairment: total bilirubin must be > 3 x ULN with any ALT level.
      • Measured creatinine clearance or calculated creatinine clearance > 30 mL/minute. Note: If a calculated creatinine clearance is used, it should be calculated according to the Cockcroft-Gault formula.
      • Hemoglobin must be ≥ 8 g/dL.

Exclusion Criteria:

  1. Participants of North/East Asian ethnicity (ie, Japanese, Chinese, Korean) will be excluded.
  2. Recurrent nausea and/or vomiting within 14 days before the first dose of alisertib or known gastrointestinal (GI) abnormality or GI procedure that could interfere with or modify the oral absorption or tolerance of alisertib. Examples include, but are not limited to, disease-related bowel obstruction, pancreatic insufficiency, use of pancreatic enzymes, a gastric condition (such as severe reflux or active peptic ulcer disease) that requires chronic and uninterrupted use of proton pump inhibitors, partial gastrectomy, history of small intestine surgery, and celiac disease.
  3. Participants requiring treatment with clinically significant enzyme inducers, such as the enzyme-inducing anti-epileptic drugs phenytoin, carbamazepine, phenobarbital, oxcarbazepine, primidone, rifampin, rifabutin, rifapentine, or St. John's wort within 14 days before the first dose of alisertib or requiring the use of these medications during the study.
  4. A medical condition requiring use of pancreatic enzymes; daily, chronic, or regular use of proton pump inhibitors (PPIs); or histamine 2 (H2) receptor antagonists. Participants who intermittently use these medications, must meet the following criteria:

    • No use of PPIs within 5 days before the first dose of alisertib.
    • No use of H2 antagonist or pancreatic enzymes within 24 hours before the first dose of alisertib.
  5. Inadequate bone marrow or other organ function (excluding hepatic impairment per eligibility criteria).
  6. Female participants who are lactating and breastfeeding or have a positive serum pregnancy test during the Screening period or a positive urine pregnancy test on Day 1 before first dose of alisertib.
  7. Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
  8. Treatment with any anticancer therapy or any investigational products within 3 weeks before the first dose of study drug.
  9. Exposure to nitrosoureas or mitomycin C within 42 days before the first dose of study drug.
  10. Radiotherapy within 14 days before the first dose of study drug.
  11. Prior treatment with radiation therapy involving ≥ 25% of the hematopoietically active bone marrow within 42 days before the first dose of study drug.
  12. Major surgery within 14 days before the first dose of study drug.
  13. Serious infection within 14 days before the first dose of study drug. Participant must have recovered from infection before first dose.
  14. Life-threatening illness unrelated to cancer.
  15. Symptomatic brain metastasis. Participants with brain metastases:

    • Must have stable neurologic status following local therapy (surgery or radiation) for at least 2 weeks after completion of the definitive therapy AND
    • Must be without neurologic dysfunction that would confound the evaluation of neurologic or other adverse events (AEs).
  16. Clinically significant coagulopathy or bleeding disorder.
  17. Severe central nervous system, pulmonary, or renal disease not related to the participant's cancer.
  18. Known human immunodeficiency virus (HIV) positive.
  19. Known history of hepatitis C infection or suspected currently active hepatitis C infection, or known or suspected history of hepatitis B infection. Participants with known or suspected history of hepatitis B infection were to be screened and excluded when any of the following conditions were met:

    • Received hematopoietic stem cell transplantation (either allogeneic or autologous), or
    • Received any rituximab-containing treatment regimen in the last 12 months before entering the study, or
    • Tested positive for the presence of at least 1 of the following 3 markers in blood (evaluated at Screening): hepatitis B surface antigen (HBsAg), antibodies against hepatitis B core antigen (anti-HBc), or hepatitis B virus deoxyribonucleic acid (HBV DNA).
  20. Any of the following cardiovascular conditions:

    • Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities.
    • Corrected QT interval (QTc) > 500 milliseconds in a 12-lead electrocardiogram (ECG) during screening.
  21. History of uncontrolled sleep apnea syndrome or other condition that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.
  22. Use of moderate or strong cytochrome P450 (CYP) 3A inhibitors or CYP3A inducers within 2 weeks before the first dose of study drug.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02214147
Other Study ID Numbers  ICMJE C14019
U1111-1155-6072 ( Other Identifier: World Health Organization )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Takeda ( Millennium Pharmaceuticals, Inc. )
Study Sponsor  ICMJE Millennium Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Clinical Science Millennium Pharmaceuticals, Inc.
PRS Account Takeda
Verification Date April 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP