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

Phase 1

Completed

• Conditions: Relapsed/Refractory Lymphoma; Advanced Solid Tumors
• Interventions: Drug: Alisertib

• Registration Number: NCT02214147
• Lead Sponsor: Millennium Pharmaceuticals, Inc.

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 Timeline

• Study First Submitted: 2014-07-30
• Study First Submitted QC: 2014-08-08
• Study First Posted: 2014-08-12
• Study Start: 2014-08-21
• Primary Completion: 2016-04-05
• Study Completion: 2016-07-18
• Status Verified: 2018-04
• Results First Submitted: 2018-04-09
• Results First Submitted QC: 2018-04-09
• Last Update Submitted: 2018-04-09
• Results First Posted: 2018-11-15
• Last Update Posted: 2018-11-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 36

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Alisertib: Normal Hepatic Function	Alisertib	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.
Alisertib: Severe Hepatic Impairment	Alisertib	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.
Alisertib: Moderate Hepatic Impairment	Alisertib	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.

Primary Outcome Measures

Name	Time	Method
Unbound Cmax: Maximum Observed Plasma Concentration for Alisertib	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	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	Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With Clinically Significant Laboratory Values	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	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.
Tmax: Time of First Occurrence of Cmax for Alisertib Metabolites M1 and M2	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	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	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.
Cmax: Maximum Observed Plasma Concentration for Alisertib Metabolites M1 and M2	Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose
Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event	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	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.