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