Pharmacokinetics of Alisertib in Adults With Advanced Solid Tumors or Relapsed/Refractory Lymphoma With Varying Degrees of Hepatic Function
Condition: Advanced Solid Tumors; Relapsed/Refractory Lymphoma
MeSH terms: Lymphoma
Intervention: Alisertib
Intervention description: Alisertib will be supplied as enteric coated tablets.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 36.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Drug Therapy

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.
    

Eligibility criteria:

        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.