Advanced Solid Tumors, Relapsed/Refractory Lymphoma
Conditions
Keywords
Drug Therapy
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.
Interventions
DRUGAlisertib
Alisertib will be supplied as enteric coated tablets.
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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 | — |
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 6 investigative sites in the United States from 21 August 2014 to 18 July 2016.
Pre-assignment details
Participants with a diagnosis of advanced solid tumors or relapsed/refractory lymphoma were assigned to 1 of 3 hepatic function groups (normal hepatic function, moderate hepatic impairment, or severe hepatic impairment) on the basis of their total bilirubin and alanine aminotransferase (ALT) values. All participants received alisertib.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 16 |
| 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. | 12 |
| 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. | 8 |
| Total | 36 |
Baseline characteristics
| Characteristic | Total | Alisertib: Normal Hepatic Function | Alisertib: Moderate Hepatic Impairment | Alisertib: Severe Hepatic Impairment |
|---|---|---|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 9.77 | 61.2 years STANDARD_DEVIATION 10.07 | 54.9 years STANDARD_DEVIATION 9.89 | 54.0 years STANDARD_DEVIATION 7.05 |
| Body surface area | 1.986 m^2 STANDARD_DEVIATION 0.3292 | 2.030 m^2 STANDARD_DEVIATION 0.3073 | 1.897 m^2 STANDARD_DEVIATION 0.4028 | 2.056 m^2 STANDARD_DEVIATION 0.197 |
| Height | 170.1 cm STANDARD_DEVIATION 12.66 | 172.9 cm STANDARD_DEVIATION 14.62 | 162.9 cm STANDARD_DEVIATION 7.79 | 178.2 cm STANDARD_DEVIATION 8.1 |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 2 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 4 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 31 Participants | 14 Participants | 11 Participants | 6 Participants |
| Race/Ethnicity, Customized Not Reported | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 31 Participants | 14 Participants | 11 Participants | 6 Participants |
| Region of Enrollment United States | 36 Participants | 16 Participants | 12 Participants | 8 Participants |
| Sex: Female, Male Female | 14 Participants | 5 Participants | 7 Participants | 2 Participants |
| Sex: Female, Male Male | 22 Participants | 11 Participants | 5 Participants | 6 Participants |
| Weight | 85.2 kg STANDARD_DEVIATION 24.044 | 84.6 kg STANDARD_DEVIATION 20.997 | 85.5 kg STANDARD_DEVIATION 33.881 | 85.8 kg STANDARD_DEVIATION 11.847 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 16 | 3 / 12 | 4 / 8 |
| other Total, other adverse events | 15 / 16 | 12 / 12 | 8 / 8 |
| serious Total, serious adverse events | 7 / 16 | 8 / 12 | 7 / 8 |
Outcome results
Primary
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
Population: Participants from the PK-evaluable population, all participants who had completed protocol-specified dosing and PK assessment in Cycle 1 with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib: Normal Hepatic Function | Unbound AUC0-∞: Area Under the Concentration-Time Curve From Time 0 to Infinity for Alisertib | 304.3 h*nmol/L | Standard Deviation 119.09 |
| Alisertib: Moderate Hepatic Impairment | Unbound AUC0-∞: Area Under the Concentration-Time Curve From Time 0 to Infinity for Alisertib | 937.6 h*nmol/L | Standard Deviation 428.98 |
| Alisertib: Severe Hepatic Impairment | Unbound AUC0-∞: Area Under the Concentration-Time Curve From Time 0 to Infinity for Alisertib | 778.0 h*nmol/L | Standard Deviation 610.51 |
90% CI: [1.84, 3.53]
Primary
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
Population: Participants from the PK-evaluable population, all participants who had completed protocol-specified dosing and PK assessment in Cycle 1 with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib: Normal Hepatic Function | Unbound AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib | 248.5 h*nmol/L | Standard Deviation 131.41 |
| Alisertib: Moderate Hepatic Impairment | Unbound AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib | 859.1 h*nmol/L | Standard Deviation 387.85 |
| Alisertib: Severe Hepatic Impairment | Unbound AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib | 735.4 h*nmol/L | Standard Deviation 444.61 |
90% CI: [2.33, 4.43]
Primary
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
Population: Pharmacokinetic (PK)-evaluable population was defined as all participants who had completed protocol-specified dosing and PK assessment in Cycle 1 with sufficient dosing and PK data to reliably estimate PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib: Normal Hepatic Function | Unbound Cmax: Maximum Observed Plasma Concentration for Alisertib | 17.3 nmol/L | Standard Deviation 9.09 |
| Alisertib: Moderate Hepatic Impairment | Unbound Cmax: Maximum Observed Plasma Concentration for Alisertib | 28.1 nmol/L | Standard Deviation 7.82 |
| Alisertib: Severe Hepatic Impairment | Unbound Cmax: Maximum Observed Plasma Concentration for Alisertib | 18.5 nmol/L | Standard Deviation 5.8 |
90% CI: [1.12, 1.8]
Secondary
AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib Metabolites M1 and M2
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.
Time frame: Cycle 1 Day 1 Pre-dose and, and at multiple timepoints (up to 168 hours) post-dose
Population: Participants from the PK-evaluable population, all participants who had completed protocol-specified dosing and PK assessment in Cycle 1 with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib: Normal Hepatic Function | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib Metabolites M1 and M2 | Metabolite M2 | 8923.1 h*nmol/L | Standard Deviation 6539 |
| Alisertib: Normal Hepatic Function | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib Metabolites M1 and M2 | Metabolite M1 | 8366.3 h*nmol/L | Standard Deviation 10790.88 |
| Alisertib: Moderate Hepatic Impairment | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib Metabolites M1 and M2 | Metabolite M1 | 159665.0 h*nmol/L | Standard Deviation 116960.23 |
| Alisertib: Moderate Hepatic Impairment | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib Metabolites M1 and M2 | Metabolite M2 | 17326.0 h*nmol/L | Standard Deviation 8562.96 |
| Alisertib: Severe Hepatic Impairment | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib Metabolites M1 and M2 | Metabolite M1 | 196750.0 h*nmol/L | Standard Deviation 117472.08 |
| Alisertib: Severe Hepatic Impairment | AUClast: Area Under the Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Alisertib Metabolites M1 and M2 | Metabolite M2 | 16987.5 h*nmol/L | Standard Deviation 9384.25 |
Secondary
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
Population: PK-evaluable population was defined as all participants who had completed protocol-specified dosing and PK assessment in Cycle 1 with sufficient dosing and PK data to reliably estimate PK parameters.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib: Normal Hepatic Function | Cmax: Maximum Observed Plasma Concentration for Alisertib Metabolites M1 and M2 | Metabolite M1 | 370.3 nmol/L | Standard Deviation 282.02 |
| Alisertib: Normal Hepatic Function | Cmax: Maximum Observed Plasma Concentration for Alisertib Metabolites M1 and M2 | Metabolite M2 | 154.6 nmol/L | Standard Deviation 82.54 |
| Alisertib: Moderate Hepatic Impairment | Cmax: Maximum Observed Plasma Concentration for Alisertib Metabolites M1 and M2 | Metabolite M1 | 1774.0 nmol/L | Standard Deviation 904.1 |
| Alisertib: Moderate Hepatic Impairment | Cmax: Maximum Observed Plasma Concentration for Alisertib Metabolites M1 and M2 | Metabolite M2 | 173.8 nmol/L | Standard Deviation 54.39 |
| Alisertib: Severe Hepatic Impairment | Cmax: Maximum Observed Plasma Concentration for Alisertib Metabolites M1 and M2 | Metabolite M1 | 2001.9 nmol/L | Standard Deviation 1094.75 |
| Alisertib: Severe Hepatic Impairment | Cmax: Maximum Observed Plasma Concentration for Alisertib Metabolites M1 and M2 | Metabolite M2 | 207.3 nmol/L | Standard Deviation 151.6 |
Secondary
Dose-normalized Trough Concentration of Alisertib on Cycle 1 Day 14
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.
Time frame: Pre-dose on Day 14 of Cycle 1
Population: Data was not collected, as many participants dropped out of the study prior to Day 14 trough concentration collection.
Secondary
Percentage of Participants Who Experienced at Least 1 Serious Adverse Event
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.
Time frame: Baseline to 30 days after last dose (Up to 312 Days)
Population: Safety population was defined as all participants who received at least 1 dose of alisertib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib: Normal Hepatic Function | Percentage of Participants Who Experienced at Least 1 Serious Adverse Event | 44 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants Who Experienced at Least 1 Serious Adverse Event | 67 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants Who Experienced at Least 1 Serious Adverse Event | 88 percentage of participants |
Secondary
Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event
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.
Time frame: Baseline to 30 days after last dose (Up to 312 Days)
Population: Safety population was defined as all participants who received at least 1 dose of alisertib.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib: Normal Hepatic Function | Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event | 100 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event | 100 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants Who Experienced at Least 1 Treatment-Emergent Adverse Event | 100 percentage of participants |
Secondary
Percentage of Participants With Clinically Significant Laboratory Values
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.
Time frame: Baseline to the end of the study (Up to 312 Days)
Population: Safety population was defined as all participants who received at least 1 dose of alisertib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Laboratory Values | Platelet count decreased | 6 percentage of participants |
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Laboratory Values | Blood alkaline phosphatase increased | 6 percentage of participants |
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Laboratory Values | Gamma-glutamyltransferase increased | 13 percentage of participants |
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Laboratory Values | Blood creatinine increased | 0 percentage of participants |
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Laboratory Values | Blood bilirubin increased | 0 percentage of participants |
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Laboratory Values | Neutrophil count decreased | 0 percentage of participants |
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Laboratory Values | White blood cell count decreased | 0 percentage of participants |
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Laboratory Values | Alanine aminotransferase increased | 0 percentage of participants |
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Laboratory Values | Transaminases increased | 0 percentage of participants |
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Laboratory Values | Blood sodium decreased | 6 percentage of participants |
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Laboratory Values | Blood calcium increased | 6 percentage of participants |
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Laboratory Values | Aspartate aminotransferase increased | 0 percentage of participants |
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Laboratory Values | Blood phosphorus decreased | 6 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Aspartate aminotransferase increased | 8 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Blood calcium increased | 0 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Blood alkaline phosphatase increased | 8 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Transaminases increased | 8 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Alanine aminotransferase increased | 8 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Blood creatinine increased | 8 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Blood phosphorus decreased | 0 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Blood sodium decreased | 8 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Neutrophil count decreased | 8 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Blood bilirubin increased | 8 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Gamma-glutamyltransferase increased | 0 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | White blood cell count decreased | 8 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Platelet count decreased | 8 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | White blood cell count decreased | 0 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Platelet count decreased | 0 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Gamma-glutamyltransferase increased | 0 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Alanine aminotransferase increased | 0 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Aspartate aminotransferase increased | 0 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Blood bilirubin increased | 0 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Transaminases increased | 0 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Blood sodium decreased | 0 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Blood calcium increased | 0 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Blood phosphorus decreased | 0 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Blood alkaline phosphatase increased | 0 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Blood creatinine increased | 0 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Laboratory Values | Neutrophil count decreased | 0 percentage of participants |
Secondary
Percentage of Participants With Clinically Significant Vital Signs
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.
Time frame: Baseline to the end of the study (Up to 312 days)
Population: Safety population was defined as all participants who received at least 1 dose of alisertib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Vital Signs | Pyrexia | 25 percentage of participants |
| Alisertib: Normal Hepatic Function | Percentage of Participants With Clinically Significant Vital Signs | Sinus tachycardia | 6 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Vital Signs | Pyrexia | 8 percentage of participants |
| Alisertib: Moderate Hepatic Impairment | Percentage of Participants With Clinically Significant Vital Signs | Sinus tachycardia | 0 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Vital Signs | Pyrexia | 38 percentage of participants |
| Alisertib: Severe Hepatic Impairment | Percentage of Participants With Clinically Significant Vital Signs | Sinus tachycardia | 0 percentage of participants |
Secondary
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
Population: PK-evaluable population was defined as all participants who had completed protocol-specified dosing and PK assessment in Cycle 1 with sufficient dosing and PK data to reliably estimate PK parameters.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Alisertib: Normal Hepatic Function | Tmax: Time of First Occurrence of Cmax for Alisertib Metabolites M1 and M2 | Metabolite M1 | 3.500 hours |
| Alisertib: Normal Hepatic Function | Tmax: Time of First Occurrence of Cmax for Alisertib Metabolites M1 and M2 | Metabolite M2 | 9.000 hours |
| Alisertib: Moderate Hepatic Impairment | Tmax: Time of First Occurrence of Cmax for Alisertib Metabolites M1 and M2 | Metabolite M1 | 24.000 hours |
| Alisertib: Moderate Hepatic Impairment | Tmax: Time of First Occurrence of Cmax for Alisertib Metabolites M1 and M2 | Metabolite M2 | 24.050 hours |
| Alisertib: Severe Hepatic Impairment | Tmax: Time of First Occurrence of Cmax for Alisertib Metabolites M1 and M2 | Metabolite M1 | 24.150 hours |
| Alisertib: Severe Hepatic Impairment | Tmax: Time of First Occurrence of Cmax for Alisertib Metabolites M1 and M2 | Metabolite M2 | 24.150 hours |