Advanced Solid Tumors, Lymphoma
Conditions
Keywords
MLN8237, Alisertib, Food effects
Brief summary
The purpose of this study is to evaluate the effect of food on the single-dose pharmacokinetics (PK) of alisertib administered as an enteric-coated tablet (ECT) formulation in participants with advanced solid tumors or lymphomas.
Detailed description
The drug being tested in this study is called alisertib. Alisertib is being tested in adult participants with advanced solid tumors or lymphomas. The study enrolled 26 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need): * Alisertib 50 mg Fed + Fasted * Alisertib 50 mg Fasted + Fed All participants will be asked to take one alisertib tablet (ECT), orally, with or without a standard high-fat breakfast Cycle 1, Day 1, with the respective alternate food intake condition (fasted to fed or fed to fasted) on Cycle 2, Day 1, each followed by 14-day rest period. Participants will take alisertib, ECT, orally BID on Days 4 to 10 of Cycles 1 and 2, each followed by 14-day rest period. From Cycle 3 onwards participants will continue taking alisertib 50 mg, ECT, orally, BID on Days 1-7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity. This multi-center trial conducted at 3 sites in the United States. Participants will make multiple visits to the clinic and plus a final visit after 30 days of receiving their last dose of drug for a follow-up assessment.
Interventions
DRUGAlisertib
Alisertib ECT
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 18 years or older * Histologically or cytologically confirmed advanced tumors or lymphomas for which standard curative or life-prolonging treatment does not exist, or is no longer effective or tolerable * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Participant must meet protocol-specified laboratory values * Suitable venous access * Female participants who are postmenopausal for at least 1 year OR are surgically sterile OR if of childbearing potential, agree to practice 2 effective methods of contraception at the same time or agree to practice true abstinence * Male participants who agree to practice effective barrier contraception during the entire study and through 4 months after the last dose of study drug OR agree to practice true abstinence
Exclusion criteria
* Prior or current investigational therapies within 4 weeks before the first dose of alisertib * Female participants who are lactating or pregnant * Participant requiring treatment with clinically significant enzyme inducers, such as the enzyme-inducing antiepileptic drugs phenytoin, carbamazepine, or phenobarbital, or rifampin, rifabutin, rifapentine, or St. John's wort within 14 days before the first dose of alisertib and during the study * Medical conditions requiring daily, chronic, or regular use of proton pump inhibitors (PPIs) within 7 days preceding the first dose of alisertib, or histamine (H2)-receptor antagonists * Participant requiring systemic anticoagulation * Ongoing nausea or vomiting that is Grade 2 or worse in intensity * Known gastrointestinal (GI) disease or GI procedures that could interfere with the oral absorption, excretion, or tolerance of alisertib * History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness such as severe chronic obstructive pulmonary disease * Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection * Participant who are lactose-intolerant or are unwilling/unable to consume the protocol specified standardized high-fat breakfast Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Cmax: Maximum Observed Plasma Concentration of Alisertib | Cycles 1 and 2, Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose |
| AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration of Alisertib | Cycles 1 and 2, Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose |
| AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity of Alisertib | Cycles 1 and 2, Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose through 30 days after the last dose of study drug (up to 225 days) | An AE is considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events. A SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. |
| Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | From first dose through 30 days after the last dose of study drug (up to 225 days) | The number of participants with any clinical significant change in safety laboratory values collected throughout the study. |
| Number of Participants With Clinically Significant Change in Vital Sign Reported as AEs | From first dose through 30 days after the last dose of study drug (up to 225 days) | The number of participants with any clinical significant change in vital signs (sitting diastolic and systolic blood pressure, heart rate, and temperature) were collected throughout the study. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 3 investigative sites in the United States from 16 July 2013 to 24 January 2017. Data cut-off for the primary analysis was 05 March 2014.
Pre-assignment details
Participants with a diagnosis of advanced solid tumors or lymphomas were enrolled to crossover fashion to receive alisertib 50 mg enteric-coated tablet (ECT), orally in fasted or fed state in Cycles 1 and 2.
Participants by arm
| Arm | Count |
|---|---|
| Alisertib 50 mg Fed + Fasted Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 50 mg, ECT, orally, twice daily (BID) on Days 4 through 10, followed by a 14-day rest period in Cycle 1 (24-day cycles), followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 50 mg, ECT, orally, BID on Days 4 through 10, followed by a 14-day rest period in Cycle 2, followed by alisertib 50 mg, ECT, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3 and onwards (21-day cycles) until disease progression, occurrence of an unacceptable alisertib-related toxicity. | 13 |
| Alisertib 50 mg Fasted + Fed Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 50 mg, ECT, orally, BID on Days 4 through 10, followed by a 14-day rest period in Cycle 1 (24-day cycles), followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 50 mg, ECT, orally, BID on Days 4 through 10, followed by a 14-day rest period in Cycle 2, followed by alisertib 50 mg, ECT, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3 and onwards (21-day cycles) until disease progression, occurrence of an unacceptable alisertib-related toxicity. | 13 |
| Total | 26 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Progressive Disease | 1 | 5 |
| Overall Study | Reason not Specified | 0 | 1 |
| Overall Study | Symptomatic Deterioration | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Alisertib 50 mg Fed + Fasted | Alisertib 50 mg Fasted + Fed | Total |
|---|---|---|---|
| Age, Continuous | 59.6 years STANDARD_DEVIATION 10.15 | 61.7 years STANDARD_DEVIATION 12.64 | 60.7 years STANDARD_DEVIATION 11.28 |
| Height | 166.9 cm STANDARD_DEVIATION 14.34 | 165.3 cm STANDARD_DEVIATION 11.32 | 166.1 cm STANDARD_DEVIATION 12.68 |
| Race/Ethnicity, Customized Black or African American | 3 Participants | 0 Participants | 3 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 5 Participants | 4 Participants | 9 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 8 Participants | 9 Participants | 17 Participants |
| Race/Ethnicity, Customized White | 10 Participants | 13 Participants | 23 Participants |
| Region of Enrollment United States | 13 Participants | 13 Participants | 26 Participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 13 Participants |
| Weight | 73.59 kg STANDARD_DEVIATION 15.484 | 78.37 kg STANDARD_DEVIATION 20.183 | 75.98 kg STANDARD_DEVIATION 17.792 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 13 | 1 / 13 |
| other Total, other adverse events | 13 / 13 | 13 / 13 |
| serious Total, serious adverse events | 7 / 13 | 7 / 13 |
Outcome results
Primary
AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity of Alisertib
Time frame: Cycles 1 and 2, Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
Population: PK population included participants with sufficient dosing data and PK concentration-time data to reliably estimate the PK parameters. Here, number of participants analysed are the participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 50 mg Fed | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity of Alisertib | 24537.5 hr*nM | Standard Deviation 9882.1 |
| Alisertib 50 mg Fasted | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity of Alisertib | 22771.4 hr*nM | Standard Deviation 10206.21 |
Comparison: The confidence intervals are calculated for the difference in the LS means of the ln-transformed AUC∞ plain values (difference = Fed/Fasted). Antilogs of the confidence limits for the difference are taken to construct the confidence intervals for the ratio of the geometric mean90% CI: [0.96, 1.39]
Primary
AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration of Alisertib
Time frame: Cycles 1 and 2, Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
Population: PK population included participants with sufficient dosing data and PK concentration-time data to reliably estimate the PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 50 mg Fed | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration of Alisertib | 24645.5 hr*nM | Standard Deviation 12467.39 |
| Alisertib 50 mg Fasted | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration of Alisertib | 20797.7 hr*nM | Standard Deviation 8847.69 |
Comparison: The confidence intervals are calculated for the difference in the LS means of the ln-transformed AUC(last) plain values (difference = Fed/Fasted). Antilogs of the confidence limits for the difference are taken to construct the confidence intervals for the ratio of the geometric mean.90% CI: [1.01, 1.34]
Primary
Cmax: Maximum Observed Plasma Concentration of Alisertib
Time frame: Cycles 1 and 2, Day 1 pre-dose and at multiple time points (up to 72 hours) post-dose
Population: Pharmacokinetic (PK) population included participants with sufficient dosing data and PK concentration-time data to reliably estimate the PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 50 mg Fed | Cmax: Maximum Observed Plasma Concentration of Alisertib | 1338.6 nM | Standard Deviation 487.25 |
| Alisertib 50 mg Fasted | Cmax: Maximum Observed Plasma Concentration of Alisertib | 1354.5 nM | Standard Deviation 432.17 |
Comparison: The confidence intervals are calculated for the difference in the LS means of the ln-transformed Cmax plain values (difference = Fed/Fasted). Antilogs of the confidence limits for the difference are taken to construct the confidence intervals for the ratio of the geometric means.90% CI: [0.85, 1.12]
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events. A SAE is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
Time frame: From first dose through 30 days after the last dose of study drug (up to 225 days)
Population: Safety population included all enrolled participants who received at least one dose of study drug. According to the protocol analysis planned, data for the safety and tolerability was collected as per the treatment sequence received in the study, irrespective of the fed or fasted condition.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alisertib 50 mg Fed | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 13 Participants |
| Alisertib 50 mg Fed | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 7 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 13 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 7 Participants |
Secondary
Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs
The number of participants with any clinical significant change in safety laboratory values collected throughout the study.
Time frame: From first dose through 30 days after the last dose of study drug (up to 225 days)
Population: Safety population included all enrolled participants who received at least one dose of study drug. According to the protocol analysis planned, data for the safety and tolerability was collected as per the treatment sequence received in the study, irrespective of the fed or fasted condition.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Anaemia | 5 Participants |
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Lymphopenia | 0 Participants |
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Blood bilirubin increased | 1 Participants |
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Neutropenia | 10 Participants |
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Leukopenia | 5 Participants |
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Thrombocytopenia | 1 Participants |
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Hypokalaemia | 0 Participants |
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Hyperbilirubinaemia | 1 Participants |
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Neutrophil count decreased | 1 Participants |
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Hyperkalaemia | 1 Participants |
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Hypomagnesaemia | 0 Participants |
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Aspartate aminotransferase increased | 0 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Aspartate aminotransferase increased | 1 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Anaemia | 3 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Hyperbilirubinaemia | 1 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Hypomagnesaemia | 1 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Neutrophil count decreased | 1 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Neutropenia | 8 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Lymphopenia | 1 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Leukopenia | 2 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Blood bilirubin increased | 0 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Thrombocytopenia | 2 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Hyperkalaemia | 0 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Laboratory Parameters Reported as AEs | Hypokalaemia | 3 Participants |
Secondary
Number of Participants With Clinically Significant Change in Vital Sign Reported as AEs
The number of participants with any clinical significant change in vital signs (sitting diastolic and systolic blood pressure, heart rate, and temperature) were collected throughout the study.
Time frame: From first dose through 30 days after the last dose of study drug (up to 225 days)
Population: Safety population included all enrolled participants who received at least one dose of study drug. According to the protocol analysis planned, data for the safety and tolerability was collected as per the treatment sequence received in the study, irrespective of the fed or fasted condition.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Vital Sign Reported as AEs | Hypertension | 0 Participants |
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Vital Sign Reported as AEs | Hypotension | 0 Participants |
| Alisertib 50 mg Fed | Number of Participants With Clinically Significant Change in Vital Sign Reported as AEs | Tachycardia | 0 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Vital Sign Reported as AEs | Hypertension | 1 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Vital Sign Reported as AEs | Hypotension | 1 Participants |
| Alisertib 50 mg Fasted | Number of Participants With Clinically Significant Change in Vital Sign Reported as AEs | Tachycardia | 1 Participants |