Advanced Solid Tumors, Lymphomas
Conditions
Keywords
East Asian Patients, Advanced solid tumors, Lymphomas, MLN8237, Alisertib, Aurora A Kinase Inhibitor, Drug therapy
Brief summary
The purpose of this study was to determine the safety profile, maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), and to characterize the pharmacokinetic (PK) profile of alisertib twice daily (BID) dosing for 7 days in East Asian participants with advanced solid tumors or lymphomas. The secondary objective was to describe any antitumor activity that may have been observed with alisertib treatment.
Detailed description
The drug being tested in this study is called alisertib (MLN8237). Alisertib is being tested to treat people who have advanced solid tumors or lymphomas for which standard curative or life-prolonging treatment did not exist or was no longer effective or tolerable. This study evaluated the safety and pharmacokinetic (PK) profile, and maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D) of alisertib, as well as any antitumor activity. The study enrolled 36 patients. Participants were assigned to one of the two treatment groups and received: * Alisertib 30 mg * Alisertib 40 mg All participants took two enteric-coated tablets every 12 hours each day for 7 days followed by a 14-day rest period in a 21-day cycle for up to 16 cycles. This multi-center trial is conducted in East Asia. The overall time to participate in this study was 24 months, unless it was determined that a participant would derive benefit from continued therapy beyond 24 months. Participants made multiple visits to the clinic, and were contacted up to a maximum of 30 days after last dose of study drug for a follow-up assessment.
Interventions
DRUGAlisertib
Alisertib 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
* Male or female East Asian participants 18 years or older * Histologically or cytologically confirmed metastatic and/or advanced solid tumors or lymphomas for which no effective standard treatment is available * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Expected survival longer than 3 months from study enrollment * Radiographically or clinically evaluable tumor * Female participants who are post menopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 30 days after the last dose of study drug or agree to abstain from heterosexual intercourse * Male participants who agree to practice effective barrier contraception through 6 months after the last dose of alisertib or agree to abstain from heterosexual intercourse * Voluntary written consent
Exclusion criteria
* Female participants who are lactating or pregnant * Treatment with any investigational products, systemic antineoplastic treatment, or antineoplastic treatment with glucocorticoids within 21 days preceding the first dose of alisertib * Treatment with nitrosoureas, mitomycin C, rituximab, alemtuzumab, or other unconjugated antibody treatment within 42 days (21 days if clear evidence of progressive disease) * Medical conditions requiring daily, chronic, or regular use of proton pump inhibitors or H2-receptor antagonists * Treatment with radioimmunoconjugates such as ibritumomab tiuxetan or tositumomab within 56 days preceding first alisertib dose * Major surgery within the 14 days preceding the first dose of alisertib * Life-threatening or uncontrolled medical illness unrelated to cancer * Known gastrointestinal (GI) disease or procedures that could interfere with the oral absorption or tolerance of alisertib * Inability to swallow capsules * Inadequate bone marrow or other organ function * Diagnosed or treated for another malignancy within 2 years of first dose of alisertib, or previously diagnosed with another malignancy and have any radiographic or biochemical marker evidence of active disease. In the case of prior prostate cancer treated with radiotherapy, the prostate specific antigen (PSA) may be detectable, but must be \< 1 ng/mL. Participants with completely resected basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy of any type are not excluded * Other severe acute or chronic medical or psychiatric conditions, including uncontrolled diabetes, or laboratory abnormality * Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CLss/F: Apparent Clearance After Extravascular Administration, at Steady State, Calculated Using AUCτ for Alisertib | Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose | — |
| T1/2: Terminal Half-Life for Alisertib | Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose | — |
| Rac: Accumulation Ratio for Alisertib | Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose | — |
| PTR: Peak Trough Ratio During a Dosing Interval, at Steady State for Alisertib | Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose | — |
| Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | Treatment Cycle 1 | MTD was defined as highest dose at which \<2 participants experienced a dose-limiting toxicity (DLT). DLT was defined as any of the following events considered possibly related to therapy with alisertib by the investigator: 1. Grade 4 neutropenia (absolute neutrophil count \<500 cells/mm\^3) for \>7 days; 2. Grade 4 neutropenia with fever (oral or ear temperature ≥38.5°C); 3. Grade 4 thrombocytopenia (platelets \<25,000/mm\^3) for \>7 days; 4. Platelet count \<10,000 cells/mm\^3; 5. ≥Grade 3 thrombocytopenia with clinically significant bleeding; 6. Delay in initiation of subsequent cycle by \>7 days due to treatment-related toxicity; 7. ≥Grade 3 nonhematological toxicity except following: a. ≥Grade 3 nausea and/or emesis in the absence of optimal antiemetic therapy; b. ≥Grade 3 diarrhea in the absence of optimal supportive therapy; c. Grade 3 fatigue lasting \<1 week; d. Other Grade 3 nonhematological toxicity that can be safely and reliably controlled to ≤Grade 2 with appropriate treatment. |
| Number of Participants With Adverse Events and Serious Adverse Events | First dose to 30 days past last dose (Up to 12.1 Months) | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious 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 Abnormal Clinical Laboratory Values Reported as Adverse Events | First dose to 30 days past last dose (Up to 12.1 Months) | Laboratory AEs in the following system organ classes (SOCs) are reported: blood and lymphatic system disorders, investigations, and metabolism and nutrition disorders. An abnormal laboratory value was assessed as an AE if that value lead to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A treatment¬-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. |
| Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events | First dose to 30 days past last dose (Up to 12.1 Months) | Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study. |
| Cmax: Maximum Observed Concentration for Alisertib | Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose | — |
| Tmax: Time to First Occurrence of Cmax for Alisertib | Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose | — |
| AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib | Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose | — |
| Dose Normalized AUCτ: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib | Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose | Dose normalized AUCτ was obtained using AUCτ divided by alisertib dose in milligrams. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response | First documented response until disease progression; approximately 12 months | DOR is defined as the time from the date of first documentation of a CR response to the date of first documentation of PD according to IWG criteria or RECIST criteria 1.1. IWG PD is defined as PD is defined as any new lesion or increase by \>50% of previously involved sites from nadir. RECIST PD is defined as unequivocal progression of existing non-target lesions. |
| Concentrations of Relevant Tumor Markers | Cycle 1, Day 1; at end of Cycle 2 and every 2 cycles thereafter; and at end treatment; approximately 12 months | — |
| Best Overall Response Rate Based on Investigator Assessment | Baseline and every 2 cycles for up to 24 months or until progressive disease | Best overall response rate is defined as the percentage of participants with complete response (CR) and/or partial response (PR) as assessed by the Investigator using Lymphoma International Working Group (IWG) Criteria or Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT, PET or MRI. IWG criteria for CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. RECIST response criteria is defined as: CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter of target lesions. |
Countries
Singapore
Participant flow
Recruitment details
Participants took part in the study at 8 investigative sites in Singapore, Taiwan, Hong Kong, and South Korea from 06 February 2012 to 08 October 2013.
Pre-assignment details
Participants with a diagnosis of advanced solid tumors or lymphomas received alisertib 30 mg or 40 mg twice a day (BID) for 7 consecutive days followed by a 14-day rest period in 21-day cycles (28-day cycles with additional 7-day rest period if all alisertib-related toxicities \[except alopecia\] were not resolved to less than Grade 2).
Participants by arm
| Arm | Count |
|---|---|
| Alisertib 30 mg Alisertib 30 mg enteric-coated tablets (ECT), orally, twice a day (BID) for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 16 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2. | 30 |
| Alisertib 40 mg Alisertib 40 mg ECT, orally, BID for 7 days, followed by a 14-day rest period, in 21-day cycles until there is evidence of disease progression or unacceptable alisertib-related toxicities (up to 7 cycles). Cycles could be extended to 28-day cycles (with additional 7-day rest period) if all alisertib-related toxicities (except alopecia) were not resolved to less than Grade 2. | 6 |
| Total | 36 |
Baseline characteristics
| Characteristic | Alisertib 30 mg | Alisertib 40 mg | Total |
|---|---|---|---|
| Age, Continuous | 57.2 years STANDARD_DEVIATION 9.52 | 50.7 years STANDARD_DEVIATION 18.25 | 56.1 years STANDARD_DEVIATION 11.35 |
| Body Surface Area (BSA) | 1.611 m^2 STANDARD_DEVIATION 0.1487 | 1.667 m^2 STANDARD_DEVIATION 0.1613 | 1.620 m^2 STANDARD_DEVIATION 0.1499 |
| Height | 162.5 cm STANDARD_DEVIATION 6.84 | 161.9 cm STANDARD_DEVIATION 6.61 | 162.4 cm STANDARD_DEVIATION 6.71 |
| Race/Ethnicity, Customized Not Hispanic or Latino | 30 Participants | 6 Participants | 36 Participants |
| Race/Ethnicity, Customized Asian (Chinese) | 17 Participants | 5 Participants | 22 Participants |
| Race/Ethnicity, Customized Asian (Korean) | 13 Participants | 0 Participants | 13 Participants |
| Race/Ethnicity, Customized Malay | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment Hong Kong | 5 Participants | 0 Participants | 5 Participants |
| Region of Enrollment Korea, Republic of | 13 Participants | 0 Participants | 13 Participants |
| Region of Enrollment Singapore | 4 Participants | 6 Participants | 10 Participants |
| Region of Enrollment Taiwan | 8 Participants | 0 Participants | 8 Participants |
| Sex: Female, Male Female | 11 Participants | 2 Participants | 13 Participants |
| Sex: Female, Male Male | 19 Participants | 4 Participants | 23 Participants |
| Weight | 57.78 kg STANDARD_DEVIATION 9.255 | 62.30 kg STANDARD_DEVIATION 11.714 | 58.53 kg STANDARD_DEVIATION 9.669 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 30 / 30 | 6 / 6 |
| serious Total, serious adverse events | 15 / 30 | 4 / 6 |
Outcome results
Primary
AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib
Time frame: Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose
Population: PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters. n in the category is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 30 mg or 40 mg | AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib | Day 1 | 9549.0 nM*hr | Standard Deviation 4119.3 |
| Alisertib 30 mg or 40 mg | AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib | Day 7 | 24377.9 nM*hr | Standard Deviation 13261.61 |
| Alisertib 40 mg | AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib | Day 1 | 11811.7 nM*hr | Standard Deviation 2845.76 |
| Alisertib 40 mg | AUCτ: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval (τ) for Alisertib | Day 7 | 30683.3 nM*hr | Standard Deviation 9575.68 |
Primary
CLss/F: Apparent Clearance After Extravascular Administration, at Steady State, Calculated Using AUCτ for Alisertib
Time frame: Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
Population: PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 30 mg or 40 mg | CLss/F: Apparent Clearance After Extravascular Administration, at Steady State, Calculated Using AUCτ for Alisertib | 2.9357 L/hr | Standard Deviation 1.37091 |
| Alisertib 40 mg | CLss/F: Apparent Clearance After Extravascular Administration, at Steady State, Calculated Using AUCτ for Alisertib | 2.8083 L/hr | Standard Deviation 1.20259 |
Primary
Cmax: Maximum Observed Concentration for Alisertib
Time frame: Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose
Population: Pharmacokinetic (PK) Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters. n in the category is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 30 mg or 40 mg | Cmax: Maximum Observed Concentration for Alisertib | Day 7 | 3000.0 nM | Standard Deviation 1329.38 |
| Alisertib 30 mg or 40 mg | Cmax: Maximum Observed Concentration for Alisertib | Day 1 | 1442.5 nM | Standard Deviation 534.8 |
| Alisertib 40 mg | Cmax: Maximum Observed Concentration for Alisertib | Day 7 | 3686.7 nM | Standard Deviation 885.45 |
| Alisertib 40 mg | Cmax: Maximum Observed Concentration for Alisertib | Day 1 | 1871.7 nM | Standard Deviation 429.62 |
Primary
Dose Normalized AUCτ: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib
Dose normalized AUCτ was obtained using AUCτ divided by alisertib dose in milligrams.
Time frame: Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
Population: PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 30 mg or 40 mg | Dose Normalized AUCτ: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib | 812.9 nM*hr/mg | Standard Deviation 441.9 |
| Alisertib 40 mg | Dose Normalized AUCτ: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib | 766.8 nM*hr/mg | Standard Deviation 238.88 |
Primary
Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D)
MTD was defined as highest dose at which \<2 participants experienced a dose-limiting toxicity (DLT). DLT was defined as any of the following events considered possibly related to therapy with alisertib by the investigator: 1. Grade 4 neutropenia (absolute neutrophil count \<500 cells/mm\^3) for \>7 days; 2. Grade 4 neutropenia with fever (oral or ear temperature ≥38.5°C); 3. Grade 4 thrombocytopenia (platelets \<25,000/mm\^3) for \>7 days; 4. Platelet count \<10,000 cells/mm\^3; 5. ≥Grade 3 thrombocytopenia with clinically significant bleeding; 6. Delay in initiation of subsequent cycle by \>7 days due to treatment-related toxicity; 7. ≥Grade 3 nonhematological toxicity except following: a. ≥Grade 3 nausea and/or emesis in the absence of optimal antiemetic therapy; b. ≥Grade 3 diarrhea in the absence of optimal supportive therapy; c. Grade 3 fatigue lasting \<1 week; d. Other Grade 3 nonhematological toxicity that can be safely and reliably controlled to ≤Grade 2 with appropriate treatment.
Time frame: Treatment Cycle 1
Population: DLT-Evaluable population is defined as participants with a common race who had not used granulocyte colony-stimulating factor (G-CSF) in cycle 1, and either experienced DLT during Cycle 1 or received at least 85% of planned doses of alisertib and have sufficient follow up data to allow investigator and sponsor to determine whether a DLT occurred.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib 30 mg or 40 mg | Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | 30 mg |
Primary
Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events
Laboratory AEs in the following system organ classes (SOCs) are reported: blood and lymphatic system disorders, investigations, and metabolism and nutrition disorders. An abnormal laboratory value was assessed as an AE if that value lead to discontinuation or delay in treatment, dose modification, therapeutic intervention, or was considered by the investigator to be a clinically significant change from baseline. A treatment¬-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug.
Time frame: First dose to 30 days past last dose (Up to 12.1 Months)
Population: Safety Population is defined as all participants who received at least one dose of alisertib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Anaemia | 9 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Platelet count decreased | 3 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | White blood cell count decreased | 7 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Blood bilirubin increased | 2 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Febrile neutropenia | 4 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Haemoglobin decreased | 1 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Aspartate aminotransferase increased | 6 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Blood creatinine increased | 0 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Thrombocytopenia | 6 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Urine output decreased | 1 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Neutrophil count decreased | 4 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Hypokalaemia | 4 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Leukopenia | 2 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Hypercalcaemia | 0 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Alanine aminotransferase increased | 4 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Hyponatraemia | 1 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Neutropenia | 19 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Hyponatraemia | 0 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Neutropenia | 5 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Anaemia | 4 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Thrombocytopenia | 1 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Febrile neutropenia | 1 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Leukopenia | 2 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | White blood cell count decreased | 0 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Aspartate aminotransferase increased | 0 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Neutrophil count decreased | 0 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Alanine aminotransferase increased | 0 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Platelet count decreased | 0 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Blood bilirubin increased | 0 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Haemoglobin decreased | 0 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Blood creatinine increased | 1 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Urine output decreased | 0 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Hypokalaemia | 3 Participants |
| Alisertib 40 mg | Number of Participants With Abnormal Clinical Laboratory Values Reported as Adverse Events | Hypercalcaemia | 1 Participants |
Primary
Number of Participants With Adverse Events and Serious Adverse Events
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A Serious Adverse Event (SAE) A serious 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: First dose to 30 days past last dose (Up to 12.1 Months)
Population: Safety Population is defined as all participants who received at least one dose of alisertib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alisertib 30 mg or 40 mg | Number of Participants With Adverse Events and Serious Adverse Events | AE | 30 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Adverse Events and Serious Adverse Events | SAE | 15 Participants |
| Alisertib 40 mg | Number of Participants With Adverse Events and Serious Adverse Events | AE | 6 Participants |
| Alisertib 40 mg | Number of Participants With Adverse Events and Serious Adverse Events | SAE | 4 Participants |
Primary
Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events
Vital signs (blood pressure, pulse rate, and oral temperature) measurements were collected throughout the study.
Time frame: First dose to 30 days past last dose (Up to 12.1 Months)
Population: Safety Population is defined as all participants who received at least one dose of alisertib.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Alisertib 30 mg or 40 mg | Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events | Hypertension | 1 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events | Hypotension | 1 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events | Bradycardia | 1 Participants |
| Alisertib 30 mg or 40 mg | Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events | Pyrexia | 8 Participants |
| Alisertib 40 mg | Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events | Pyrexia | 1 Participants |
| Alisertib 40 mg | Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events | Hypertension | 0 Participants |
| Alisertib 40 mg | Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events | Bradycardia | 0 Participants |
| Alisertib 40 mg | Number of Participants With Clinically Significant Changes in Vital Signs Reported as Adverse Events | Hypotension | 0 Participants |
Primary
PTR: Peak Trough Ratio During a Dosing Interval, at Steady State for Alisertib
Time frame: Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
Population: PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 30 mg or 40 mg | PTR: Peak Trough Ratio During a Dosing Interval, at Steady State for Alisertib | 2.254 ratio | Standard Deviation 0.6458 |
| Alisertib 40 mg | PTR: Peak Trough Ratio During a Dosing Interval, at Steady State for Alisertib | 2.207 ratio | Standard Deviation 0.3946 |
Primary
Rac: Accumulation Ratio for Alisertib
Time frame: Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
Population: PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 30 mg or 40 mg | Rac: Accumulation Ratio for Alisertib | 2.830 ratio | Standard Deviation 1.2955 |
| Alisertib 40 mg | Rac: Accumulation Ratio for Alisertib | 2.690 ratio | Standard Deviation 1.0638 |
Primary
T1/2: Terminal Half-Life for Alisertib
Time frame: Cycle 1 Day 7 predose and at multiple time points (up to 12 hours) postdose
Population: PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 30 mg or 40 mg | T1/2: Terminal Half-Life for Alisertib | 16.750 hr | Standard Deviation 8.171 |
| Alisertib 40 mg | T1/2: Terminal Half-Life for Alisertib | 14.795 hr | Standard Deviation 4.5715 |
Primary
Tmax: Time to First Occurrence of Cmax for Alisertib
Time frame: Cycle 1 Days 1 and 7 predose and at multiple time points (up to 12 hours) postdose
Population: PK Population is defined as all participants with sufficient dosing and PK concentration time data to reliably estimate PK parameters. n in the category is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Alisertib 30 mg or 40 mg | Tmax: Time to First Occurrence of Cmax for Alisertib | Day 1 | 3.0 hr |
| Alisertib 30 mg or 40 mg | Tmax: Time to First Occurrence of Cmax for Alisertib | Day 7 | 2.9 hr |
| Alisertib 40 mg | Tmax: Time to First Occurrence of Cmax for Alisertib | Day 1 | 2.0 hr |
| Alisertib 40 mg | Tmax: Time to First Occurrence of Cmax for Alisertib | Day 7 | 2.0 hr |
Secondary
Best Overall Response Rate Based on Investigator Assessment
Best overall response rate is defined as the percentage of participants with complete response (CR) and/or partial response (PR) as assessed by the Investigator using Lymphoma International Working Group (IWG) Criteria or Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT, PET or MRI. IWG criteria for CR is defined as the disappearance of all evidence of disease and PR is defined as regression of measurable disease and no new sites. RECIST response criteria is defined as: CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter of target lesions.
Time frame: Baseline and every 2 cycles for up to 24 months or until progressive disease
Population: Safety Population is defined as all participants who received at least one dose of alisertib.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib 30 mg or 40 mg | Best Overall Response Rate Based on Investigator Assessment | CR | 0 percentage of participants |
| Alisertib 30 mg or 40 mg | Best Overall Response Rate Based on Investigator Assessment | PR | 3 percentage of participants |
| Alisertib 40 mg | Best Overall Response Rate Based on Investigator Assessment | CR | 0 percentage of participants |
| Alisertib 40 mg | Best Overall Response Rate Based on Investigator Assessment | PR | 0 percentage of participants |
Secondary
Concentrations of Relevant Tumor Markers
Time frame: Cycle 1, Day 1; at end of Cycle 2 and every 2 cycles thereafter; and at end treatment; approximately 12 months
Population: Data was not analyzed as per the change in planned analysis (protocol amendment).
Secondary
Duration of Response
DOR is defined as the time from the date of first documentation of a CR response to the date of first documentation of PD according to IWG criteria or RECIST criteria 1.1. IWG PD is defined as PD is defined as any new lesion or increase by \>50% of previously involved sites from nadir. RECIST PD is defined as unequivocal progression of existing non-target lesions.
Time frame: First documented response until disease progression; approximately 12 months
Population: Safety Population is defined as all participants who received at least one dose of alisertib. Participants with response were evaluated.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib 30 mg or 40 mg | Duration of Response | 169 days |