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| ID | Type | Description | Link |
|---|---|---|---|
| U1111-1187-6657 | Registry Identifier | WHO |
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The purposes of this study were to estimate the relative (Rel) bioavailability (BA) of an oral solution (OS) formulation of alisertib in reference to a powder-in-capsule (PIC) formulation, to characterize the effect of food on the single-dose pharmacokinetics (PK) of alisertib OS and enteric-coated tablets (ECT), to characterize the multiple-dose safety, tolerability, and steady-state PK of alisertib administered as an OS, and to characterize the multiple-dose safety and tolerability of alisertib administered as an ECT.
The drug being tested in this study is called alisertib (MLN8237). Alisertib is being tested to treat people who have advanced solid tumors. This study will look at the relative bioavailability (BA) (Part A), food effect and multiple-dose PK and safety of the oral solution (OS) (Part B) and food effect and safety of the enteric-coated tablet (ECT) formulation (Part C).
The study enrolled 53 patients (pts). Prior to initiation of Part A, 4 participants were enrolled in a dose escalation cohort. Participants in the study received:
• Alisertib 15 mg to 50 mg orally In the first 2 cycles of all 3 parts of the study, a single dose of alisertib was administered on Day 1 (PIC or OS in Part A [n=19 pts]; OS, in the fed or fasted state, in Part B [n=6 pts]; ECT, in the fed or fasted state, in Part C [n=24 pts]), In Part A, participants then continued on the PIC formulation at 40 mg BID for 7 days (Days 3 - 9). In Part B, participants continued on the OS formulation at a calculated dose administered BID for 7 days (Days 3 - 9). In Part C, the ECT formulation was continued at 40 mg BID for 7 days (Days 3 - 9); however, dose escalation to 50 mg BID was permitted after Cycle 1 based on tolerability and safety findings in the prior cycles. All participants took doses at a gap of 12 hours each day for 7 days followed by a 14-day rest period in a 21-days cycle for the remaining cycles.
This multi-center trial was conducted in the United States. The overall time to participate in this study was 30 months. Participants made multiple visits to the clinic, and final assessments were performed approximately 30 days after last dose of study drug.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Dose Escalation | Experimental | A single dose of alisertib 15 mg, oral solution (OS) was administered on Day 1, followed by alisertib 40 mg, powder-in-capsule (PIC), orally, twice a day (BID) on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, was administered on Cycle 2 Day 1 followed by alisertib 40 mg on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Subsequent cycles, alisertib 40 or 50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
|
| Part A: Relative Bioavailability OS/PIC (Sequence A) | Experimental | A single dose of alisertib 25 mg, OS, administered on Day 1, followed by alisertib 40 mg PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, administered on Cycle 2 Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles, alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
|
| Part A: Relative Bioavailability PIC/OS (Sequence B) | Experimental | A single dose of alisertib 50 mg, PIC, orally administered on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 25 mg, OS, once on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Alisertib | Drug | Alisertib OS Alisertib PIC Alisertib PIC |
|
| Measure | Description | Time Frame |
|---|---|---|
| Part A: Dose-normalized Cmax (Maximum Observed Concentration) for Estimation of Relative Bioavailability for Alisertib Oral Solution (OS) Versus Powder in Capsule Formulations (PIC) | Dose normalized Cmax was obtained using Cmax divided by alisertib dose in milligrams to provide values adjusted to a 1 mg alisertib dose. | Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual adverse event (AE) that was judged by the investigator to be treatment related. |
| Part A: Dose-normalized AUClast (Area Under the Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration) for Estimation of Relative Bioavailability for Alisertib Oral Solution (OS) Versus Powder in Capsule Formulations (PIC) | Dose normalized AUClast was obtained using Cmax divided by alisertib dose in milligrams to provide values adjusted to a 1 mg alisertib dose. | Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
| Part B: Cmax: Maximum Observed Concentration for Alisertib Administered as an Oral Solution With Food Versus Without Food | Not performed. | Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
| Part B: AUClast: Area Under the Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration for Alisertib Administered as an Oral Solution With Food Versus Without Food | Not performed. | Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
| Measure | Description | Time Frame |
|---|---|---|
| Best Overall Response (CR+PR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Best overall response is defined as the number of participants with Complete Response (CR) + Partial Response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT or MRI. CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter (LD) of target lesions. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease, taking as reference the smallest sum LD since the treatment started. |
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Inclusion Criteria:
Each participant must meet all of the following inclusion criteria to be enrolled in the study:
Exclusion Criteria:
Participants meeting any of the following exclusion criteria are not to be enrolled in the study:
Female participants who are pregnant or lactating
Serious medical or psychiatric illness that could interfere with protocol completion
Major surgery within 14 days of first dose of alisertib
Antineoplastic therapy, radiation therapy or any experimental therapy 21 days prior to first dose of alisertib
Nitrosoureas or mitomycin-C within 6 weeks before the first dose of alisertib.
Autologous stem cell transplant within 3 months before the first dose of alisertib, or prior allogeneic stem cell transplant at any time.
Active infection requiring systemic therapy, or other serious infection
Inability to swallow oral medication
Gastrointestinal (GI) disease or GI procedure that could interfere with oral absorption or tolerance of alisertib
Symptomatic brain metastasis
Uncontrolled cardiovascular condition
Diagnosis or treatment of another malignancy within 2 years preceding first dose of study drug except nonmelanoma skin cancer or in situ malignancy completely resected
Known history of human immunodeficiency virus (HIV) infection, hepatitis B, or hepatitis C
Lactose-intolerant (Parts A and B only)
Prior history of metabolic acidosis (Parts A and B only)
Use of enzyme-inducing antiepileptic drugs such as phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin, rifapentine or St. John's wort within 14 days prior to the first dose of alisertib
A medical condition requiring use of pancreatic enzymes; or daily, chronic , or regular use of proton pump inhibitors (PPI); or histamine (H2) receptor antagonists. Participants who intermittently use these medications must meet the following:
Participants requiring full systemic anticoagulation
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| Name | Affiliation | Role |
|---|---|---|
| Medical Director Clinical Science | Millennium Pharmaceuticals, Inc. | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Premiere Oncology, A Medical Corporation | Santa Monica | California | 90404 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26689566 | Derived | Falchook GS, Zhou X, Venkatakrishnan K, Kurzrock R, Mahalingam D, Goldman JW, Jung J, Ullmann CD, Milch C, Rosen LS, Sarantopoulos J. Effect of Food on the Pharmacokinetics of the Investigational Aurora A Kinase Inhibitor Alisertib (MLN8237) in Patients with Advanced Solid Tumors. Drugs R D. 2016 Mar;16(1):45-52. doi: 10.1007/s40268-015-0114-8. | |
| 26073352 |
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Participants with a diagnosis of advanced solid tumors were enrolled to receive alisertib in 1 of 4 parts: Dose Escalation, Part A (relative bioavailability), Part B (food effect and multiple-dose pharmacokinetics of alisertib oral solution [OS]), and Part C (food effect and safety of alisertib enteric-coated tablets [ECT]).
Participants took part in the study at 3 investigative sites in the United States from 25 September 2009 to 01 July 2014.
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| ID | Title | Description |
|---|---|---|
| FG000 | Dose Escalation Cohort | A single dose of alisertib 15 mg, oral solution (OS) was administered on Day 1, followed by alisertib 40 mg, powder-in-capsule (PIC), orally, twice a day (BID) on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, was administered on Cycle 2 Day 1 followed by alisertib 40 mg on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Subsequent cycles, alisertib 40 or 50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| FG001 | Part A: Relative Bioavailability OS/PIC (Sequence A) | A single dose of alisertib 25 mg, OS, administered on Day 1, followed by alisertib 40 mg PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, administered on Cycle 2 Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles, alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| FG002 | Part A: Relative Bioavailability PIC/OS (Sequence B) | A single dose of alisertib 50 mg, PIC, orally administered on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 25 mg, OS, once on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| FG003 | Part B: OS Food Effect Fed/Fasted (Sequence A) | Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose): A single dose of alisertib 35 mg oral solution (OS), in fed state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 35 mg administered, OS, in fasted state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg, PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted, based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| FG004 | Part B: OS Food Effect Fasted/Fed (Sequence B) | A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| FG005 | Part C: ECT Food Effect Fed/Fasted (Sequence A) | Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| FG006 | Part C: ECT Food Effect Fasted/Fed (Sequence B) | Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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Safety population is defined as all participants who receive any amount of alisertib. Efficacy analysis included all participants who had a baseline response assessment and at least one on-study response assessment.
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| ID | Title | Description |
|---|---|---|
| BG000 | Dose Escalation Cohort | A single dose of alisertib 15 mg, oral solution (OS) was administered on Day 1, followed by alisertib 40 mg, powder-in-capsule (PIC), orally, twice a day (BID) on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, was administered on Cycle 2 Day 1 followed by alisertib 40 mg on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Subsequent cycles, alisertib 40 or 50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Part A: Dose-normalized Cmax (Maximum Observed Concentration) for Estimation of Relative Bioavailability for Alisertib Oral Solution (OS) Versus Powder in Capsule Formulations (PIC) | Dose normalized Cmax was obtained using Cmax divided by alisertib dose in milligrams to provide values adjusted to a 1 mg alisertib dose. | Pharmacokinetic (PK)-evaluable population including all participants with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis. Data for Cycle 1 and Cycle 2 were combined for analyses. | Posted | Mean | Standard Deviation | nM/mg | Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual adverse event (AE) that was judged by the investigator to be treatment related. |
|
Up to 30 days after the last dose of study drug (up to 27.4 months approximately)
At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Dose Escalation Cohort | A single dose of alisertib 15 mg, oral solution (OS) was administered on Day 1, followed by alisertib 40 mg, powder-in-capsule (PIC), orally, twice a day (BID) on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, was administered on Cycle 2 Day 1 followed by alisertib 40 mg on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Subsequent cycles, alisertib 40 or 50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Diarrhoea | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Medical Director | Takeda | +1-877-825-3327 | trialdisclosures@takeda.com |
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| ID | Term |
|---|---|
| C550258 | MLN 8237 |
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|
| Part B: OS Food Effect Fed/Fasted (Sequence A) | Experimental | Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose): A single dose of alisertib 35 mg oral solution (OS), in fed state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 35 mg administered, OS, in fasted state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg, PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted, based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
|
| Part B: OS Food Effect Fasted/Fed (Sequence B) | Experimental | A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
|
| Part C: ECT Food Effect Fed/Fasted (Sequence A) | Experimental | Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
|
| Part C: ECT Food Effect Fasted/Fed (Sequence B) | Experimental | Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
|
|
| Part B: Cmax: Maximum Plasma Concentration for Alisertib Oral Solution Following Multiple-Dose Administration | Not performed. | Cycle 1 Day 9 predose and at multiple time points (up to 12 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
| Part B: Tmax: Time of First Occurrence of Cmax Over the Dosing Interval for Alisertib Oral Solution Following Multiple-Dose Administration | Not performed. | Cycle 1 Day 9 predose and at multiple time points (up to 12 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
| Part B: AUCÏ„: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval for Alisertib Oral Solution Following Multiple-Dose Administration | Not performed. | Cycle 1 Day 9 predose and at multiple time points (up to 12 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
| Part C: Cmax: Maximum Observed Concentration for Alisertib Administered as an Enteric-Coated Capsule (ECT) With Food Versus Without Food | Participants were randomized to receive 50-mg alisertib as an ECT (single, 50-mg strength tablets) under fasted or fed (following a standardized high-fat meal) conditions. | Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
| Part C: AUClast: Area Under the Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration for Alisertib Administered as an Enteric-Coated Capsule (ECT) With Food Versus Without Food | Cycles 1 and 2 on Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
| Part C: AUC∞: Area Under the Concentration-Time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Alisertib Administered as an Enteric-Coated Capsule (ECT) With Food Versus Without Food | Cycles 1 and 2 on Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Up to 30 days after the last dose of study drug (up to 27.4 months) |
| Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% | Laboratory AEs reported at an incidence of at least 5% overall in the following system organ classes (SOCs) are reported: blood and lymphatic system disorders, metabolism and nutrition disorders, investigations, and hepatobiliary disorders. Abnormal laboratory value were assessed as an AE if the value leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 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. | Up to 30 days after the last dose of study drug (up to 27.4 months) |
| Number of Participants With Abnormal Vital Signs Reported as Adverse Events | Vital signs (blood pressure, heart rate, and oral temperature) measurements were obtained throughout the study. | Up to 30 days after the last dose of study drug (up to 24 months approximately) |
| At the completion of Cycle 2 and every 2 cycles (every 6 weeks) until Cycle 6 (18 weeks). After Cycle 6 (18 weeks), CT/MRI scans (with contrast) were to be performed every 3 cycles (9 weeks) until PD was documented. |
| Falchook GS, Venkatakrishnan K, Sarantopoulos J, Kurzrock R, Mita AC, Fu S, Mita MM, Zhou X, Jung JA, Ullmann CD, Milch C, Rosen LS. Relative bioavailability of a prototype oral solution of the Aurora A kinase inhibitor alisertib (MLN8237) in patients with advanced solid tumors. Int J Clin Pharmacol Ther. 2015 Jul;53(7):563-72. doi: 10.5414/CP202359. |
| Adverse Event |
|
| BG001 | Part A: Relative Bioavailability OS/PIC (Sequence A) | A single dose of alisertib 25 mg, OS, administered on Day 1, followed by alisertib 40 mg PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. A single dose of alisertib 50 mg PIC, orally, administered on Cycle 2 Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles, alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| BG002 | Part A: Relative Bioavailability PIC/OS (Sequence B) | A single dose of alisertib 50 mg, PIC, orally administered on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 25 mg, OS, once on Day 1, followed by alisertib 40 mg, PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in a 23-day cycle. Subsequent cycles followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| BG003 | Part B: OS Food Effect Fed/Fasted (Sequence A) | Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose): A single dose of alisertib 35 mg oral solution (OS), in fed state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1, in a 23-day cycle. Cycle 2 Day 1 alisertib 35 mg administered, OS, in fasted state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg, PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted, based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| BG004 | Part B: OS Food Effect Fasted/Fed (Sequence B) | A single dose of alisertib 35 mg, OS, in fasted state, administered on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 2 Day 1 alisertib 30 mg, OS administered in fed state, once on Day 1, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in a 23-day cycle. Cycle 3 onwards, participants received alisertib 40 mg PIC, orally, BID on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| BG005 | Part C: ECT Food Effect Fed/Fasted (Sequence A) | Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2 in a 23-day cycle. Cycle 3 onwards, participants were administered alisertib 40 mg BID ECT on Days 1-7 with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| BG006 | Part C: ECT Food Effect Fasted/Fed (Sequence B) | Alisertib 50 mg, ECT, orally, in fasted state, once on Day 1, followed by alisertib 40 mg, ECT, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 in a 23-day cycle, followed by alisertib 50 mg, ECT, orally, in fed state, once on Day 1, followed by alisertib 40 or 50 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 2, a 23-day cycle. Cycle 3 onwards participants were administered alisertib 40 mg BID ECT on Days 1-7, with dose reduction to 30 mg BID or escalation to 50 mg BID permitted based on individual tolerance, followed by a 14-day rest period, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. |
| BG007 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Number | participants |
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| Race/Ethnicity, Customized | Number | participants |
|
| Region of Enrollment | Number | participants |
|
| Height | Number analyzed is the number of participants with available Baseline Height data. | Mean | Full Range | cm |
|
| Weight | Mean | Full Range | kg |
|
| Body Surface Area (BSA) | BSA = sqrt [height (cm) x weight (kg)/3600] | Number analyzed is the number of participants with available Baseline BSA data. | Mean | Full Range | m^2 |
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| OG001 | Part A: Alisertib PIC | Alisertib 50 mg, PIC, orally once on Day 1 in Cycle 1 or Cycle 2. |
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| Primary | Part A: Dose-normalized AUClast (Area Under the Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration) for Estimation of Relative Bioavailability for Alisertib Oral Solution (OS) Versus Powder in Capsule Formulations (PIC) | Dose normalized AUClast was obtained using Cmax divided by alisertib dose in milligrams to provide values adjusted to a 1 mg alisertib dose. | PK evaluable population including all participants with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis. Data for Cycle 1 and Cycle 2 were combined for analyses. | Posted | Mean | Standard Deviation | nM*hr/mg | Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
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| Primary | Part B: Cmax: Maximum Observed Concentration for Alisertib Administered as an Oral Solution With Food Versus Without Food | Not performed. | Data from Part B were not analyzed as planned because this part of the study was terminated after only 6 of the planned 14 PK-evaluable participants were enrolled, as the OS was not stable and gelled prior to dosing. With PK evaluability being compromised by gelling of the OS, the data were not analyzed as planned. | Posted | Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
|
|
| Primary | Part B: AUClast: Area Under the Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration for Alisertib Administered as an Oral Solution With Food Versus Without Food | Not performed. | Data from Part B were not analyzed as planned because this part of the study was terminated after only 6 of the planned 14 PK-evaluable participants were enrolled, as the OS was not stable and gelled prior to dosing. With PK evaluability being compromised by gelling of the OS, the data were not analyzed as planned. | Posted | Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
|
|
| Primary | Part B: Cmax: Maximum Plasma Concentration for Alisertib Oral Solution Following Multiple-Dose Administration | Not performed. | Data from Part B were not analyzed as planned because this part of the study was terminated after only 6 of the planned 14 PK-evaluable participants were enrolled, as the OS was not stable and gelled prior to dosing. With PK evaluability being compromised by gelling of the OS, the data were not analyzed as planned. | Posted | Cycle 1 Day 9 predose and at multiple time points (up to 12 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
|
|
| Primary | Part B: Tmax: Time of First Occurrence of Cmax Over the Dosing Interval for Alisertib Oral Solution Following Multiple-Dose Administration | Not performed. | Data from Part B were not analyzed as planned because this part of the study was terminated after only 6 of the planned 14 PK-evaluable participants were enrolled, as the OS was not stable and gelled prior to dosing. With PK evaluability being compromised by gelling of the OS, the data were not analyzed as planned. | Posted | Cycle 1 Day 9 predose and at multiple time points (up to 12 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
|
|
| Primary | Part B: AUCÏ„: Area Under the Concentration-Time Curve From Time 0 to End of Dosing Interval for Alisertib Oral Solution Following Multiple-Dose Administration | Not performed. | Data from Part B were not analyzed as planned because this part of the study was terminated after only 6 of the planned 14 PK-evaluable participants were enrolled, as the OS was not stable and gelled prior to dosing. With PK evaluability being compromised by gelling of the OS, the data were not analyzed as planned. | Posted | Cycle 1 Day 9 predose and at multiple time points (up to 12 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
|
|
| Primary | Part C: Cmax: Maximum Observed Concentration for Alisertib Administered as an Enteric-Coated Capsule (ECT) With Food Versus Without Food | Participants were randomized to receive 50-mg alisertib as an ECT (single, 50-mg strength tablets) under fasted or fed (following a standardized high-fat meal) conditions. | PK-evaluable population including all participants with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis. | Posted | Mean | Standard Deviation | nM | Cycles 1 and 2 Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
|
|
|
|
| Primary | Part C: AUClast: Area Under the Concentration-Time Curve From Time 0 to Time of the Last Quantifiable Concentration for Alisertib Administered as an Enteric-Coated Capsule (ECT) With Food Versus Without Food | The PK evaluable population including all participants with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis. | Posted | Mean | Standard Deviation | nM*h | Cycles 1 and 2 on Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
|
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| Primary | Part C: AUC∞: Area Under the Concentration-Time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Alisertib Administered as an Enteric-Coated Capsule (ECT) With Food Versus Without Food | The PK evaluable population including all participants with sufficient dosing and PK data to reliably estimate PK parameters, with data available for analysis. | Posted | Mean | Standard Error | nM*h | Cycles 1 and 2 on Day 1 predose and at multiple time points (up to 48 hours) postdose, and, if clinically feasible, at the time of a serious or unusual AE that was judged by the investigator to be treatment related. |
|
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| Primary | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | 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. | Safety population was defined as all participants who receive any amount of alisertib. | Posted | Number | participants | Up to 30 days after the last dose of study drug (up to 27.4 months) |
|
|
|
| Primary | Number of Participants With Abnormal Laboratory Values Reported as Adverse Events at an Incidence of at Least 5% | Laboratory AEs reported at an incidence of at least 5% overall in the following system organ classes (SOCs) are reported: blood and lymphatic system disorders, metabolism and nutrition disorders, investigations, and hepatobiliary disorders. Abnormal laboratory value were assessed as an AE if the value leads to discontinuation or delay in treatment, dose modification, therapeutic intervention, or is 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. | Safety Population is defined as all participants who receive any amount of alisertib. | Posted | Number | participants | Up to 30 days after the last dose of study drug (up to 27.4 months) |
|
|
|
| Primary | Number of Participants With Abnormal Vital Signs Reported as Adverse Events | Vital signs (blood pressure, heart rate, and oral temperature) measurements were obtained throughout the study. | Safety Population is defined as all participants who receive any amount of alisertib. | Posted | Number | participants | Up to 30 days after the last dose of study drug (up to 24 months approximately) |
|
|
|
| Secondary | Best Overall Response (CR+PR) Based on Investigator's Assessment According to the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | Best overall response is defined as the number of participants with Complete Response (CR) + Partial Response (PR) as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 for target lesions and assessed by CT or MRI. CR is defined as disappearance of all target lesions and PR is defined as 30% decrease in the sum of the longest diameter (LD) of target lesions. Stable Disease (SD) is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease, taking as reference the smallest sum LD since the treatment started. | Efficacy analysis included all participants who had a baseline response assessment and at least one on-study response assessment. | Posted | Number | participants | At the completion of Cycle 2 and every 2 cycles (every 6 weeks) until Cycle 6 (18 weeks). After Cycle 6 (18 weeks), CT/MRI scans (with contrast) were to be performed every 3 cycles (9 weeks) until PD was documented. |
|
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|
| 2 |
| 4 |
| 4 |
| 4 |
| EG001 | Part A: Relative Bioavailability | Alisertib 25 or 50 mg, OS, once on Day 1, in alternating dosage in Cycles 1 and 2, followed by alisertib 40 mg PIC, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycles 1 and 2, in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1 through 7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. | 4 | 19 | 19 | 19 |
| EG002 | Part B: OS Food Effect | Alisertib 35 mg (35 mg = relative bioavailability estimate in Part A as dose of OS that was calculated to yield the area under the concentration time curve of a 50-mg PIC dose), OS, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 30 mg, OS, BID on Days 3-9, followed by a 14-day rest period in Cycle 1 and 2, in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. | 2 | 6 | 6 | 6 |
| EG003 | Part C: ECT Food Effect | Alisertib 50 mg, enteric-coated tablets (ECT), orally, in fed state, once on Day 1, in alternating fed/fasted states in Cycles 1 and 2, followed by alisertib 40 mg, ECT, orally, BID on Days 3 through 9, followed by a 14-day rest period in Cycle 1 and Cycle 2 in 23-day cycles, followed by alisertib 40-50 mg (individual dosage based on tolerability in Cycles 1 and 2), PIC, orally, BID on Days 1-7, followed by a 14-day rest period in Cycle 3, in 21-day cycles until disease progression, occurrence of an unacceptable alisertib-related toxicity, or the start of another anticancer therapy. | 11 | 24 | 24 | 24 |
| Neutropenia | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Febrile neutropenia | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 17.0 | Systematic Assessment |
|
| Pain | General disorders | MedDRA 17.0 | Systematic Assessment |
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| Pyrexia | General disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hyperbilirubinaemia | Hepatobiliary disorders | MedDRA 17.0 | Systematic Assessment |
|
| Sepsis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Anuria | Renal and urinary disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hydronephrosis | Renal and urinary disorders | MedDRA 17.0 | Systematic Assessment |
|
| Renal failure acute | Renal and urinary disorders | MedDRA 17.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Respiratory arrest | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment | One treatment-emergent death occurred during treatment with alisertib and is not related. |
|
| Small intestinal obstruction | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Female genital tract fistula | Reproductive system and breast disorders | MedDRA 17.0 | Systematic Assessment |
|
| Gastroenteritis viral | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Bile duct stone | Hepatobiliary disorders | MedDRA 17.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Stomatitis | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Vomiting | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Abdominal pain | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Abdominal distension | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Dysphagia | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Abdominal pain upper | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Flatulence | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Abdominal discomfort | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Dry mouth | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Dyspepsia | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Ascites | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Colitis | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Haematochezia | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Haemorrhoids | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
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| Ileus | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Neutropenia | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Leukopenia | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
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| Anaemia | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Thrombocytopenia | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Lymphopenia | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Leukocytosis | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Alopecia | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Palmar-plantar erythrodysaesthesia syndrome | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Rash macular | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Hyperhidrosis | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Palmar erythema | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Pruritus generalised | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Rash | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Dry skin | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Night sweats | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Papule | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Rash generalised | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Skin disorder | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Skin lesion | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
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| Urticaria | Skin and subcutaneous tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Fatigue | General disorders | MedDRA 17.0 | Systematic Assessment |
|
| Asthenia | General disorders | MedDRA 17.0 | Systematic Assessment |
|
| Pyrexia | General disorders | MedDRA 17.0 | Systematic Assessment |
|
| Oedema peripheral | General disorders | MedDRA 17.0 | Systematic Assessment |
|
| Early satiety | General disorders | MedDRA 17.0 | Systematic Assessment |
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| Chest discomfort | General disorders | MedDRA 17.0 | Systematic Assessment |
|
| Mucosal inflammation | General disorders | MedDRA 17.0 | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
|
| Dehydration | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hypomagnesaemia | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hyperglycaemia | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
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| Hypokalaemia | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hypoalbuminaemia | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
|
| Gout | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hypercalcaemia | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hyperuricaemia | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hypophosphataemia | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
|
| Oral candidiasis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Sinusitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Upper respiratory tract infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Urinary tract infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Oral herpes | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Clostridium difficile infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Fungal skin infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Herpes simplex | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Skin infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Vaginal infection | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| Back pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Myalgia | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Pain in extremity | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Muscular weakness | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Musculoskeletal discomfort | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Axillary mass | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Flank pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Muscle spasms | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Musculoskeletal chest pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Pathological fracture | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Cognitive disorder | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Memory impairment | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Balance disorder | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Brain oedema | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hypoaesthesia | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Nerve compression | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Weight decreased | Investigations | MedDRA 17.0 | Systematic Assessment |
|
| White blood cell count decreased | Investigations | MedDRA 17.0 | Systematic Assessment |
|
| Aspartate aminotransferase increased | Investigations | MedDRA 17.0 | Systematic Assessment |
|
| Gamma-glutamyltransferase increased | Investigations | MedDRA 17.0 | Systematic Assessment |
|
| Neutrophil count decreased | Investigations | MedDRA 17.0 | Systematic Assessment |
|
| Alanine aminotransferase increased | Investigations | MedDRA 17.0 | Systematic Assessment |
|
| Blood urea increased | Investigations | MedDRA 17.0 | Systematic Assessment |
|
| Lymphocyte count decreased | Investigations | MedDRA 17.0 | Systematic Assessment |
|
| Blood phosphorus decreased | Investigations | MedDRA 17.0 | Systematic Assessment |
|
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Dyspnoea exertional | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Nasal congestion | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Paranasal sinus hypersecretion | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Pleural effusion | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Productive cough | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
|
| Anxiety | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
|
| Confusional state | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
|
| Delirium | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA 17.0 | Systematic Assessment |
|
| Raynaud's phenomenon | Vascular disorders | MedDRA 17.0 | Systematic Assessment |
|
| Vision blurred | Eye disorders | MedDRA 17.0 | Systematic Assessment |
|
| Diplopia | Eye disorders | MedDRA 17.0 | Systematic Assessment |
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| Eyelid pain | Eye disorders | MedDRA 17.0 | Systematic Assessment |
|
| Lacrimation increased | Eye disorders | MedDRA 17.0 | Systematic Assessment |
|
| Visual impairment | Eye disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hyperbilirubinaemia | Hepatobiliary disorders | MedDRA 17.0 | Systematic Assessment |
|
| Jaundice | Hepatobiliary disorders | MedDRA 17.0 | Systematic Assessment |
|
| Tachycardia | Cardiac disorders | MedDRA 17.0 | Systematic Assessment |
|
| Vaginal haemorrhage | Reproductive system and breast disorders | MedDRA 17.0 | Systematic Assessment |
|
| Vulvovaginal pruritus | Reproductive system and breast disorders | MedDRA 17.0 | Systematic Assessment |
|
| Fall | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
|
| Contusion | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
|
| Forearm fracture | Injury, poisoning and procedural complications | MedDRA 17.0 | Systematic Assessment |
|
| Cancer pain | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 17.0 | Systematic Assessment |
|
| Tumour flare | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | MedDRA 17.0 | Systematic Assessment |
|
| Inappropriate antidiuretic hormone secretion | Endocrine disorders | MedDRA 17.0 | Systematic Assessment |
|
| Drug hypersensitivity | Immune system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hyponatraemia | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
|
In general, Investigators may publish clinical data after the earlier of (i) publication by the Sponsor or (ii) 12 months following the abandonment, early termination or database lock; provided a copy of the publication provided to Sponsor at least 30 days ahead of publication, the Sponsor's confidential information is removed as may be requested by Sponsor and Investigator defers publication for up to 60 days in the event Sponsor provides notice that it intends to file a patent application.
| Male |
|
|
|
|
| SAE |
|
| Leukopenia |
|
| Anaemia |
|
| Thrombocytopenia |
|
| Lymphopenia |
|
| Hypomagnesaemia |
|
| Hyperglycaemia |
|
| Hypokalaemia |
|
| White blood cell count decreased |
|
| Aspartate aminotransferase increased |
|
| Gamma-glutamyltransferase increased |
|
| Lymphocyte count decreased |
|
| Neutrophil count decreased |
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| Hyperbilirubinaemia |
|
| Hypotension |
|
| Tachycardia |
|
| Sinus bradycardia |
|
| Best Overall Response of Stable Disease |
|