Advanced Malignancies
Conditions
Brief summary
This is a multicenter, dose escalation, phase 1 study of MLN8237 in adult participants with advanced malignancies (excluding those with primary bone marrow involvement, such as leukemias and multiple myeloma).
Detailed description
The drug tested in this study is called alisertib. Alisertib is being tested to treat people who have advanced malignancies. This study determined the dose-limiting toxicity, maximum tolerated dose, safety and pharmacokinetics (how the drug moves through the body) for alisertib when given once or twice a day for 7 to 21 days. This open label study enrolled 59 patients. Participants were enrolled in one of 10 dose escalation arms: * Alisertib 5 mg once daily (QD) for 7 Days (D) * Alisertib 80 mg QD 7D * Alisertib 150 mg QD 7D * Alisertib 50 mg twice daily (BID) 7D * Alisertib 60 mg BID 7D * Alisertib 75 mg BID 7D * Alisertib 100 mg BID 7D * Alisertib 50 mg QD 14D * Alisertib 50 mg QD 21D * Alisertib 70 mg QD 21D All participants received treatment until their disease progressed or they experienced unacceptable alisertib-related toxicity. This multi-center trial was conducted in Spain. The overall time to participate in this study was 730 days. Participants made multiple visits to the clinic, including a final visit 30 days after receiving their last dose of alisertib for a follow-up assessment.
Interventions
DRUGalisertib
Alisertib (MLN8237) capsules
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Have a histologically or cytologically confirmed metastatic and/or advanced malignancy (including lymphomas but excluding malignancies with extensive bone marrow involvement such as leukemias and multiple myeloma) for which standard treatment does not offer curative or life-prolonging potential. 2. Aged 18 years or more. 3. Eastern Cooperative Oncology Group performance status 0 or 1. 4. Have an expected survival longer than 3 months from enrollment in the study. 5. Radiographically or clinically evaluable tumor. 6. Suitable venous access for the conduct of blood sampling. 7. Recovered from the reversible effects of prior antineoplastic therapy (with the exception of alopecia and grade 1 neuropathy) with at least 4 weeks elapsed since the last exposure to cytotoxic chemotherapy or to radiotherapy and at least 6 weeks elapsed since exposure to nitrosoureas or mitomycin C. Participants treated with fully human monoclonal antibodies must not have received treatment with such antibodies for at least 6 weeks, and those treated with chimeric monoclonal antibodies must not have received treatment with such antibodies for at least 4 weeks. Participants treated with noncytotoxic small molecule drugs (eg, tyrosine kinase inhibitors, such as Tarceva® \[erlotinib\], and hormonal agents, such as Femara® \[letrozole\]) must not have received treatment with these drugs for at least 2 weeks before the first dose of alisertib was given. 8. Male participants must use an appropriate method of barrier contraception and inform any sexual partners that they must also use a reliable method of contraception from the time of informed consent until 3 months after the last dose of study treatment. 9. Female participants must be postmenopausal at least 1 year, OR surgically sterile, OR if of childbearing potential, agree to 2 effective methods of nonhormonal contraception, or agree to completely abstain from heterosexual intercourse. 10. Able to give written consent.
Exclusion criteria
1. Pregnant or lactating. 2. Major surgery or serious infection within the 28 days preceding the first dose of study treatment. 3. Life-threatening or uncontrolled medical illness unrelated to cancer. 4. Ongoing nausea or vomiting of any severity. 5. \>Grade 1 diarrhea. Participants who require ongoing therapy with an antimotility agent to control diarrhea to a Grade 1 or lower level are not allowed to participate in this trial. 6. Known gastrointestinal disease or gastrointestinal procedures that could interfere with the oral absorption or tolerance of MLN8237. 7. History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness such as severe chronic obstructive pulmonary disease. 8. Difficulty swallowing capsules. 9. Inability to take nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose of MLN8237. 10. Received more than 4 previous cytotoxic chemotherapeutic regimens, including regimens used as adjuvant or neo-adjuvant therapies (in participants with metastatic breast cancer, a total of 5 previous cytotoxic chemotherapeutic regimens is permitted). 11. Prior treatment with high-dose chemotherapy, defined as chemotherapy requiring the use of peripheral blood or bone marrow stem cell support for hematopoietic reconstitution. 12. Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone marrow for the distribution of active bone marrow in adults). 13. Clinical and/or radiographic evidence of cerebral metastases. However, participants who have a history of central nervous system metastasis but who have no radiographic or clinical evidence of residual tumor (eg, following complete surgical resection or stereotactic radiosurgery) are not excluded from participation in this study. 14. Absolute neutrophil count(ANC) \< 1500/mm\^3; platelet count\< 100,000/mm\^3. 15. Serum creatinine \>1.6 mg/dL or a measured or estimated (Cockcroft-Gault formula) creatinine clearance \<40 mL/min 16. Bilirubin \>1.5 times the upper limit of the normal range (ULN); aspartate aminotransferase(AST)/alanine aminotransferase(ALT) \>2.5 times the ULN, and alkaline phosphatase(ALP) \>2.5 times the ULN. Both the AST and ALP could be elevated up to 5 times the ULN if their elevation could be reasonably ascribed to the presence of metastatic disease to liver and/or to bone; however, the ALT in all circumstances must have been \<2.5 times the ULN. 17. Abnormalities on 12-lead electrocardiogram considered by the investigator to be clinically significant or baseline prolongation of the rate-corrected QT interval (eg, repeated demonstration of QTc interval \>450 milliseconds). 18. Known history of human immunodeficiency virus (HIV) infection, hepatitis B or hepatitis C. 19. Less than 4 weeks between the last dose of an investigational agent and the first dose of MLN8237. 20. Admission or evidence of benzodiazepine dependence or abuse and/or alcohol abuse or an inability to restrict consumption of alcohol to no more than 1 standard unit of alcohol per day during the study and for 30 days from the last dose of study treatment. 21. Activated partial thromboplastin time (aPTT) and/or prothrombin time (PT) exceeding the upper limit of the normal range. 22. Known bleeding diathesis or history of abnormal bleeding. 23. Ongoing therapy with an anticoagulant (e.g., aspirin, plavix, coumadin).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Alisertib | Signing of the Informed Consent through 30 days following the last dose of study drug (up to 730 days) | The MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 participants. |
| Number of Participants With Dose-Limiting Toxicity (DLT) | First dose through 30 days following the last dose of study drug (up to 730 days) | DLT was evaluated using the National Cancer Institutes Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0; defined as any of the following events related to alisertib therapy: 1. Grade 4 neutropenia lasting for ≥7 consecutive days during recovery 2. Grade 4 neutropenia with fever and/or infection 3. Confirmed platelet count \<25,000/mm\^3 4. ≥Grade 3 nausea and/or emesis despite the use of an antiemetic prophylaxis 5. ≥Grade 3 diarrhea that occurred despite therapy with loperamide 6. Any other Grade 3 or greater nonhematologic toxicity, with the following exceptions: Grade 3 arthralgia/myalgias, Any grade of alopecia, Brief (\< 1 week) Grade 3 fatigue 7. Treatment delay of \>1 week because of a failure of adequate hematologic or nonhematologic recovery from the previous cycle of treatment. 8. Other alisertib-related nonhematologic toxicities ≥ Grade 2 that, in the opinion of the investigator, required a dose reduction or discontinuation of therapy with alisertib. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7 | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7 | — |
| AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Cycle1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7 | — |
| Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7 or 8 (BID arms) | — |
| Accumulation Ratio (Rac) for Alisertib 7 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7 | Rac for Day 7=AUCt Day 7/AUCt Day 1. |
| Peak/Trough Ratio for Aliserib 7 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7 | — |
| CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7 | — |
| Cmax: Maximum Observed Concentration for Alisertib 14 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14 | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib 14 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14 | — |
| AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 14 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14 | — |
| Accumulation Ratio (Rac) for Alisertib 14 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14 | Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1. |
| Peak/Trough Ratio for Aliserib 14 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14 | — |
| CLss/F: Apparent Oral Clearance at Steady State 14 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14 | — |
| Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21 | — |
| AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21 | — |
| Terminal Half-Life (t1/2) for Alisertib 21 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 21 | — |
| Accumulation Ratio (Rac) for Alisertib 21 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21 | Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1. Rac for Day 21=AUCt Day 21/AUCt Day 1. |
| Peak/Trough Ratio for Aliserib 21 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21 | — |
| CLss/F: Apparent Oral Clearance at Steady State 21 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21 | — |
| Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Day 7, 6 and 24 hours post-dose. | Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement. |
| Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing | Cycle 1: Pre-dose (Baseline) and Day 1 and 7, 6 hours post-dose; Day 14, 6 and 24 hours post-dose | Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement. |
| Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing | Cycle 1: Pre-dose (Baseline) and Day 7, 14 and 21, 6 hours post-dose | Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement. |
| Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Cycle 1: Day 1, 6 hours post-dose; Days 7 6 and 24 hours post-dose; Day 21: 6 hours post-dose | Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement. |
| Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing | Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose | Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement. |
| Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing | Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose; Day 21: 6 hours post-dose | Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement. |
| Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Cycle 1: Pre-dose (Baseline) and Days 1 and 7, 6 hours post-dose | Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement. |
| Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 14 Day Dosing | Cycle 1: Pre-dose (Baseline) and Day 7, 6 hours post-dose | Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement. |
| Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing | Cycle 1: Pre-dose (Baseline) and Days 7 and 21, 6 hours post-dose | Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement. |
| Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21 | — |
| Terminal Half-Life (t1/2) for Alisertib 14 Day Dosing | Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14 | — |
Other
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | Cycle 1: Pre-dose | A blood sample was collected prior to alisertib dosing for the purpose of genotyping for polymorphisms in UGT1A1. The percentage of participants in the polymorphism categories: wt/wt, wt/\*28, \*28/\*28, \*28/wt, \*28/other and other/other is reported. wt=wild type. \*28 polymorphism in the promoter region of a UGT1A1 allele resulting in reduced UGT1A1 expression. |
Countries
Spain
Participant flow
Recruitment details
Participants took part in the study at 2 investigative sites in Spain from 22 October 2007 to 05 April 2011.
Pre-assignment details
Participants with a diagnosis of advanced malignancies were enrolled in a dose escalation study, alisertib 5, 80 150 mg once daily (QD) for 7 days; 50, 60, 75, 100 mg twice daily for 7 days; 50 mg QD for 14 days; 50, 70 mg QD for 21 days.
Participants by arm
| Arm | Count |
|---|---|
| Alisertib 5 mg QD 7D Alisertib 5 mg, capsules, orally, once daily (QD) for 7 days (D) followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 3 cycles). | 3 |
| Alisertib 80 mg QD 7D Alisertib 80 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 4 cycles). | 3 |
| Alisertib 150 mg QD 7D Alisertib 150 mg, capsules, orally, QD for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). | 3 |
| Alisertib 50 mg BID 7D Alisertib 50 mg, capsules, orally, twice daily (BID) for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 29 cycles). | 14 |
| Alisertib 60 mg BID 7D Alisertib 60 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 6 cycles). | 6 |
| Alisertib 75 mg BID 7D Alisertib 75 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 8 cycles). | 3 |
| Alisertib 100 mg BID 7D Alisertib 100 mg, capsules, orally, BID for 7 days followed by a 14-day recovery period in each 21-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 21 cycles). | 6 |
| Alisertib 50 mg QD 14D Alisertib 50 mg, capsules, orally, QD for 14 days followed by a 14-day recovery period in each 28-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 25 cycles). | 7 |
| Alisertib 50 mg QD 21D Alisertib 50 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 10 cycles). | 7 |
| Alisertib 70 mg QD 21D Alisertib 70 mg, capsules, orally, QD for 21 days followed by a 14-day recovery period in each 35-day cycle until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles). | 7 |
| Total | 59 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Occurrence of Adverse Event(s) | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Patient Declined Further Treatment | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 0 | 1 |
| Overall Study | Progressive Disease | 3 | 3 | 3 | 12 | 4 | 1 | 3 | 6 | 5 | 5 |
| Overall Study | Reason not Specified | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Symptomatic Deterioration | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 0 |
| Overall Study | Unsatisfactory Therapeutic Response | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Alisertib 80 mg QD 7D | Alisertib 150 mg QD 7D | Alisertib 50 mg BID 7D | Alisertib 60 mg BID 7D | Alisertib 75 mg BID 7D | Alisertib 5 mg QD 7D | Alisertib 100 mg BID 7D | Alisertib 50 mg QD 14D | Alisertib 50 mg QD 21D | Alisertib 70 mg QD 21D | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 62.3 years STANDARD_DEVIATION 13.8 | 55.7 years STANDARD_DEVIATION 20.79 | 62.5 years STANDARD_DEVIATION 11.67 | 59.2 years STANDARD_DEVIATION 18.74 | 48.3 years STANDARD_DEVIATION 14.84 | 52.7 years STANDARD_DEVIATION 9.07 | 58.7 years STANDARD_DEVIATION 8.69 | 58.0 years STANDARD_DEVIATION 13.83 | 53.0 years STANDARD_DEVIATION 11.08 | 64.7 years STANDARD_DEVIATION 5.53 | 58.8 years STANDARD_DEVIATION 12.46 |
| Body Surface Area (BSA) | 1.85 m^2 STANDARD_DEVIATION 0.191 | 1.81 m^2 STANDARD_DEVIATION 0.047 | 1.85 m^2 STANDARD_DEVIATION 0.225 | 1.70 m^2 STANDARD_DEVIATION 0.102 | 2.07 m^2 STANDARD_DEVIATION 0.098 | 1.93 m^2 STANDARD_DEVIATION 0.393 | 1.78 m^2 STANDARD_DEVIATION 0.244 | 1.87 m^2 STANDARD_DEVIATION 0.204 | 1.75 m^2 STANDARD_DEVIATION 0.231 | 1.90 m^2 STANDARD_DEVIATION 0.145 | 1.84 m^2 STANDARD_DEVIATION 0.208 |
| Height | 164.3 cm STANDARD_DEVIATION 10.79 | 167.3 cm STANDARD_DEVIATION 1.53 | 165.8 cm STANDARD_DEVIATION 9.26 | 160.5 cm STANDARD_DEVIATION 4.76 | 171.3 cm STANDARD_DEVIATION 10.26 | 164.0 cm STANDARD_DEVIATION 7.21 | 165.2 cm STANDARD_DEVIATION 10.21 | 169.9 cm STANDARD_DEVIATION 10.92 | 160.4 cm STANDARD_DEVIATION 11.57 | 167.6 cm STANDARD_DEVIATION 8.4 | 165.4 cm STANDARD_DEVIATION 9.15 |
| Race/Ethnicity, Customized Hispanic/Latino | 3 participants | 3 participants | 14 participants | 6 participants | 3 participants | 3 participants | 6 participants | 7 participants | 6 participants | 5 participants | 56 participants |
| Race/Ethnicity, Customized Not Hispanic/Latino | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized | 3 participants | 3 participants | 14 participants | 6 participants | 3 participants | 3 participants | 6 participants | 7 participants | 7 participants | 7 participants | 59 participants |
| Region of Enrollment Spain | 3 participants | 3 participants | 14 participants | 6 participants | 3 participants | 3 participants | 6 participants | 7 participants | 7 participants | 7 participants | 59 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 6 Participants | 4 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants | 3 Participants | 2 Participants | 22 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 8 Participants | 2 Participants | 3 Participants | 3 Participants | 4 Participants | 5 Participants | 4 Participants | 5 Participants | 37 Participants |
| Weight | 75.2 kg STANDARD_DEVIATION 10.56 | 70.3 kg STANDARD_DEVIATION 4.24 | 74.4 kg STANDARD_DEVIATION 16.48 | 64.8 kg STANDARD_DEVIATION 6.83 | 90.5 kg STANDARD_DEVIATION 7.74 | 83.7 kg STANDARD_DEVIATION 32.13 | 69.6 kg STANDARD_DEVIATION 16.22 | 76.7 kg STANDARD_DEVIATION 15.06 | 69.1 kg STANDARD_DEVIATION 14.78 | 77.9 kg STANDARD_DEVIATION 11.91 | 74.0 kg STANDARD_DEVIATION 14.95 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 39 | 3 / 30 | 3 / 101 | 14 / 142 | 6 / 68 | 3 / 68 | 6 / 194 | 7 / 119 | 7 / 67 | 7 / 68 |
| serious Total, serious adverse events | 1 / 3 | 1 / 3 | 1 / 3 | 6 / 14 | 3 / 6 | 1 / 3 | 5 / 6 | 1 / 7 | 3 / 7 | 4 / 7 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Alisertib
The MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 participants.
Time frame: Signing of the Informed Consent through 30 days following the last dose of study drug (up to 730 days)
Population: DLT Evaluable Population was defined as all participants who received at least 75% of their planned alisertib doses for their first cycle of treatment (unless interrupted by DLT) and had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib 5 mg QD 7D | Maximum Tolerated Dose (MTD) of Alisertib | 50 mg BID for 7 Days |
Primary
Number of Participants With Dose-Limiting Toxicity (DLT)
DLT was evaluated using the National Cancer Institutes Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0; defined as any of the following events related to alisertib therapy: 1. Grade 4 neutropenia lasting for ≥7 consecutive days during recovery 2. Grade 4 neutropenia with fever and/or infection 3. Confirmed platelet count \<25,000/mm\^3 4. ≥Grade 3 nausea and/or emesis despite the use of an antiemetic prophylaxis 5. ≥Grade 3 diarrhea that occurred despite therapy with loperamide 6. Any other Grade 3 or greater nonhematologic toxicity, with the following exceptions: Grade 3 arthralgia/myalgias, Any grade of alopecia, Brief (\< 1 week) Grade 3 fatigue 7. Treatment delay of \>1 week because of a failure of adequate hematologic or nonhematologic recovery from the previous cycle of treatment. 8. Other alisertib-related nonhematologic toxicities ≥ Grade 2 that, in the opinion of the investigator, required a dose reduction or discontinuation of therapy with alisertib.
Time frame: First dose through 30 days following the last dose of study drug (up to 730 days)
Population: DLT Evaluable Population was defined as all participants who received at least 75% of their planned alisertib doses for their first cycle of treatment (unless interrupted by DLT) and had sufficient follow-up data to allow the investigators and sponsor to determine whether DLT occurred.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib 5 mg QD 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 80 mg QD 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 150 mg QD 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 50 mg BID 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 60 mg BID 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 2 participants |
| Alisertib 75 mg BID 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 2 participants |
| Alisertib 100 mg BID 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 3 participants |
| Alisertib 50 mg QD 14D | Number of Participants With Dose-Limiting Toxicity (DLT) | 1 participants |
| Alisertib 50 mg QD 21D | Number of Participants With Dose-Limiting Toxicity (DLT) | 1 participants |
| Alisertib 70 mg QD 21D | Number of Participants With Dose-Limiting Toxicity (DLT) | 3 participants |
Secondary
Accumulation Ratio (Rac) for Alisertib 14 Day Dosing
Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1.
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Population: Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis Rac. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Accumulation Ratio (Rac) for Alisertib 14 Day Dosing | Day 7 | 1.671 ratio | Standard Deviation 0.8242 |
| Alisertib 5 mg QD 7D | Accumulation Ratio (Rac) for Alisertib 14 Day Dosing | Day 14 | 1.813 ratio | Standard Deviation 0.5001 |
Secondary
Accumulation Ratio (Rac) for Alisertib 21 Day Dosing
Rac for Day 7=AUCt Day 7/AUCt Day 1. Rac for Day 14=AUCt Day 7/AUCt Day 1. Rac for Day 21=AUCt Day 21/AUCt Day 1.
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Population: Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis Rac. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Accumulation Ratio (Rac) for Alisertib 21 Day Dosing | Day 14 | 2.482 ratio | Standard Deviation 2.7166 |
| Alisertib 5 mg QD 7D | Accumulation Ratio (Rac) for Alisertib 21 Day Dosing | Day 21 | 1.678 ratio | Standard Deviation 0.7587 |
| Alisertib 80 mg QD 7D | Accumulation Ratio (Rac) for Alisertib 21 Day Dosing | Day 14 | 2.103 ratio | Standard Deviation 0.3861 |
| Alisertib 80 mg QD 7D | Accumulation Ratio (Rac) for Alisertib 21 Day Dosing | Day 21 | 1.933 ratio | Standard Deviation 1.1104 |
Secondary
Accumulation Ratio (Rac) for Alisertib 7 Day Dosing
Rac for Day 7=AUCt Day 7/AUCt Day 1.
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
Population: Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis Rac.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg QD 7D | Accumulation Ratio (Rac) for Alisertib 7 Day Dosing | 0.874 ratio | Standard Deviation 0 |
| Alisertib 80 mg QD 7D | Accumulation Ratio (Rac) for Alisertib 7 Day Dosing | 0.892 ratio | Standard Deviation 0.1331 |
| Alisertib 150 mg QD 7D | Accumulation Ratio (Rac) for Alisertib 7 Day Dosing | 1.954 ratio | Standard Deviation 0.9092 |
| Alisertib 50 mg BID 7D | Accumulation Ratio (Rac) for Alisertib 7 Day Dosing | 2.295 ratio | Standard Deviation 0.9846 |
| Alisertib 60 mg BID 7D | Accumulation Ratio (Rac) for Alisertib 7 Day Dosing | 2.583 ratio | Standard Deviation 0.8959 |
| Alisertib 75 mg BID 7D | Accumulation Ratio (Rac) for Alisertib 7 Day Dosing | 7.765 ratio | Standard Deviation 1.9163 |
| Alisertib 100 mg BID 7D | Accumulation Ratio (Rac) for Alisertib 7 Day Dosing | 2.350 ratio | Standard Deviation 1.4926 |
Secondary
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 14 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Population: Pharmacokinetic (PK) Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 14 Day Dosing | Day 1 | 15363.0 nM*hr | Geometric Coefficient of Variation 24.82 |
| Alisertib 5 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 14 Day Dosing | Day 7 | 17918.8 nM*hr | Geometric Coefficient of Variation 78.55 |
| Alisertib 5 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 14 Day Dosing | Day 14 | 16449.8 nM*hr | Geometric Coefficient of Variation 59.87 |
Secondary
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Population: Pharmacokinetic (PK) Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing | Day 1 | 11701.0 nM*hr | Geometric Coefficient of Variation 49.78 |
| Alisertib 5 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing | Day 14 | 20262.8 nM*hr | Geometric Coefficient of Variation 71.34 |
| Alisertib 5 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing | Day 21 | 18264.9 nM*hr | Geometric Coefficient of Variation 28.67 |
| Alisertib 80 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing | Day 1 | 18953.4 nM*hr | Geometric Coefficient of Variation 56.89 |
| Alisertib 80 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing | Day 14 | 30918.3 nM*hr | Geometric Coefficient of Variation 55.68 |
| Alisertib 80 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 21 Day Dosing | Day 21 | 24515.6 nM*hr | Geometric Coefficient of Variation 23.8 |
Secondary
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing
Time frame: Cycle1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7
Population: PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 1 | 975.0 nM*hour(h) | — |
| Alisertib 5 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 7 | 658.5 nM*hour(h) | Geometric Coefficient of Variation 35.64 |
| Alisertib 80 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 1 | 18204.2 nM*hour(h) | Geometric Coefficient of Variation 36.19 |
| Alisertib 80 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 7 | 16101.6 nM*hour(h) | Geometric Coefficient of Variation 38.81 |
| Alisertib 150 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 1 | 27262.7 nM*hour(h) | Geometric Coefficient of Variation 38 |
| Alisertib 150 mg QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 7 | 48421.8 nM*hour(h) | Geometric Coefficient of Variation 36.53 |
| Alisertib 50 mg BID 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 1 | 6314.1 nM*hour(h) | Geometric Coefficient of Variation 82.32 |
| Alisertib 50 mg BID 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 7 | 17795.6 nM*hour(h) | Geometric Coefficient of Variation 43.87 |
| Alisertib 60 mg BID 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 1 | 9771.5 nM*hour(h) | Geometric Coefficient of Variation 53.77 |
| Alisertib 60 mg BID 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 7 | 25853.3 nM*hour(h) | Geometric Coefficient of Variation 41.44 |
| Alisertib 75 mg BID 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 1 | 6895.3 nM*hour(h) | Geometric Coefficient of Variation 9.21 |
| Alisertib 75 mg BID 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 7 | 51684.4 nM*hour(h) | Geometric Coefficient of Variation 24.87 |
| Alisertib 100 mg BID 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 1 | 16541.5 nM*hour(h) | Geometric Coefficient of Variation 65.99 |
| Alisertib 100 mg BID 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib 7 Day Dosing | Day 7 | 40166.7 nM*hour(h) | Geometric Coefficient of Variation 51.9 |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing
Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
Time frame: Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose
Population: Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing | Day 1, 6 hours post-dose | 0.000 cells/mm | Standard Deviation 0 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing | Day 7, 6 hours post-dose | 0.390 cells/mm | Standard Deviation 0.8721 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing | Day 14, 6 hours post-dose | 0.484 cells/mm | Standard Deviation 0.7869 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 14 Day Dosing | Day 14, 24 hours post-dose | 0.260 cells/mm | Standard Deviation 0.3834 |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing
Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
Time frame: Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Days 7 and 14, 6 and 24 hours post-dose; Day 21: 6 hours post-dose
Population: Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing | Day 7, 6 hours post-dose | 0.606 cells/mm | Standard Deviation 0.9954 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing | Day 14, 6 hours post-dose | 0.146 cells/mm | Standard Deviation 0.2355 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing | Day 21, 6 hours post-dose | 0.134 cells/mm | Standard Deviation 0.1698 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing | Day 7, 6 hours post-dose | 0.379 cells/mm | Standard Deviation 0.6276 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing | Day 14, 6 hours post-dose | 0.404 cells/mm | Standard Deviation 0.4334 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 21 Day Dosing | Day 21, 6 hours post-dose | 0.230 cells/mm | Standard Deviation 0.1283 |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing
Apoptotic index was defined as the mean number of apoptotic cells per mm length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µm skin sections stained with hematoxylin and eosin. A positive change from Baseline indicates improvement.
Time frame: Cycle 1: Day 1, 6 hours post-dose; Days 7 6 and 24 hours post-dose; Day 21: 6 hours post-dose
Population: Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 24 hour post-dose | 0.040 cells/mm | Standard Deviation 0.0693 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 6 hour post-dose | 0.040 cells/mm | Standard Deviation 0.0693 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 1, 6 hour post-dose | 0.080 cells/mm | Standard Deviation 0.0693 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 6 hour post-dose | 0.560 cells/mm | Standard Deviation 0.9699 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 1, 6 hour post-dose | 0.000 cells/mm | Standard Deviation 0 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 24 hour post-dose | 0.343 cells/mm | Standard Deviation 0.4944 |
| Alisertib 150 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 24 hour post-dose | 2.145 cells/mm | Standard Deviation 1.6476 |
| Alisertib 150 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 1, 6 hour post-dose | 0.097 cells/mm | Standard Deviation 0.085 |
| Alisertib 150 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 6 hour post-dose | 1.303 cells/mm | Standard Deviation 0.595 |
| Alisertib 50 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 6 hour post-dose | 1.525 cells/mm | Standard Deviation 2.2399 |
| Alisertib 50 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 1, 6 hour post-dose | 0.040 cells/mm | Standard Deviation 0.0634 |
| Alisertib 50 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 24 hour post-dose | 1.050 cells/mm | Standard Deviation 1.749 |
| Alisertib 60 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 6 hour post-dose | 3.173 cells/mm | Standard Deviation 4.317 |
| Alisertib 60 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 1, 6 hour post-dose | 0.000 cells/mm | Standard Deviation 0 |
| Alisertib 60 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 24 hour post-dose | 0.830 cells/mm | Standard Deviation 0 |
| Alisertib 75 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 1, 6 hour post-dose | 0.055 cells/mm | Standard Deviation 0.0778 |
| Alisertib 75 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 24 hour post-dose | 7.715 cells/mm | Standard Deviation 0.1202 |
| Alisertib 75 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 6 hour post-dose | 6.040 cells/mm | Standard Deviation 1.9928 |
| Alisertib 100 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 24 hour post-dose | 4.713 cells/mm | Standard Deviation 1.1924 |
| Alisertib 100 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 7, 6 hour post-dose | 5.162 cells/mm | Standard Deviation 2.2801 |
| Alisertib 100 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Apoptotic Index 7 Day Dosing | Day 1, 6 hour post-dose | 0.242 cells/mm | Standard Deviation 0.2566 |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing
Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time frame: Cycle 1: Pre-dose (Baseline) and Day 1 and 7, 6 hours post-dose; Day 14, 6 and 24 hours post-dose
Population: Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing | Day 1, 6 Hours Post-Dose | 1.180 cells/mm | Standard Deviation 0 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing | Day 7, 6 Hours Post-Dose | 0.950 cells/mm | Standard Deviation 0.9963 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing | Day 14, 6 Hours Post-Dose | 1.146 cells/mm | Standard Deviation 1.6239 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 14 Day Dosing | Day 7, 24 Hours Post-Dose | 0.368 cells/mm | Standard Deviation 0.4464 |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing
Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time frame: Cycle 1: Pre-dose (Baseline) and Day 7, 14 and 21, 6 hours post-dose
Population: Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing | Day 14, 6 Hours Post-Dose | 0.341 cells/mm | Standard Deviation 0.3182 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing | Day 21, 6 Hours Post-Dose | 0.250 cells/mm | Standard Deviation 1.453 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing | Day 7, 6 Hours Post-Dose | 1.534 cells/mm | Standard Deviation 1.9201 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing | Day 7, 6 Hours Post-Dose | 1.900 cells/mm | Standard Deviation 2.2774 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing | Day 14, 6 Hours Post-Dose | 1.168 cells/mm | Standard Deviation 0.7587 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 21 Day Dosing | Day 21, 6 Hours Post-Dose | 0.565 cells/mm | Standard Deviation 0.5565 |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing
Mitotic index was defined as the mean number of mitotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Mitotic cells were counted manually within the BEL of 4, 5 micrometer (µm) skin sections stained with fluorescent-tagged antibodies specific to 2 mitotic markers; histone H3 phosphorylated on serine 10 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time frame: Cycle 1: Pre-dose (Baseline) and Day 1, 6 hours post-dose; Day 7, 6 and 24 hours post-dose.
Population: Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 24 Hours Post-Dose | 0.140 cells/mm | Standard Deviation 0.1179 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 Hours Post-Dose | 0.193 cells/mm | Standard Deviation 0.165 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 Hours Post-Dose | 0.187 cells/mm | Standard Deviation 0.0709 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 Hours Post-Dose | 0.617 cells/mm | Standard Deviation 0.7514 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 Hours Post-Dose | 0.107 cells/mm | Standard Deviation 0.0777 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 24 Hours Post-Dose | 0.397 cells/mm | Standard Deviation 0.2159 |
| Alisertib 150 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 24 Hours Post-Dose | 5.270 cells/mm | Standard Deviation 3.8325 |
| Alisertib 150 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 Hours Post-Dose | 0.197 cells/mm | Standard Deviation 0.0814 |
| Alisertib 150 mg QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 Hours Post-Dose | 2.703 cells/mm | Standard Deviation 0.7112 |
| Alisertib 50 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 Hours Post-Dose | 3.489 cells/mm | Standard Deviation 2.6893 |
| Alisertib 50 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 Hours Post-Dose | 0.310 cells/mm | Standard Deviation 0.2087 |
| Alisertib 50 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 24 Hours Post-Dose | 3.184 cells/mm | Standard Deviation 4.4984 |
| Alisertib 60 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 Hours Post-Dose | 6.220 cells/mm | Standard Deviation 5.7549 |
| Alisertib 60 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 Hours Post-Dose | 0.378 cells/mm | Standard Deviation 0.4107 |
| Alisertib 60 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 24 Hours Post-Dose | 1.250 cells/mm | Standard Deviation 0 |
| Alisertib 75 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 Hours Post-Dose | 0.175 cells/mm | Standard Deviation 0.2333 |
| Alisertib 75 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 24 Hours Post-Dose | 25.190 cells/mm | Standard Deviation 1.7678 |
| Alisertib 75 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 Hours Post-Dose | 8.757 cells/mm | Standard Deviation 4.0493 |
| Alisertib 100 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 24 Hours Post-Dose | 17.123 cells/mm | Standard Deviation 9.4877 |
| Alisertib 100 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 Hours Post-Dose | 9.150 cells/mm | Standard Deviation 8.905 |
| Alisertib 100 mg BID 7D | Change From Baseline in Alisertib Skin Punch Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 Hours Post-Dose | 0.850 cells/mm | Standard Deviation 1.0741 |
Secondary
Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 14 Day Dosing
Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
Time frame: Cycle 1: Pre-dose (Baseline) and Day 7, 6 hours post-dose
Population: Pharmacodynamics Evaluable Population was defined as all participants who received at least the first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 14 Day Dosing | 0.008 percentage of cells | Standard Deviation 0 |
Secondary
Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing
Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
Time frame: Cycle 1: Pre-dose (Baseline) and Days 7 and 21, 6 hours post-dose
Population: Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing | Day 7, 6 hours post-dose | 0.027 percentage of cells | Standard Deviation 0.0171 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing | Day 21, 6 hours post-dose | 0.014 percentage of cells | Standard Deviation 0.0072 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing | Day 7, 6 hours post-dose | 0.050 percentage of cells | Standard Deviation 0.0243 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 21 Day Dosing | Day 21, 6 hours post-dose | 0.054 percentage of cells | Standard Deviation 0.0038 |
Secondary
Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing
Tumor biopsy sections were immunoflourescently labeled with proliferative marker Ki67 and mitotic marker pHistH3. DNA was stained with a fluorescent marker as well. The Mitotic index was determined from the percentage of pHistH3 immunopositive cells within the Ki67 positive area. A positive change from Baseline indicates improvement.
Time frame: Cycle 1: Pre-dose (Baseline) and Days 1 and 7, 6 hours post-dose
Population: Pharmacodynamics Evaluable Population was defined as all participants who received at least first dose of alisertib, had a baseline skin punch biopsy sample, and had at least 1 additional skin punch biopsy taken during Cycle 1 of treatment. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 hours post-dose | 0.125 percentage of cells | Standard Deviation 0.1061 |
| Alisertib 5 mg QD 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 hours post-dose | 1.145 percentage of cells | Standard Deviation 0.0354 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 hours post-dose | 0.610 percentage of cells | Standard Deviation 0 |
| Alisertib 80 mg QD 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 hours post-dose | 0.590 percentage of cells | Standard Deviation 0 |
| Alisertib 150 mg QD 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 hours post-dose | 6.460 percentage of cells | Standard Deviation 9.1075 |
| Alisertib 150 mg QD 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 hours post-dose | 15.500 percentage of cells | Standard Deviation 13.5623 |
| Alisertib 50 mg BID 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 hours post-dose | 1.464 percentage of cells | Standard Deviation 1.3294 |
| Alisertib 50 mg BID 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 hours post-dose | 2.020 percentage of cells | Standard Deviation 2.9567 |
| Alisertib 60 mg BID 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 hours post-dose | 1.080 percentage of cells | Standard Deviation 0.3394 |
| Alisertib 60 mg BID 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 hours post-dose | 3.115 percentage of cells | Standard Deviation 3.1608 |
| Alisertib 75 mg BID 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 hours post-dose | 0.090 percentage of cells | Standard Deviation 0 |
| Alisertib 75 mg BID 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 hours post-dose | 5.840 percentage of cells | Standard Deviation 0 |
| Alisertib 100 mg BID 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 1, 6 hours post-dose | 2.907 percentage of cells | Standard Deviation 2.0284 |
| Alisertib 100 mg BID 7D | Change From Baseline in Alisertib Tumor Biopsy Mitotic Index 7 Day Dosing | Day 7, 6 hours post-dose | 3.527 percentage of cells | Standard Deviation 2.1258 |
Secondary
CLss/F: Apparent Oral Clearance at Steady State 14 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Population: Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for CLss/F analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | CLss/F: Apparent Oral Clearance at Steady State 14 Day Dosing | Day 7 | 5.381 L/hr | Geometric Coefficient of Variation 92.8272 |
| Alisertib 5 mg QD 7D | CLss/F: Apparent Oral Clearance at Steady State 14 Day Dosing | Day 14 | 5.856 L/hr | Geometric Coefficient of Variation 98.2758 |
Secondary
CLss/F: Apparent Oral Clearance at Steady State 21 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Population: Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for CLss/F analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | CLss/F: Apparent Oral Clearance at Steady State 21 Day Dosing | Day 14 | 4.753 L/hr | Geometric Coefficient of Variation 70.5636 |
| Alisertib 5 mg QD 7D | CLss/F: Apparent Oral Clearance at Steady State 21 Day Dosing | Day 21 | 5.276 L/hr | Geometric Coefficient of Variation 28.1356 |
| Alisertib 80 mg QD 7D | CLss/F: Apparent Oral Clearance at Steady State 21 Day Dosing | Day 14 | 4.364 L/hr | Geometric Coefficient of Variation 47.3164 |
| Alisertib 80 mg QD 7D | CLss/F: Apparent Oral Clearance at Steady State 21 Day Dosing | Day 21 | 5.593 L/hr | Geometric Coefficient of Variation 21.8384 |
Secondary
CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
Population: Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for CLss/F analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg QD 7D | CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing | 14.055 liter(L)/hr | Geometric Coefficient of Variation 27.6995 |
| Alisertib 80 mg QD 7D | CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing | 9.604 liter(L)/hr | Geometric Coefficient of Variation 35.511 |
| Alisertib 150 mg QD 7D | CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing | 5.967 liter(L)/hr | Geometric Coefficient of Variation 31.2592 |
| Alisertib 50 mg BID 7D | CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing | 5.414 liter(L)/hr | Geometric Coefficient of Variation 57.9221 |
| Alisertib 60 mg BID 7D | CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing | 4.182 liter(L)/hr | Geometric Coefficient of Variation 51.2761 |
| Alisertib 75 mg BID 7D | CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing | 2.795 liter(L)/hr | Geometric Coefficient of Variation 23.5794 |
| Alisertib 100 mg BID 7D | CLss/F: Apparent Oral Clearance at Steady State 7 Day Dosing | 4.798 liter(L)/hr | Geometric Coefficient of Variation 49.4182 |
Secondary
Cmax: Maximum Observed Concentration for Alisertib 14 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Population: PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 14 Day Dosing | Day 1 | 1145.4 nM | Geometric Coefficient of Variation 53.09 |
| Alisertib 5 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 14 Day Dosing | Day 7 | 1418.1 nM | Geometric Coefficient of Variation 70.96 |
| Alisertib 5 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 14 Day Dosing | Day 14 | 1671.1 nM | Geometric Coefficient of Variation 51.66 |
Secondary
Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Population: PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing | Day 1 | 1112.3 nM | Geometric Coefficient of Variation 42.99 |
| Alisertib 5 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing | Day 14 | 1524.1 nM | Geometric Coefficient of Variation 64.25 |
| Alisertib 5 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing | Day 21 | 1651.7 nM | Geometric Coefficient of Variation 30.7 |
| Alisertib 80 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing | Day 14 | 2595.0 nM | Geometric Coefficient of Variation 42.98 |
| Alisertib 80 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing | Day 1 | 2220.3 nM | Geometric Coefficient of Variation 47.57 |
| Alisertib 80 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 21 Day Dosing | Day 21 | 2093.7 nM | Geometric Coefficient of Variation 11.68 |
Secondary
Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7
Population: Pharmacokinetic (PK) Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 1 | 123.15 nanomolar (nM) | Geometric Coefficient of Variation 6.554 |
| Alisertib 5 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 7 | 109.13 nanomolar (nM) | Geometric Coefficient of Variation 34.458 |
| Alisertib 80 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 1 | 1774.12 nanomolar (nM) | Geometric Coefficient of Variation 36.496 |
| Alisertib 80 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 7 | 1502.89 nanomolar (nM) | Geometric Coefficient of Variation 32.818 |
| Alisertib 150 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 1 | 2014.81 nanomolar (nM) | Geometric Coefficient of Variation 22.038 |
| Alisertib 150 mg QD 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 7 | 4136.24 nanomolar (nM) | Geometric Coefficient of Variation 26.253 |
| Alisertib 50 mg BID 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 1 | 1035.3 nanomolar (nM) | Geometric Coefficient of Variation 75.7 |
| Alisertib 50 mg BID 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 7 | 1964.4 nanomolar (nM) | Geometric Coefficient of Variation 46.26 |
| Alisertib 60 mg BID 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 1 | 1536.1 nanomolar (nM) | Geometric Coefficient of Variation 44.7 |
| Alisertib 60 mg BID 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 7 | 3412.5 nanomolar (nM) | Geometric Coefficient of Variation 27.06 |
| Alisertib 75 mg BID 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 1 | 1266.6 nanomolar (nM) | Geometric Coefficient of Variation 45.69 |
| Alisertib 75 mg BID 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 7 | 5710.4 nanomolar (nM) | Geometric Coefficient of Variation 23.89 |
| Alisertib 100 mg BID 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 1 | 3196.4 nanomolar (nM) | Geometric Coefficient of Variation 51.11 |
| Alisertib 100 mg BID 7D | Cmax: Maximum Observed Concentration for Alisertib 7 Day Dosing | Day 7 | 4694.2 nanomolar (nM) | Geometric Coefficient of Variation 38.86 |
Secondary
Peak/Trough Ratio for Aliserib 14 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Population: Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Peak/Trough Ratio for Aliserib 14 Day Dosing | Day 7 | 4.415 ratio | Standard Deviation 2.5016 |
| Alisertib 5 mg QD 7D | Peak/Trough Ratio for Aliserib 14 Day Dosing | Day 14 | 7.412 ratio | Standard Deviation 4.2472 |
Secondary
Peak/Trough Ratio for Aliserib 21 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Population: Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg QD 7D | Peak/Trough Ratio for Aliserib 21 Day Dosing | Day 14 | 4.070 ratio | Standard Deviation 2.4751 |
| Alisertib 5 mg QD 7D | Peak/Trough Ratio for Aliserib 21 Day Dosing | Day 21 | 4.792 ratio | Standard Deviation 2.5652 |
| Alisertib 80 mg QD 7D | Peak/Trough Ratio for Aliserib 21 Day Dosing | Day 14 | 3.628 ratio | Standard Deviation 0.4864 |
| Alisertib 80 mg QD 7D | Peak/Trough Ratio for Aliserib 21 Day Dosing | Day 21 | 4.658 ratio | Standard Deviation 2.1825 |
Secondary
Peak/Trough Ratio for Aliserib 7 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7
Population: Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg QD 7D | Peak/Trough Ratio for Aliserib 7 Day Dosing | 5.950 ratio | Standard Deviation 0.3253 |
| Alisertib 80 mg QD 7D | Peak/Trough Ratio for Aliserib 7 Day Dosing | 4.650 ratio | Standard Deviation 0.2163 |
| Alisertib 150 mg QD 7D | Peak/Trough Ratio for Aliserib 7 Day Dosing | 4.507 ratio | Standard Deviation 0.3029 |
| Alisertib 50 mg BID 7D | Peak/Trough Ratio for Aliserib 7 Day Dosing | 3.083 ratio | Standard Deviation 2.2296 |
| Alisertib 60 mg BID 7D | Peak/Trough Ratio for Aliserib 7 Day Dosing | 3.050 ratio | Standard Deviation 1.4056 |
| Alisertib 75 mg BID 7D | Peak/Trough Ratio for Aliserib 7 Day Dosing | 1.867 ratio | Standard Deviation 0.6009 |
| Alisertib 100 mg BID 7D | Peak/Trough Ratio for Aliserib 7 Day Dosing | 2.256 ratio | Standard Deviation 1.2013 |
Secondary
Terminal Half-Life (t1/2) for Alisertib 14 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Population: Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data for analysis of t1/2. No data was available for analysis at Day 7.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg QD 7D | Terminal Half-Life (t1/2) for Alisertib 14 Day Dosing | 26.62 hr | Standard Deviation 13.611 |
Secondary
Terminal Half-Life (t1/2) for Alisertib 21 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 21
Population: Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for t1/2 analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg QD 7D | Terminal Half-Life (t1/2) for Alisertib 21 Day Dosing | 20.13 hr | Standard Deviation 6.326 |
| Alisertib 80 mg QD 7D | Terminal Half-Life (t1/2) for Alisertib 21 Day Dosing | 26.13 hr | Standard Deviation 9.78 |
Secondary
Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 10 hours) on Day 7 or 8 (BID arms)
Population: Participants from the PK Evaluable Population, all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available for t1/2 analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 80 mg QD 7D | Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing | 18.25 hr | Standard Deviation 8.697 |
| Alisertib 150 mg QD 7D | Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing | 19.80 hr | Standard Deviation 6.129 |
| Alisertib 50 mg BID 7D | Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing | 15.913 hr | Standard Deviation 6.4766 |
| Alisertib 60 mg BID 7D | Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing | 19.475 hr | Standard Deviation 15.5019 |
| Alisertib 75 mg BID 7D | Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing | 18.500 hr | Standard Deviation 7.6295 |
| Alisertib 100 mg BID 7D | Terminal Half-Life (t1/2) for Alisertib 7 Day Dosing | 13.637 hr | Standard Deviation 6.8712 |
Secondary
Tmax: Time of First Occurrence of Cmax for Alisertib 14 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 7 and 14
Population: PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Alisertib 5 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 14 Day Dosing | Day 1 | 2.030 hr |
| Alisertib 5 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 14 Day Dosing | Day 7 | 2.000 hr |
| Alisertib 5 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 14 Day Dosing | Day 14 | 2.000 hr |
Secondary
Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Days 14 and 21
Population: PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Alisertib 5 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing | Day 1 | 4.000 hr |
| Alisertib 5 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing | Day 14 | 2.070 hr |
| Alisertib 5 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing | Day 21 | 2.100 hr |
| Alisertib 80 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing | Day 1 | 2.000 hr |
| Alisertib 80 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing | Day 14 | 2.130 hr |
| Alisertib 80 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 21 Day Dosing | Day 21 | 2.125 hr |
Secondary
Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing
Time frame: Cycle 1: Pre-dose and multiple time-points (up to 24 hour) post-dose on Day 1 and Pre-dose and multiple time-points (up to 10 hours) on Day 7
Population: PK Evaluable Population was defined as all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Alisertib 5 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 1 | 1.920 hour(hr) |
| Alisertib 5 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 7 | 1.670 hour(hr) |
| Alisertib 80 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 1 | 2.730 hour(hr) |
| Alisertib 80 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 7 | 1.580 hour(hr) |
| Alisertib 150 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 1 | 4.000 hour(hr) |
| Alisertib 150 mg QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 7 | 1.550 hour(hr) |
| Alisertib 50 mg BID 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 1 | 2.040 hour(hr) |
| Alisertib 50 mg BID 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 7 | 2.000 hour(hr) |
| Alisertib 60 mg BID 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 1 | 2.000 hour(hr) |
| Alisertib 60 mg BID 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 7 | 2.000 hour(hr) |
| Alisertib 75 mg BID 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 1 | 2.000 hour(hr) |
| Alisertib 75 mg BID 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 7 | 4.170 hour(hr) |
| Alisertib 100 mg BID 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 1 | 3.835 hour(hr) |
| Alisertib 100 mg BID 7D | Tmax: Time of First Occurrence of Cmax for Alisertib 7 Day Dosing | Day 7 | 1.580 hour(hr) |
Other Pre-specified
Percentage of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1
A blood sample was collected prior to alisertib dosing for the purpose of genotyping for polymorphisms in UGT1A1. The percentage of participants in the polymorphism categories: wt/wt, wt/\*28, \*28/\*28, \*28/wt, \*28/other and other/other is reported. wt=wild type. \*28 polymorphism in the promoter region of a UGT1A1 allele resulting in reduced UGT1A1 expression.
Time frame: Cycle 1: Pre-dose
Population: Safety population was defined as all participants who received any amount of study drug. A blood sample was not evaluable for 3 participants and was missing for 5 participants. Data is presented for one arm because the data was collected prior to the participant receiving their assigned treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib 5 mg QD 7D | Percentage of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | wt/wt | 34 percentage of participants |
| Alisertib 5 mg QD 7D | Percentage of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | wt/*28 | 44 percentage of participants |
| Alisertib 5 mg QD 7D | Percentage of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | *28/*28 | 7 percentage of participants |
| Alisertib 5 mg QD 7D | Percentage of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | *28/wt | 0 percentage of participants |
| Alisertib 5 mg QD 7D | Percentage of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | *28/other | 0 percentage of participants |
| Alisertib 5 mg QD 7D | Percentage of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | other/other | 2 percentage of participants |