Advanced Malignancies
Conditions
Keywords
Drug therapy
Brief summary
To determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of MLN8237 when given by mouth (PO) for a minimum of 7 and a maximum of 21 consecutive days, followed by a 14-day recovery period.
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 87 participants. Participants were enrolled in one of 3 treatment groups: * Powder-in-Capsule (PIC) Dose Escalation (alisertib 5, 10, 20, 40, 80, 110 or 150 mg PIC , once daily (QD) for 7 days (D),or alisertib 25 mg, PIC, orally, QD 14D, or alisertib 25, 50 or 70 mg, PIC, orally, QD 21D, or alisertib 50 or 60 mg, PIC, orally, twice daily (BID) 7D, alisertib 40 mg, PIC, orally, BID 14D * ECT Dose Escalation (alisertib 10 or 20 mg, Enteric-coated Tablets (ECT), orally, QD for 7 to 21 days * Relative Bioavailability (alisertib 40 mg ECT or PIC, orally, BID 7D in cycle 1, followed by alisertib 40 mg in the opposite formulation (PIC or ECT) orally, BID 7D in cycle 2, followed by alisertib 50 mg PIC orally, BID 7D in each additional All participants received treatment until their disease progressed or they experienced unacceptable alisertib-related toxicity. This multi-center trial was conducted in the United States. The overall time to participate in this study was 1011 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) will be supplied in capsules of 5 or 25 mg and will be given on an empty stomach, with patients remaining nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose. Each dose will be given by mouth with 8 ounces of water for 7 to 21 consecutive days. A 14-day recovery period will follow each dosing period regardless of its duration.
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
* Histologically or cytologically confirmed metastatic and/or advanced solid tumors (including lymphomas) for which no effective standard treatment is available * Aged 18 years or more * Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 * Expected survival longer than 3 months from enrollment in the study * Radiographically or clinically evaluable tumor; however, measurable disease as defined by (RECIST) criteria is not required for participation in this study * Suitable venous access for the conduct of blood sampling for MLN8237 PK * 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®, and hormonal agents, such as Femara®) must not have received treatment with these drugs for at least 2 weeks before the first dose of MLN8237 is given. * Male participants must use an appropriate method of barrier contraception (eg, condoms) and inform any sexual partners that they must also use a reliable method of contraception (eg, birth control pills) from the time of informed consent until 3 months after the last dose of study treatment. * Female participants must be postmenopausal, surgically sterilized, or willing to use reliable methods of birth control (eg, a hormonal contraceptive, an intrauterine device, diaphragm with spermicide, or abstinence) and inform male sexual partners that they must also use a reliable method of contraception (eg, condoms) from the time of informed consent until 3 months after the last dose of study treatment. * Willing and able to give written informed consent before the conduct of any study related procedure that is not part of normal medical care, and willing to comply with the protocol
Exclusion criteria
* Pregnant or lactating * Major surgery or serious infection within the 28 days preceding the first dose of study treatment * Life-threatening illness or uncontrolled medical illness unrelated to cancer * Ongoing nausea or vomiting of any severity * \> Grade 1 diarrhea * Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of MLN8237. Examples include but are not limited to partial gastrectomy, history of small intestine surgery, and celiac disease. * History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease. * Difficulty swallowing capsules * Inability to take nothing by mouth except for water and prescribed medications for 2 hours before and 1 hour after each dose of MLN8237 * Received more than 4 previous cytotoxic chemotherapeutic regimens including regimens used as adjuvant or neo-adjuvant therapies. There is no limit on the number of noncytotoxic therapies (eg, hormonal and immunologic) that participants may have received. Tyrosine kinase inhibitors (eg, Tarceva and Iressa®) are considered noncytotoxic compounds. * Prior treatment with high-dose chemotherapy, defined as chemotherapy requiring the use of peripheral blood or bone marrow stem cell support for hematopoietic reconstitution * Prior treatment with radiation therapy involving ≥25% of the hematopoietically active bone marrow * Clinical and/or radiographic evidence of cerebral metastases. However, participants who have a history of central nervous system (CNS) 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 * Absolute neutrophil count \<1500/mm\^3; platelet count \<100,000/mm\^3 * Serum creatinine \>1.6 mg/dl or a measured or estimated creatinine clearance \<40 mL/minute * 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 may be elevated up to 5 times the ULN if their elevation can be reasonably ascribed to the presence of metastatic disease to liver and/or to bone; however, the ALT must in all circumstances be \<2.5 times the ULN * Abnormalities on 12-lead electrocardiogram (ECG) 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) * Left ventricular ejection fraction (LVEF) \< 50% * Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection. Testing for these agents is not required in the absence of clinical findings or suspicion. * Less than 4 weeks between the last dose of an investigational agent and the first dose of MLN8237 * 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. A standard unit of alcohol is defined as one 12-oz (150mL) beer, 1.5 oz (45mL) of 80-proof alcohol, or one 6-oz (175mL) glass of wine. * Lactose intolerant, for the food effect cohort only.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-Limiting Toxicity (DLT) | Cycle 1 Day 1 up to Day 35 (alisertib daily for 7 to 21 days followed by a 14-day recovery period) | DLT was evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and was defined as any of the following events related to therapy with alisertib: 1. Grade 4 neutropenia lasting ≥7 consecutive days 2. Grade 4 neutropenia with fever and/or infection 3. Platelet count \<25,000/mm\^3 4. Grade 3 or greater nausea and/or emesis despite use of optimal antiemetic prophylaxis 5. Grade 3 or greater diarrhea despite maximal supportive 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 due to failure of adequate hematologic or nonhematologic recovery from 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. |
| Maximum Tolerated Dose (MTD) of Alisertib | From first dose of study drug to 30 days after the last dose (up to 1011 days) | MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 patients. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From first dose of study drug to 30 days after the last dose (up to 1011 days) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose | — |
| CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose | — |
| Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| AUCt: Area Under the Concentration--Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| Terminal Half-Life for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Cycle 1 Day 14 predose and at multiple time-points (up to 10 hours) postdose | — |
| Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose | — |
| Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose | — |
| CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose | — |
| Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose | — |
| CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose | — |
| Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose | — |
| AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose | — |
| Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Cycle 1 Day 21 predose and at multiple time points (up to 10 hours) postdose | — |
| Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Cycle 1 Days 14 and 21 predose and at multiple timepoints (up to 10 hours) postdose | — |
| Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Cycle 1 Days 14 and 21 predose and at multiple timepoints up to 10 hours postdose | — |
| CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Cycle 1 Days 14 and 21 predose and at multiple timepoints up to 10 hours postdose | — |
| Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Cycle 1 Day 1 predose and at multiple time points (up to 24 hours) postdose | — |
| CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Cycle 1 Day 1 predose and at multiple time points (up to 24 hours) postdose | — |
| Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Cycle 1 Day 8 | — |
| Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose | — |
| CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose | — |
| Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing | Cycle 1 Days 1 and 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing | Cycle 1 Days 1 and 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose | — |
| AUCt: Area Under the Concentration-time Curve From Time 0 to Time t as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7 | Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| Cmax: Maximum Observed Concentration as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7 | Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose | 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 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (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 as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose | Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement. |
| Effect of Food on the Pharmacokinetics (PK) of Alisertib | Up to 6 months | The effects of food on the PK of alisertib were to be evaluated using the preferred alisertib regimen (unit dose and formulation) based on the results from the relative bioavailability study. |
| Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 14 Days (QD14D) Dosing | Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose | 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 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (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 as Measured by Apoptotic Index With PIC Once Daily for 14 Days (QD14D) Dosing | Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose | Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement. |
| Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Days 7 and 21, 6 hours postdose | 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 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (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 as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Days 7 and 21, 6 hours postdose | Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement. |
| Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing | Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Day 7, 6 hours postdose | 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 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (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 as Measured by Apoptotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing | Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Day 7, 6 hours postdose | Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement. |
| Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 14 Days (BID14D) Dosing | Baseline and Cycle 1 Day 7, 6 hours postdose | Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement. |
| Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | Cycle 1 Day 1 predose | One peripheral blood sample (approximately 4 mL) was to be obtained on Day 1 of Cycle 1 prior to the first dose of alisertib to genotype patients for polymorphisms in UGT1A1 because UGT1A1 is one of the enzymes responsible for glucuronidation of alisertib, which is expected to contribute to the clearance of alisertib. wt=wild type \*28=polymorphism in the promoter region of a UGT1A1 allele resulting in reduced UGT1A1 expression. |
| Best Overall Response Based on Investigator Assessment | Beginning at the end of Cycle 2, every 2 cycles until progressive disease (PD); Participants who discontinue study drug before PD: Follow-Up (FU) every 8-12 weeks until PD or as per institutional practice (Up to 33.2 months) | Best overall response is defined as the percentage 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. According to RECIST: CR is defined as disappearance of all target and nontarget lesions and normalization of tumor marker level (if applicable); PR is defined as ≥30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, persistence of 1 or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits. |
| Duration Of Response (DOR) | Beginning at the end of Cycle 2, every 2 cycles until progressive disease (PD); Participants who discontinue study drug before PD: Follow-Up (FU) every 8-12 weeks until PD or as per institutional practice (Up to 33.2 months) | DOR is defined as the time from the date of first documentation of a confirmed response to the date of first documented PD. PD is defined as 20% increase in the sum of the longest diameter of target lesions. |
| Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 14 Days (BID14D) Dosing | Baseline and Cycle 1 Day 7, 6 hours postdose | 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 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement. |
| Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
| AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose | — |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 3 investigative sites in the United States from 15 May 2007 to 23 February 2011.
Pre-assignment details
Participants with a diagnosis of advanced malignancies were enrolled in 1 of 3 treatment groups, alisertib 5 to 150 mg Powder-in-Capsule (PIC) dose escalation cohort, alisertib 10 or 20 mg Enteric-coated Tablet (ECT) dose escalation cohort, or alisertib 40 mg PIC/ECT in a crossover design followed by alisertib 50 mg relative bioavailability cohort.
Participants by arm
| Arm | Count |
|---|---|
| PIC Dose Escalation Alisertib 5, 10, 20, 40, 80, 110 or 150 mg, PIC, orally, once daily (QD) for 7 days, followed by a 14-day recovery period or alisertib 25 mg, PIC, orally, QD for 14 days, followed by a 14-day recovery period or alisertib 25, 50 or 70 mg, PIC, orally, QD for 21 days followed by a 14-day recovery period or alisertib 50 or 60 mg, PIC, orally, twice daily (BID) for 7 days followed by a 14-day recovery period or alisertib 40 mg, PIC, orally, BID for 14 days followed by a 14-day recovery period in each cycle until disease progression or unacceptable alisertib-related toxicity (up to 51 cycles). | 65 |
| ECT Dose Escalation Alisertib 10 or 20 mg, Enteric-coated Tablet (ECT) formulation, orally, once daily (QD) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 2 cycles). | 2 |
| Relative Bioavailability Alisertib 40 mg ECT or PIC formulation, orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 1, followed by alisertib 40 mg in the opposite formulation (PIC or ECT) orally, twice daily (BID) for 7 days followed by a 14--day recovery period in cycle 2, followed by alisertib 50 mg PIC formulation orally, twice daily (BID) for 7 days followed by a 14--day recovery period in each cycle until disease progression or unacceptable alisertib--related toxicity (up to 9 cycles). | 20 |
| Total | 87 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Occurrence of Adverse Event(s) | 10 | 0 | 0 |
| Overall Study | Patient Declined Further Treatment | 0 | 0 | 3 |
| Overall Study | Progressive Disease | 41 | 2 | 15 |
| Overall Study | Reason Not Specified | 10 | 0 | 2 |
| Overall Study | Symptomatic Deterioration | 2 | 0 | 0 |
| Overall Study | Unsatisfactory Therapeutic Response | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | PIC Dose Escalation | ECT Dose Escalation | Relative Bioavailability | Total |
|---|---|---|---|---|
| Age, Continuous | 61.6 years STANDARD_DEVIATION 10.44 | 57.0 years STANDARD_DEVIATION 15.56 | 56.9 years STANDARD_DEVIATION 11.71 | 60.4 years STANDARD_DEVIATION 10.88 |
| Body Surface Area (BSA) | 1.91 m^2 STANDARD_DEVIATION 0.263 | 1.75 m^2 STANDARD_DEVIATION 0.147 | 1.99 m^2 STANDARD_DEVIATION 0.294 | 1.92 m^2 STANDARD_DEVIATION 0.27 |
| Height | 169.3 cm STANDARD_DEVIATION 10.06 | 165.1 cm STANDARD_DEVIATION 0 | 171.5 cm STANDARD_DEVIATION 12.51 | 169.7 cm STANDARD_DEVIATION 10.55 |
| Race/Ethnicity, Customized Black or African American | 9 participants | 0 participants | 2 participants | 11 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 participants | 0 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 56 participants | 2 participants | 20 participants | 78 participants |
| Race/Ethnicity, Customized Not Reported | 7 participants | 0 participants | 0 participants | 7 participants |
| Race/Ethnicity, Customized Other | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 55 participants | 2 participants | 18 participants | 75 participants |
| Region of Enrollment United States | 65 participants | 2 participants | 20 participants | 87 participants |
| Sex: Female, Male Female | 33 Participants | 1 Participants | 9 Participants | 43 Participants |
| Sex: Female, Male Male | 32 Participants | 1 Participants | 11 Participants | 44 Participants |
| Weight | 78.24 kg STANDARD_DEVIATION 18.13 | 67.36 kg STANDARD_DEVIATION 11.226 | 83.97 kg STANDARD_DEVIATION 21.706 | 79.33 kg STANDARD_DEVIATION 18.976 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 65 / 65 | 2 / 2 | 20 / 20 |
| serious Total, serious adverse events | 26 / 65 | 0 / 2 | 1 / 20 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Alisertib
MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 patients.
Time frame: From first dose of study drug to 30 days after the last dose (up to 1011 days)
Population: DLT-Evaluable Population included 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 PIC QD 7D | Maximum Tolerated Dose (MTD) of Alisertib | 50 mg BID for 7 Days |
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.
Time frame: From first dose of study drug to 30 days after the last dose (up to 1011 days)
Population: Safety Population included all participants who received any amount of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 65 participants |
| Alisertib 5 mg PIC QD 7D | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 26 participants |
| Alisertib 10 mg PIC QD 7D | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 2 participants |
| Alisertib 10 mg PIC QD 7D | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 0 participants |
| Alisertib 20 mg PIC QD 7D | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 20 participants |
| Alisertib 20 mg PIC QD 7D | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 participants |
Primary
Number of Participants With Dose-Limiting Toxicity (DLT)
DLT was evaluated according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and was defined as any of the following events related to therapy with alisertib: 1. Grade 4 neutropenia lasting ≥7 consecutive days 2. Grade 4 neutropenia with fever and/or infection 3. Platelet count \<25,000/mm\^3 4. Grade 3 or greater nausea and/or emesis despite use of optimal antiemetic prophylaxis 5. Grade 3 or greater diarrhea despite maximal supportive 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 due to failure of adequate hematologic or nonhematologic recovery from 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: Cycle 1 Day 1 up to Day 35 (alisertib daily for 7 to 21 days followed by a 14-day recovery period)
Population: DLT-Evaluable Population included 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 PIC QD 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 10 mg PIC QD 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 20 mg PIC QD 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 40 mg PIC QD 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 80 mg PIC QD 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 110 mg PIC QD 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 1 participants |
| Alisertib 150 mg PIC QD 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 3 participants |
| Alisertib 25 mg PIC QD 14D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 25 mg PIC QD 21D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 50 mg PIC QD 21D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 70 mg PIC QD 21D | Number of Participants With Dose-Limiting Toxicity (DLT) | 1 participants |
| Alisertib 50 mg PIC BID 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 2 participants |
| Alisertib 60 mg PIC BID 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 2 participants |
| Alisertib 40 mg PIC BID 14D | Number of Participants With Dose-Limiting Toxicity (DLT) | 2 participants |
| Alisertib 10 mg ECT QD7 | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 20 mg ECT QD7 | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
Secondary
Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time frame: Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 7 | 1.203 ratio | Standard Deviation 0.6964 |
| Alisertib 5 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 14 | 1.133 ratio | Standard Deviation 0.2303 |
Secondary
Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time frame: Cycle 1 Days 14 and 21 predose and at multiple timepoints (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 1.560 ratio | Standard Deviation 0.5543 |
| Alisertib 5 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 1.560 ratio | Standard Deviation 1.0516 |
| Alisertib 10 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 1.230 ratio | Standard Deviation 0.4193 |
| Alisertib 10 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 1.373 ratio | Standard Deviation 0.4474 |
| Alisertib 20 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 1.440 ratio | Standard Deviation 0.1493 |
| Alisertib 20 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 1.335 ratio | Standard Deviation 0.4749 |
Secondary
Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 1.753 ratio | Standard Deviation 0.2754 |
| Alisertib 10 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 6.350 ratio | Standard Deviation 7.2408 |
| Alisertib 20 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 2.037 ratio | Standard Deviation 0.9708 |
| Alisertib 40 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 1.997 ratio | Standard Deviation 0.9393 |
| Alisertib 80 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 1.535 ratio | Standard Deviation 0.3323 |
| Alisertib 110 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 1.677 ratio | Standard Deviation 0.6788 |
| Alisertib 150 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 1.588 ratio | Standard Deviation 0.4129 |
Secondary
Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | 2.474 ratio | Standard Deviation 1.0467 |
| Alisertib 10 mg PIC QD 7D | Accumulation Ratio (Rac) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | 2.543 ratio | Standard Deviation 0.195 |
Secondary
Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | 800.0 ng | Standard Deviation 1385.64 |
Secondary
Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time points (up to 24 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | 3047.7 ng | Standard Deviation 5278.71 |
| Alisertib 10 mg PIC QD 7D | Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | 5766.7 ng | Standard Deviation 7971.95 |
| Alisertib 20 mg PIC QD 7D | Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | 9391.4 ng | Standard Deviation 11410.18 |
Secondary
Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 0.0 ng | Standard Deviation 0 |
| Alisertib 10 mg PIC QD 7D | Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 0.0 ng | Standard Deviation 0 |
| Alisertib 20 mg PIC QD 7D | Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 0.0 ng | Standard Deviation 0 |
| Alisertib 40 mg PIC QD 7D | Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 4806.7 ng | Standard Deviation 8325.39 |
| Alisertib 80 mg PIC QD 7D | Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 18815.0 ng | Standard Deviation 1675.84 |
| Alisertib 110 mg PIC QD 7D | Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 13813.3 ng | Standard Deviation 16387.22 |
| Alisertib 150 mg PIC QD 7D | Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 14473.3 ng | Standard Deviation 15603.71 |
Secondary
Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | 13775.0 ng | Standard Deviation 7937.14 |
| Alisertib 10 mg PIC QD 7D | Ae: Amount of Alisertib Excreted in Urine Over the Collection Period for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | 8498.3 ng | Standard Deviation 6866.09 |
Secondary
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7
Time frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7 | 12700.0 nM*h | Standard Deviation 6557.58 |
| Alisertib 10 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7 | 14190.7 nM*h | Standard Deviation 7097.72 |
Secondary
AUCt: Area Under the Concentration--Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | AUCt: Area Under the Concentration--Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 1 | 8061.6 nM*h | Geometric Coefficient of Variation 17.3 |
| Alisertib 5 mg PIC QD 7D | AUCt: Area Under the Concentration--Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 7 | 8634.0 nM*h | Geometric Coefficient of Variation 42.7 |
| Alisertib 5 mg PIC QD 7D | AUCt: Area Under the Concentration--Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 14 | 8978.0 nM*h | Geometric Coefficient of Variation 20.15 |
Secondary
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 13199.3 nM*h | Geometric Coefficient of Variation 70.05 |
| Alisertib 5 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 1 | 10058.0 nM*h | Geometric Coefficient of Variation 66.85 |
| Alisertib 5 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 15131.7 nM*h | Geometric Coefficient of Variation 49.89 |
| Alisertib 10 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 19336.3 nM*h | Geometric Coefficient of Variation 26.85 |
| Alisertib 10 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 17168.2 nM*h | Geometric Coefficient of Variation 32.09 |
| Alisertib 10 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 1 | 14686.6 nM*h | Geometric Coefficient of Variation 44.04 |
| Alisertib 20 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 23499.8 nM*h | Geometric Coefficient of Variation 65.64 |
| Alisertib 20 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 23197.2 nM*h | Geometric Coefficient of Variation 17.75 |
| Alisertib 20 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 1 | 22114.8 nM*h | Geometric Coefficient of Variation 68.66 |
Secondary
AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 1682.4 nM*h | Geometric Coefficient of Variation 31.06 |
| Alisertib 5 mg PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 2919.5 nM*h | Geometric Coefficient of Variation 32.31 |
| Alisertib 10 mg PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 2525.8 nM*h | Geometric Coefficient of Variation 21.87 |
| Alisertib 10 mg PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 10602.9 nM*h | Geometric Coefficient of Variation 107.87 |
| Alisertib 20 mg PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 5772.1 nM*h | Geometric Coefficient of Variation 10.68 |
| Alisertib 20 mg PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 10927.5 nM*h | Geometric Coefficient of Variation 45.27 |
| Alisertib 40 mg PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 12045.4 nM*h | Geometric Coefficient of Variation 57.01 |
| Alisertib 40 mg PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 21976.0 nM*h | Geometric Coefficient of Variation 96.64 |
| Alisertib 80 mg PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 20958.1 nM*h | Geometric Coefficient of Variation 38.92 |
| Alisertib 80 mg PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 27825.5 nM*h | Geometric Coefficient of Variation 53.59 |
| Alisertib 110 mg PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 29460.7 nM*h | Geometric Coefficient of Variation 39.43 |
| Alisertib 110 mg PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 46271.1 nM*h | Geometric Coefficient of Variation 33.38 |
| Alisertib 150 mg PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 38582.1 nM*h | Geometric Coefficient of Variation 45.95 |
| Alisertib 150 mg PIC QD 7D | AUCt: Area Under the Concentration-Time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 53031.9 nM*h | Geometric Coefficient of Variation 26.22 |
Secondary
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing | 9684.8 nM*h | Geometric Coefficient of Variation 71.5 |
Secondary
AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Day 1 | 11166.3 nM*h | Geometric Coefficient of Variation 37.45 |
| Alisertib 5 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Day 7 | 32291.5 nM*h | Geometric Coefficient of Variation 40.82 |
| Alisertib 10 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Day 1 | 13200.4 nM*h | Geometric Coefficient of Variation 26.7 |
| Alisertib 10 mg PIC QD 7D | AUCt: Area Under the Concentration-time Curve From Time 0 to Time t for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Day 7 | 27386.1 nM*h | Geometric Coefficient of Variation 37.43 |
Secondary
Best Overall Response Based on Investigator Assessment
Best overall response is defined as the percentage 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. According to RECIST: CR is defined as disappearance of all target and nontarget lesions and normalization of tumor marker level (if applicable); PR is defined as ≥30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, persistence of 1 or more nontarget lesion(s) and/or maintenance of tumor marker level above the normal limits.
Time frame: Beginning at the end of Cycle 2, every 2 cycles until progressive disease (PD); Participants who discontinue study drug before PD: Follow-Up (FU) every 8-12 weeks until PD or as per institutional practice (Up to 33.2 months)
Population: Safety Population included all participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib 5 mg PIC QD 7D | Best Overall Response Based on Investigator Assessment | 1 percentage of participants |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 14 Days (QD14D) Dosing
Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.
Time frame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 14 Days (QD14D) Dosing | Day 1, Hour 6 | 0.000 apoptotic cells/millimeter of BEL | Standard Deviation 0 |
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 14 Days (QD14D) Dosing | Day 1, Hour 24 | 0.000 apoptotic cells/millimeter of BEL | Standard Deviation 0 |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing
Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.
Time frame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Days 7 and 21, 6 hours postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 1, Hour 6 | 0.122 apoptotic cells/millimeter of BEL | Standard Deviation 0.2117 |
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 1, Hour 24 | 0.042 apoptotic cells/millimeter of BEL | Standard Deviation 0.0722 |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 21, Hour 6 | 0.099 apoptotic cells/millimeter of BEL | — |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 1, Hour 6 | 0.000 apoptotic cells/millimeter of BEL | Standard Deviation 0 |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 1, Hour 24 | 0.042 apoptotic cells/millimeter of BEL | Standard Deviation 0.0719 |
| Alisertib 20 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 21, Hour 6 | 0.032 apoptotic cells/millimeter of BEL | Standard Deviation 0.0552 |
| Alisertib 20 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 1, Hour 24 | 0.000 apoptotic cells/millimeter of BEL | Standard Deviation 0 |
| Alisertib 20 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 7, Hour 6 | 0.000 apoptotic cells/millimeter of BEL | Standard Deviation 0 |
| Alisertib 20 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 1, Hour 6 | 0.000 apoptotic cells/millimeter of BEL | — |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing
Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.
Time frame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | 0.010 apoptotic cells/millimeter of BEL | Standard Deviation 0.1175 |
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | 0.009 apoptotic cells/millimeter of BEL | Standard Deviation 0.1164 |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | -0.090 apoptotic cells/millimeter of BEL | Standard Deviation 0.1278 |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | 0.065 apoptotic cells/millimeter of BEL | Standard Deviation 0.1404 |
| Alisertib 20 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | 0.042 apoptotic cells/millimeter of BEL | Standard Deviation 0.0731 |
| Alisertib 20 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | 0.000 apoptotic cells/millimeter of BEL | Standard Deviation 0 |
| Alisertib 40 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | 0.040 apoptotic cells/millimeter of BEL | Standard Deviation 0.0701 |
| Alisertib 40 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | 0.037 apoptotic cells/millimeter of BEL | Standard Deviation 0.0634 |
| Alisertib 80 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | 0.121 apoptotic cells/millimeter of BEL | Standard Deviation 0.1317 |
| Alisertib 80 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | 0.074 apoptotic cells/millimeter of BEL | Standard Deviation 0.1286 |
| Alisertib 110 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | 0.036 apoptotic cells/millimeter of BEL | Standard Deviation 0.053 |
| Alisertib 110 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | 0.151 apoptotic cells/millimeter of BEL | Standard Deviation 0.1721 |
| Alisertib 150 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | -0.042 apoptotic cells/millimeter of BEL | Standard Deviation 0.1262 |
| Alisertib 150 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | 0.139 apoptotic cells/millimeter of BEL | Standard Deviation 0.2069 |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 14 Days (BID14D) Dosing
Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.
Time frame: Baseline and Cycle 1 Day 7, 6 hours postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 14 Days (BID14D) Dosing | 2.837 apoptotic cells/millimeter of BEL |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing
Apoptotic index was defined as the mean number of apoptotic cells per millimeter (mm) length of the basoepithelial layer (BEL). Apoptotic cells were counted manually within the BEL of 4, 5 µM skin sections by staining with hematoxylin-eosin. A positive change from Baseline indicates improvement.
Time frame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Day 7, 6 hours postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing | Day 1, Hour 6 | -0.016 apoptotic cells/millimeter of BEL | Standard Deviation 0.0494 |
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing | Day 1, Hour 24 | 0.055 apoptotic cells/millimeter of BEL | Standard Deviation 0.1691 |
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing | Day 7, Hour 6 | 2.142 apoptotic cells/millimeter of BEL | Standard Deviation 3.251 |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing | Day 1, Hour 6 | 0.020 apoptotic cells/millimeter of BEL | Standard Deviation 0.0491 |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Apoptotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing | Day 1, Hour 24 | 0.080 apoptotic cells/millimeter of BEL | Standard Deviation 0.1958 |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 14 Days (QD14D) 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 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time frame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 14 Days (QD14D) Dosing | Day 1, Hour 6 | 0.134 mitotic cells/millimeter of BEL | Standard Deviation 0.1723 |
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 14 Days (QD14D) Dosing | Day 1, Hour 24 | 0.047 mitotic cells/millimeter of BEL | Standard Deviation 0.0589 |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) 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 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time frame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Days 7 and 21, 6 hours postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 1, Hour 6 | 0.380 mitotic cells/millimeter of BEL | Standard Deviation 0.4165 |
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 1, Hour 24 | 0.021 mitotic cells/millimeter of BEL | Standard Deviation 0.1081 |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 1, Hour 24 | 0.082 mitotic cells/millimeter of BEL | Standard Deviation 0.1796 |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 1, Hour 6 | 0.405 mitotic cells/millimeter of BEL | Standard Deviation 0.469 |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 21, Hour 6 | 0.045 mitotic cells/millimeter of BEL | — |
| Alisertib 20 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 1, Hour 24 | 0.289 mitotic cells/millimeter of BEL | Standard Deviation 0.5746 |
| Alisertib 20 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 7, Hour 6 | 0.479 mitotic cells/millimeter of BEL | Standard Deviation 0.304 |
| Alisertib 20 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 21, Hour 6 | 0.742 mitotic cells/millimeter of BEL | Standard Deviation 0.5782 |
| Alisertib 20 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 21 Days (QD21D) Dosing | Day 1, Hour 6 | 0.510 mitotic cells/millimeter of BEL | — |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) 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 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time frame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | 0.405 mitotic cells/millimeter of BEL | Standard Deviation 0.2701 |
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | 0.019 mitotic cells/millimeter of BEL | Standard Deviation 0.1914 |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | -0.103 mitotic cells/millimeter of BEL | Standard Deviation 0.0186 |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | 0.614 mitotic cells/millimeter of BEL | Standard Deviation 0.5437 |
| Alisertib 20 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | 0.005 mitotic cells/millimeter of BEL | Standard Deviation 0.0709 |
| Alisertib 20 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | 0.263 mitotic cells/millimeter of BEL | Standard Deviation 0.1461 |
| Alisertib 40 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | 0.168 mitotic cells/millimeter of BEL | Standard Deviation 0.5146 |
| Alisertib 40 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | 0.141 mitotic cells/millimeter of BEL | Standard Deviation 0.3852 |
| Alisertib 80 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | 0.488 mitotic cells/millimeter of BEL | Standard Deviation 1.0215 |
| Alisertib 80 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | 0.108 mitotic cells/millimeter of BEL | Standard Deviation 0.4081 |
| Alisertib 110 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | 0.261 mitotic cells/millimeter of BEL | Standard Deviation 0.4597 |
| Alisertib 110 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | 1.764 mitotic cells/millimeter of BEL | Standard Deviation 2.638 |
| Alisertib 150 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 24 | 0.239 mitotic cells/millimeter of BEL | Standard Deviation 0.6992 |
| Alisertib 150 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Once Daily for 7 Days (QD7D) Dosing | Day 1, Hour 6 | 0.865 mitotic cells/millimeter of BEL | Standard Deviation 0.942 |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 14 Days (BID14D) 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 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time frame: Baseline and Cycle 1 Day 7, 6 hours postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 14 Days (BID14D) Dosing | 1.507 mitotic cells/millimeter of BEL |
Secondary
Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 7 Days (BID7D) 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 µM skin sections by staining with fluorescent-tagged antibodies specific to 2 mitotic markers-serine 10 phosphohistone H3 (pHistH3) and MPM2. Deoxyribonucleic acid (DNA) was stained with a fluorescent marker as well. A positive change from Baseline indicates improvement.
Time frame: Baseline and Cycle 1 Day 1, 6 hours and 24 hours postdose and Day 7, 6 hours postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing | Day 1, Hour 6 | 0.054 mitotic cells/millimeter of BEL | Standard Deviation 0.3022 |
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing | Day 1, Hour 24 | 2.578 mitotic cells/millimeter of BEL | Standard Deviation 2.2875 |
| Alisertib 5 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing | Day 7, Hour 6 | 5.486 mitotic cells/millimeter of BEL | Standard Deviation 5.8688 |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing | Day 1, Hour 6 | 0.364 mitotic cells/millimeter of BEL | Standard Deviation 0.2574 |
| Alisertib 10 mg PIC QD 7D | Change From Baseline in Alisertib Skin Punch Biopsy as Measured by Mitotic Index With PIC Twice Daily for 7 Days (BID7D) Dosing | Day 1, Hour 24 | 1.435 mitotic cells/millimeter of BEL | Standard Deviation 0.8329 |
Secondary
CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alisertib 5 mg PIC QD 7D | CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | 0.0004930 L/h |
Secondary
CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time points (up to 24 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | 0.0008640 L/h | — |
| Alisertib 10 mg PIC QD 7D | CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | 0.0012323 L/h | Standard Deviation 0.0011184 |
| Alisertib 20 mg PIC QD 7D | CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | 0.0007865 L/h | Standard Deviation 0.00042447 |
Secondary
CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 0.0012630 L/h | — |
| Alisertib 10 mg PIC QD 7D | CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 0.0013860 L/h | — |
| Alisertib 20 mg PIC QD 7D | CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 0.0009414 L/h | Standard Deviation 0.00063956 |
| Alisertib 40 mg PIC QD 7D | CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 0.0006710 L/h | Standard Deviation 0.00060091 |
Secondary
CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | 0.001 ng | Standard Deviation 0.0011 |
| Alisertib 10 mg PIC QD 7D | CLr: Renal Clearance of Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | 0.001 ng | Standard Deviation 0.0004 |
Secondary
CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time frame: Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 7 | 6.030 L/h | Standard Deviation 2.9963 |
| Alisertib 5 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 14 | 5.433 L/h | Standard Deviation 0.9808 |
Secondary
CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time frame: Cycle 1 Days 14 and 21 predose and at multiple timepoints up to 10 hours postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 3.181 L/h | Geometric Coefficient of Variation 42.5706 |
| Alisertib 5 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 3.656 L/h | Geometric Coefficient of Variation 89.575 |
| Alisertib 10 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 5.612 L/h | Geometric Coefficient of Variation 28.6881 |
| Alisertib 10 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 4.984 L/h | Geometric Coefficient of Variation 25.6945 |
| Alisertib 20 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 5.825 L/h | Geometric Coefficient of Variation 17.7291 |
| Alisertib 20 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 5.745 L/h | Geometric Coefficient of Variation 42.3818 |
Secondary
CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given timepoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 3.302 liters (L)/h | Geometric Coefficient of Variation 35.8915 |
| Alisertib 10 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 1.817 liters (L)/h | Geometric Coefficient of Variation 107.8347 |
| Alisertib 20 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 3.525 liters (L)/h | Geometric Coefficient of Variation 49.1267 |
| Alisertib 40 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 3.511 liters (L)/h | Geometric Coefficient of Variation 72.1346 |
| Alisertib 80 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 5.545 liters (L)/h | Geometric Coefficient of Variation 41.0258 |
| Alisertib 110 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 4.348 liters (L)/h | Geometric Coefficient of Variation 61.5266 |
| Alisertib 150 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 5.450 liters (L)/h | Geometric Coefficient of Variation 37.3021 |
Secondary
CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | 2.984 L/h | Geometric Coefficient of Variation 43.8719 |
| Alisertib 10 mg PIC QD 7D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | 4.220 L/h | Geometric Coefficient of Variation 47.9681 |
Secondary
Cmax: Maximum Observed Concentration as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7
Time frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Cmax: Maximum Observed Concentration as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7 | 1666.1 nM | Standard Deviation 765.28 |
| Alisertib 10 mg PIC QD 7D | Cmax: Maximum Observed Concentration as Assessment of Relative Bioavailability for Alisertib as Enteric-coated Tablet (ECT) Versus PIC at Day 7 | 2027.9 nM | Standard Deviation 928.96 |
Secondary
Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 1 | 778.7 nM | Geometric Coefficient of Variation 24.28 |
| Alisertib 5 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 7 | 995.5 nM | Geometric Coefficient of Variation 43.21 |
| Alisertib 5 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 14 | 808.9 nM | Geometric Coefficient of Variation 37.96 |
Secondary
Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 1343.3 nM | Geometric Coefficient of Variation 60.32 |
| Alisertib 5 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 1 | 898.2 nM | Geometric Coefficient of Variation 86.35 |
| Alisertib 5 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 1104.7 nM | Geometric Coefficient of Variation 45.15 |
| Alisertib 10 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 1722.0 nM | Geometric Coefficient of Variation 38.82 |
| Alisertib 10 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 1 | 1725.9 nM | Geometric Coefficient of Variation 54.7 |
| Alisertib 10 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 1564.2 nM | Geometric Coefficient of Variation 38.8 |
| Alisertib 20 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 1 | 2237.0 nM | Geometric Coefficient of Variation 54.18 |
| Alisertib 20 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 1974.5 nM | Geometric Coefficient of Variation 59.49 |
| Alisertib 20 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 2598.3 nM | Geometric Coefficient of Variation 12.49 |
Secondary
Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 208.4 nM | Geometric Coefficient of Variation 27.96 |
| Alisertib 5 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 285.7 nM | Geometric Coefficient of Variation 32.74 |
| Alisertib 10 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 279.1 nM | Geometric Coefficient of Variation 46.2 |
| Alisertib 10 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 931.5 nM | Geometric Coefficient of Variation 81.68 |
| Alisertib 20 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 759.3 nM | Geometric Coefficient of Variation 11.82 |
| Alisertib 20 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 1114.1 nM | Geometric Coefficient of Variation 36.96 |
| Alisertib 40 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 1245.4 nM | Geometric Coefficient of Variation 20.6 |
| Alisertib 40 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 1681.6 nM | Geometric Coefficient of Variation 64.62 |
| Alisertib 80 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 1661.3 nM | Geometric Coefficient of Variation 45.2 |
| Alisertib 80 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 2376.3 nM | Geometric Coefficient of Variation 51.06 |
| Alisertib 110 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 2717.8 nM | Geometric Coefficient of Variation 44.62 |
| Alisertib 110 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 3586.4 nM | Geometric Coefficient of Variation 48.28 |
| Alisertib 150 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 4260.3 nM | Geometric Coefficient of Variation 42.62 |
| Alisertib 150 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 4467.8 nM | Geometric Coefficient of Variation 24.58 |
Secondary
Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing
Time frame: Cycle 1 Days 1 and 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing | Day 1 | 1236.6 nM | Geometric Coefficient of Variation 37.29 |
| Alisertib 5 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing | Day 7 | 2060.0 nM | — |
Secondary
Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Day 1 | 1581.1 nM | Geometric Coefficient of Variation 37.34 |
| Alisertib 5 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Day 7 | 3376.4 nM | Geometric Coefficient of Variation 41.74 |
| Alisertib 10 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Day 1 | 1867.1 nM | Geometric Coefficient of Variation 29.03 |
| Alisertib 10 mg PIC QD 7D | Cmax: Maximum Observed Concentration for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Day 7 | 3080.8 nM | Geometric Coefficient of Variation 38.79 |
Secondary
Duration Of Response (DOR)
DOR is defined as the time from the date of first documentation of a confirmed response to the date of first documented PD. PD is defined as 20% increase in the sum of the longest diameter of target lesions.
Time frame: Beginning at the end of Cycle 2, every 2 cycles until progressive disease (PD); Participants who discontinue study drug before PD: Follow-Up (FU) every 8-12 weeks until PD or as per institutional practice (Up to 33.2 months)
Population: Safety Population included all participants who received any amount of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib 5 mg PIC QD 7D | Duration Of Response (DOR) | 470 days |
Secondary
Effect of Food on the Pharmacokinetics (PK) of Alisertib
The effects of food on the PK of alisertib were to be evaluated using the preferred alisertib regimen (unit dose and formulation) based on the results from the relative bioavailability study.
Time frame: Up to 6 months
Population: The effects of food on the PK of alisertib was not conducted. As the development of alisertib was transitioned from the PIC to the ECT formulation and the clinical dose of alisertib ECT had not been determined yet, it was decided that the effect of food would be evaluated in a different study at the appropriate clinical dose, administered as ECT.
Secondary
Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1
One peripheral blood sample (approximately 4 mL) was to be obtained on Day 1 of Cycle 1 prior to the first dose of alisertib to genotype patients for polymorphisms in UGT1A1 because UGT1A1 is one of the enzymes responsible for glucuronidation of alisertib, which is expected to contribute to the clearance of alisertib. wt=wild type \*28=polymorphism in the promoter region of a UGT1A1 allele resulting in reduced UGT1A1 expression.
Time frame: Cycle 1 Day 1 predose
Population: Safety Population included all participants who received any amount of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | wt/wt | 38 participants |
| Alisertib 5 mg PIC QD 7D | Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | wt/*28 | 30 participants |
| Alisertib 5 mg PIC QD 7D | Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | *28/*28 | 9 participants |
| Alisertib 5 mg PIC QD 7D | Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | *28/other | 4 participants |
| Alisertib 5 mg PIC QD 7D | Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | other/other | 2 participants |
| Alisertib 5 mg PIC QD 7D | Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | Not Determined | 1 participants |
| Alisertib 5 mg PIC QD 7D | Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | Missing | 3 participants |
Secondary
Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time frame: Cycle 1 Days 7 and 14 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 14 | 5.073 ratio | Standard Deviation 2.2113 |
| Alisertib 5 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 7 | 6.877 ratio | Standard Deviation 1.1151 |
Secondary
Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time frame: Cycle 1 Days 14 and 21 predose and at multiple timepoints up to 10 hours postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 (MEAN) | Dispersion |
|---|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 4.773 ratio | Standard Deviation 0.9001 |
| Alisertib 5 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 3.637 ratio | Standard Deviation 1.8675 |
| Alisertib 10 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 7.543 ratio | Standard Deviation 5.4982 |
| Alisertib 10 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 4.157 ratio | Standard Deviation 2.1051 |
| Alisertib 20 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 6.392 ratio | Standard Deviation 2.0824 |
| Alisertib 20 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 5.570 ratio | Standard Deviation 2.5772 |
Secondary
Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 4.107 ratio | Standard Deviation 0.846 |
| Alisertib 10 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 5.195 ratio | Standard Deviation 3.9527 |
| Alisertib 20 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 5.430 ratio | Standard Deviation 2.4856 |
| Alisertib 40 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 3.907 ratio | Standard Deviation 2.3944 |
| Alisertib 80 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 3.850 ratio | Standard Deviation 2.0612 |
| Alisertib 110 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 4.922 ratio | Standard Deviation 2.589 |
| Alisertib 150 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 4.610 ratio | Standard Deviation 0.5314 |
Secondary
Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | 2.193 ratio | Standard Deviation 1.1346 |
| Alisertib 10 mg PIC QD 7D | Peak/Trough Ratio for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | 1.890 ratio | Standard Deviation 0.2012 |
Secondary
Terminal Half-Life for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time frame: Cycle 1 Day 14 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Terminal Half-Life for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | 65.67 h | Standard Deviation 43.859 |
Secondary
Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time frame: Cycle 1 Day 21 predose and at multiple time points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | 31.667 h | Standard Deviation 6.7122 |
| Alisertib 10 mg PIC QD 7D | Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | 23.650 h | Standard Deviation 16.9487 |
| Alisertib 20 mg PIC QD 7D | Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | 22.378 h | Standard Deviation 19.8802 |
Secondary
Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time frame: Cycle 1 Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given timepoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 24.950 h | Standard Deviation 20.4354 |
| Alisertib 10 mg PIC QD 7D | Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 35.150 h | Standard Deviation 23.4052 |
| Alisertib 20 mg PIC QD 7D | Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 26.400 h | Standard Deviation 19.7684 |
| Alisertib 40 mg PIC QD 7D | Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 18.155 h | Standard Deviation 12.5087 |
| Alisertib 80 mg PIC QD 7D | Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 39.333 h | Standard Deviation 18.8006 |
| Alisertib 110 mg PIC QD 7D | Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 13.427 h | Standard Deviation 4.3465 |
| Alisertib 150 mg PIC QD 7D | Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | 16.766 h | Standard Deviation 9.7804 |
Secondary
Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time frame: Cycle 1 Day 8
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis, with data available at the given time-point.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | 20.215 h | Standard Deviation 15.5083 |
| Alisertib 10 mg PIC QD 7D | Terminal Half-Life (t1/2) for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | 18.200 h | Standard Deviation 3.2212 |
Secondary
Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included all participants for whom there were sufficient dosing and alisertib concentration-time data to permit noncompartmental PK analysis.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Alisertib 5 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 1 | 4.000 h |
| Alisertib 5 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 7 | 2.000 h |
| Alisertib 5 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing | Day 14 | 2.000 h |
Secondary
Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple timepoints up to 24 hours postdose and Days 14 and 21 predose and at multiple time points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 2.000 h |
| Alisertib 5 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 1 | 2.020 h |
| Alisertib 5 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 2.000 h |
| Alisertib 10 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 2.000 h |
| Alisertib 10 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 1 | 2.285 h |
| Alisertib 10 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 2.000 h |
| Alisertib 20 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 1 | 2.000 h |
| Alisertib 20 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 21 | 2.000 h |
| Alisertib 20 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing | Day 14 | 2.000 h |
Secondary
Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 2.000 hours (h) |
| Alisertib 5 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 1.500 hours (h) |
| Alisertib 10 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 2.000 hours (h) |
| Alisertib 10 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 3.750 hours (h) |
| Alisertib 20 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 1.500 hours (h) |
| Alisertib 20 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 1.500 hours (h) |
| Alisertib 40 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 2.000 hours (h) |
| Alisertib 40 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 2.000 hours (h) |
| Alisertib 80 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 2.000 hours (h) |
| Alisertib 80 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 2.000 hours (h) |
| Alisertib 110 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 2.000 hours (h) |
| Alisertib 110 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 3.710 hours (h) |
| Alisertib 150 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 1 | 2.000 hours (h) |
| Alisertib 150 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Once Daily for 7 Days (QD7D) Dosing | Day 7 | 2.000 hours (h) |
Secondary
Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing
Time frame: Cycle 1 Days 1 and 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing | Day 1 | 3.00 h |
| Alisertib 5 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 14 Days (BID14D) Dosing | Day 7 | 1.70 h |
Secondary
Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing
Time frame: Cycle 1 Day 1 predose and at multiple time-points (up to 24 hours) postdose and Day 7 predose and at multiple time-points (up to 10 hours) postdose
Population: Pharmacokinetic (PK)-Evaluable Population included 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 PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Day 1 | 2.000 h |
| Alisertib 5 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Day 7 | 2.015 h |
| Alisertib 10 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Day 1 | 2.000 h |
| Alisertib 10 mg PIC QD 7D | Tmax: Time of First Occurrence of Cmax for Alisertib as Powder-in-Capsule (PIC) With Twice Daily for 7 Days (BID7D) Dosing | Day 7 | 2.000 h |