Anaplastic Large Cell Lymphoma, Angioimmunoblastic T-cell Lymphoma, B-Cell Chronic Lymphocytic Leukemia, B-cell Follicular Lymphoma, B-cell Mantle Cell Lymphoma, B-cell Marginal Zone Lymphoma, B-cell Small Lymphocytic Lymphoma, Diffuse Large B-cell Lymphoma, Enteropathy Associated T-cell Lymphoma, Multiple Myeloma, NK Lymphoma, Noncutaneous Peripheral T-cell Lymphoma Not Otherwise Specified, Waldenstrom's Macroglobulinemia
Conditions
Keywords
Drug therapy
Brief summary
This is an open-label, multicenter, phase 1 study of MLN8237 in participants with advanced hematological malignancies for whom there are limited standard treatment options.
Detailed description
The drug being tested in this study is called alisertib. Alisertib is being tested to treat people who have advanced hematological 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 58 patients. Participants were enrolled in one of 3 treatment groups: * Part 1: Powder-in-Capsule (PIC) Dose Escalation (alisertib 25 mg PIC, orally twice daily \[BID\] on Day 1 \[loading dose\] and then alisertib 25 or 35 mg PIC once daily \[QD\] for 21 days (D), or alisertib 35, 45, 65 or 90 mg PIC, orally, QD for 14D) in 28-day cycles * Part 1: Enteric-coated Tablet (ECT) Dose Escalation (alisertib 40 mg, ECT, orally, QD for 14D or alisertib 30, 40 or 50 mg, orally, BID for 7D) in 28-day cycles * Part 2: Participants with Peripheral T-cell Lymphoma (PTCL) (alisertib 50 mg ECT, orally, BID for 7D) in 21-day cycles All participants received treatment for 12 months or 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 422 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) PIC or ECT
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Relapsed or refractory disease and a histologically or cytologically confirmed hematological malignancy of the following type for which standard curative treatment does not exist or is no longer effective: * B-cell Follicular lymphoma * B-cell Marginal zone lymphoma * Diffuse large B-cell lymphoma * B-cell Mantle cell lymphoma * B-cell Small lymphocytic lymphoma (SLL) * B-Cell Chronic lymphocytic leukemia (B-CLL) * Multiple myeloma * Waldenstrom's macroglobulinemia * Noncutaneous peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) * Angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma, enteropathy associated T-cell lymphoma (EATCL), NK lymphoma (NKL) * Participants with diffuse large B-cell lymphoma must have failed, be ineligible for, or have refused an autologous stem cell transplant. There is no restriction regarding the maximum number of prior regimens. * Aged 18 years or older * Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2 * Radiographically or clinically evaluable disease for Part 1 of this study and measurable disease for Part 2 of this study * Suitable venous access for the conduct of blood sampling for MLN8237 pharmacokinetics (PK) * Recovered from the reversible effects of prior antineoplastic treatment (with the exception of alopecia and Grade 1 neuropathy)
Exclusion criteria
* Pregnant or lactating * Treatment with clinically significant enzyme inducers within 14 days prior to the first dose of MLN8237 as specified in the protocol * Prior allogeneic bone marrow (or other organ) transplantation * Newly diagnosed or uncontrolled cancer-related central nervous system (CNS) disease * Systemic antineoplastic treatment within 21 days preceding the first dose of study treatment. Exceptions requiring a 42-day recovery period from last treatment include: Nitrosoureas, mitomycin C or Rituximab, alemtuzumab (Campath®), or other unconjugated therapeutic antibody (21 days if clear evidence of progressive disease) * Treatment with radioimmunoconjugates or toxin immunoconjugates such as ibritumomab tiuxetan (Zevalin™), or tositumomab (Bexxar®) within 56 days preceding the first dose of study treatment * Antineoplastic treatment with glucocorticoids within 21 days preceding the first dose of study treatment * Radiotherapy involving \<25% of the hematopoietically active bone marrow within 21 days preceding first dose of study treatment * Radiotherapy involving ≥25% of the hematopoietically active bone marrow within 42 days preceding first dose of study treatment * Inability to swallow capsules or known gastrointestinal (GI) disease or GI procedures 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 * Known or suspected human immunodeficiency virus (HIV) positive or hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection. Testing is not required in the absence of clinical findings or suspicion. * Participants who fail to meet laboratory values as specified in the protocol during the screening period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | — |
| AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | — |
| Terminal Half-Life (t1/2) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | — |
| Accumulation Ratio (Rac) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | — |
| Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | — |
| Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | — |
| AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | — |
| Number of Participants With Dose-Limiting Toxicity (DLT) | From first dose of study drug to 30 days after the last dose (up to 422 days) | 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 \>21 days due to failure of adequate hematologic or non-hematologic recovery from previous cycle of treatment 8. Other alisertib related non-hematologic 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 422 days) | MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 participants. |
| Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1 | Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1 | Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose | — |
| AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose | — |
| Terminal Half-Life (t1/2) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose | — |
| Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose | — |
| Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose | — |
| CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose | — |
| Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | — |
| Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | — |
| CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | — |
| Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | — |
| AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | — |
| Terminal Half Life for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | — |
| Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | — |
| CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose | — |
| Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 | Cycle 1 Day 1 predose and at multiple timepoints (up to 12 hours) postdose | — |
| Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 | Cycle 1 Day 1 predose and at multiple timepoints (up to 12 hours) postdose | — |
| Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose | — |
| AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 | Cycle 1 Days 1 predose and at multiple timepoints (up to 12 hours) postdose | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of Response (DOR) | Baseline and every 2 cycles up to Month 12 until disease progression, 30 days after end of treatment (up to 422 days) | DOR is defined as the time from the date of first documentation of a response (either CR or PR) to the date of first documentation of progressive disease (PD) according to International Working Group (IWG) criteria. CR is defined as the disappearance of all evidence of disease and the definition for PR includes at least a 50% decrease in sum of the product of the diameters and no new lesions. PD is defined as any new lesion or increase by \>50% of previously involved sites from nadir. |
| 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 participants 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. Not determined = blood sample was not evaluable. |
| Number of Participants With Polymorphisms in Aurora A Kinase | Cycle 1 Day 1 predose | — |
| Best Overall Response Rate Based on Investigator's Assessment | Baseline and every 2 cycles up to Month 12 until disease progression, 30 days after end of treatment (up to 422 days) | Best overall response rate is defined as the percentage of participants with complete response (CR) or partial response (PR) as assessed by the Investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease and the definition for PR includes at least a 50% decrease in sum of the product of the diameters and no new lesions. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 10 investigative sites in the United States from 11 July 2008 to19 October 2016.
Pre-assignment details
Participants with a diagnosis of advanced hematological malignancies were enrolled 1 of 3 treatment groups, Part 1:alisertib powder-in capsule (PIC) 25 to 90 mg dose escalation cohort, Part 1: alisertib 30 to 50 mg enteric-coated tablet (ECT) dose escalation cohort, or Part 2: alisertib ECT 50 mg participants with peripheral T-cell lymphoma (PTCL).
Participants by arm
| Arm | Count |
|---|---|
| Part 1: PIC Dose Escalation Alisertib 25 or 35 mg, Powder-in-Capsule (PIC) formulation, orally, once daily (QD) for 21 days followed by a 7-day recovery period in 28-day cycles or alisertib 35, 45, 65 or 90 mg PIC, orally, QD for 14 days followed by a 14-day recovery period in 28-day cycles, until disease progression or unacceptable alisertib-related toxicity (up to 14 cycles). All participants received an initial starting dosage of alisertib PIC 25 mg, orally, twice daily (BID) on Day 1 (loading dose), followed by their respective dosage assignment. | 28 |
| Part 1: ECT Dose Escalation Alisertib 40 mg, Enteric-coated Tablet (ECT) formulation, orally, QD for 14 days followed by a 14-day recovery period in 28-day cycles, or alisertib 30, 40 or 50 mg ECT, orally BID for 7 days followed by a 14-day recovery period in 21-day cycles, until disease progression or unacceptable alisertib-related toxicity (up to 15 cycles). | 28 |
| Part 2: PTCL Participants with peripheral T-cell lymphoma (PTCL) received alisertib 50 mg ECT, orally, BID for 7 days followed by a 14-day recovery period in 21-day cycles, until disease progression or unacceptable alisertib-related toxicity (up to 2 cycles). | 2 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 4 | 5 | 0 |
| Overall Study | Progressive Disease | 19 | 18 | 0 |
| Overall Study | Reason not Specified | 3 | 0 | 1 |
| Overall Study | Symptomatic Deterioration | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 0 |
Baseline characteristics
| Characteristic | Part 1: PIC Dose Escalation | Part 1: ECT Dose Escalation | Part 2: PTCL | Total |
|---|---|---|---|---|
| Age, Continuous | 61.4 years STANDARD_DEVIATION 8.91 | 59.5 years STANDARD_DEVIATION 14.22 | 63.0 years STANDARD_DEVIATION 24.04 | 60.5 years STANDARD_DEVIATION 12.03 |
| Body Surface Area | 1.93 m^2 STANDARD_DEVIATION 0.282 | 1.88 m^2 STANDARD_DEVIATION 0.289 | 2.05 m^2 STANDARD_DEVIATION 0.434 | 1.91 m^2 STANDARD_DEVIATION 0.286 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 7 Participants | 0 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 20 Participants | 2 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Height | 165.9 cm STANDARD_DEVIATION 11.25 | 164.6 cm STANDARD_DEVIATION 10.95 | 160.6 cm STANDARD_DEVIATION 6.43 | 165.1 cm STANDARD_DEVIATION 10.89 |
| Race/Ethnicity, Customized Asian | 0 participants | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 3 participants | 1 participants | 0 participants | 4 participants |
| Race/Ethnicity, Customized Not Reported | 1 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 24 participants | 26 participants | 2 participants | 52 participants |
| Region of Enrollment United States | 28 participants | 28 participants | 2 participants | 58 participants |
| Sex: Female, Male Female | 14 Participants | 15 Participants | 2 Participants | 31 Participants |
| Sex: Female, Male Male | 14 Participants | 13 Participants | 0 Participants | 27 Participants |
| Weight | 81.40 kg STANDARD_DEVIATION 20.031 | 77.62 kg STANDARD_DEVIATION 19.747 | 97.65 kg STANDARD_DEVIATION 43.911 | 80.13 kg STANDARD_DEVIATION 20.573 |
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 | 28 / 28 | 28 / 28 | 2 / 2 |
| serious Total, serious adverse events | 12 / 28 | 15 / 28 | 2 / 2 |
Outcome results
Primary
Accumulation Ratio (Rac) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7
Time frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Accumulation Ratio (Rac) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 2.9 ratio | Standard Deviation 0.5 |
| Alisertib 35 mg PIC QD 21D | Accumulation Ratio (Rac) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 2.8 ratio | Standard Deviation 1 |
| Alisertib 35 mg PIC QD 14D | Accumulation Ratio (Rac) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 2.3 ratio | Standard Deviation 0.9 |
Primary
Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14
Time frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 2.4 ratio | Standard Deviation 0 |
| Alisertib 35 mg PIC QD 21D | Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 1.5 ratio | Standard Deviation 0.5 |
| Alisertib 35 mg PIC QD 14D | Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 1.9 ratio | Standard Deviation 1.6 |
Primary
Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21
Time frame: Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 1.9 ratio | Standard Deviation 1.1 |
| Alisertib 35 mg PIC QD 21D | Accumulation Ratio (Rac) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 1.5 ratio | Standard Deviation 0.5 |
Primary
AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14
Time frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed are participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 14306 nM*h | Geometric Coefficient of Variation 20.3 |
Primary
AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1
Time frame: Cycle 1 Days 1 predose and at multiple timepoints (up to 12 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 | 5518 nM*hr | Geometric Coefficient of Variation 18.3 |
| Alisertib 35 mg PIC QD 21D | AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 | 7095 nM*hr | Geometric Coefficient of Variation 42.5 |
| Alisertib 35 mg PIC QD 14D | AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 | 9732 nM*hr | Geometric Coefficient of Variation 48.5 |
Primary
AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7
Time frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 16024 nM*hr | Geometric Coefficient of Variation 20.3 |
| Alisertib 35 mg PIC QD 21D | AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 18624 nM*hr | Geometric Coefficient of Variation 27.3 |
| Alisertib 35 mg PIC QD 14D | AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 17914 nM*hr | Geometric Coefficient of Variation 48.6 |
Primary
AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14
Time frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 23444 nM*h | — |
| Alisertib 35 mg PIC QD 21D | AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 19671 nM*h | Geometric Coefficient of Variation 64.8 |
| Alisertib 35 mg PIC QD 14D | AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 28864 nM*h | Geometric Coefficient of Variation 39.9 |
Primary
AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21
Time frame: Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 14846 nM*h | Geometric Coefficient of Variation 69.7 |
| Alisertib 35 mg PIC QD 21D | AUCt: Area Under the Concentration Time Curve From Time 0 to Time t for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 16528 nM*h | Geometric Coefficient of Variation 35.6 |
Primary
CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14
Time frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed are participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alisertib 25mg PIC QD 21D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 2.5 L/h |
Primary
CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7
Time frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 3.7 L/h | Geometric Coefficient of Variation 0.7 |
| Alisertib 35 mg PIC QD 21D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 4.4 L/h | Geometric Coefficient of Variation 1.9 |
| Alisertib 35 mg PIC QD 14D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 6.7 L/h | Geometric Coefficient of Variation 5.6 |
Primary
CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14
Time frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 2.9 L/h | — |
| Alisertib 35 mg PIC QD 21D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 4.3 L/h | Geometric Coefficient of Variation 44 |
| Alisertib 35 mg PIC QD 14D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 4.3 L/h | Geometric Coefficient of Variation 53 |
Primary
CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21
Time frame: Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis, with data available at the given time point. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 3.2 L/h | Geometric Coefficient of Variation 113 |
| Alisertib 35 mg PIC QD 21D | CLss/F: Apparent Oral Clearance at Steady State for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 4.1 L/h | Geometric Coefficient of Variation 45 |
Primary
Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 1
Time frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | 1227 nM | Geometric Coefficient of Variation 41.3 |
Primary
Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14
Time frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed are participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Alisertib 25mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 1608 nM |
Primary
Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1
Time frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 12 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 | 886 nM | Geometric Coefficient of Variation 39.7 |
| Alisertib 35 mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 | 1114 nM | Geometric Coefficient of Variation 37.1 |
| Alisertib 35 mg PIC QD 14D | Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 | 1531 nM | Geometric Coefficient of Variation 58.4 |
Primary
Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7
Time frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 2025 nM | Geometric Coefficient of Variation 29.6 |
| Alisertib 35 mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 2586 nM | Geometric Coefficient of Variation 35.7 |
| Alisertib 35 mg PIC QD 14D | Cmax: Maximum Observed Concentration for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 2058 nM | Geometric Coefficient of Variation 44.6 |
Primary
Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1
Time frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | 726.5 nM | Geometric Coefficient of Variation 34.8 |
| Alisertib 35 mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | 1637.0 nM | Geometric Coefficient of Variation 58 |
| Alisertib 35 mg PIC QD 14D | Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | 1773.4 nM | Geometric Coefficient of Variation 44.3 |
| Alisertib 45 mg PIC QD 14D | Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | 2497.4 nM | Geometric Coefficient of Variation 24.3 |
Primary
Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14
Time frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 2193.5 nM | — |
| Alisertib 35 mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 1634.4 nM | Geometric Coefficient of Variation 52.5 |
| Alisertib 35 mg PIC QD 14D | Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 2300.2 nM | Geometric Coefficient of Variation 40.3 |
Primary
Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1
Time frame: Cycle 1 Day 1 predose and at multiple timepoints (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 non-compartmental PK analysis.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1 | 833.2 nM | Geometric Coefficient of Variation 49.5 |
| Alisertib 35 mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1 | 1078.3 nM | Geometric Coefficient of Variation 26.4 |
Primary
Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21
Time frame: Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 1337.6 nM | Geometric Coefficient of Variation 57.8 |
| Alisertib 35 mg PIC QD 21D | Cmax: Maximum Observed Concentration for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 1451.9 nM | Geometric Coefficient of Variation 26.2 |
Primary
Maximum Tolerated Dose (MTD) of Alisertib
MTD was defined as the highest dose at which DLT occurred in 0/3 or 1/6 participants.
Time frame: From first dose of study drug to 30 days after the last dose (up to 422 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 25mg PIC QD 21D | Maximum Tolerated Dose (MTD) of Alisertib | 50 mg BID for 7 days |
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 \>21 days due to failure of adequate hematologic or non-hematologic recovery from previous cycle of treatment 8. Other alisertib related non-hematologic toxicities ≥Grade 2 that, in the opinion of the investigator required a dose reduction or discontinuation of therapy with alisertib.
Time frame: From first dose of study drug to 30 days after the last dose (up to 422 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 25mg PIC QD 21D | Number of Participants With Dose-Limiting Toxicity (DLT) | 1 participants |
| Alisertib 35 mg PIC QD 21D | Number of Participants With Dose-Limiting Toxicity (DLT) | 2 participants |
| Alisertib 35 mg PIC QD 14D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 45 mg PIC QD 14D | Number of Participants With Dose-Limiting Toxicity (DLT) | 1 participants |
| Alisertib 65 mg PIC QD 14D | Number of Participants With Dose-Limiting Toxicity (DLT) | 2 participants |
| Alisertib 90 mg PIC QD 14D | Number of Participants With Dose-Limiting Toxicity (DLT) | 2 participants |
| Alisertib 40 mg ECT QD 14D | Number of Participants With Dose-Limiting Toxicity (DLT) | 2 participants |
| Alisertib 30 mg ECT BID 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 40 mg ECT BID 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 0 participants |
| Alisertib 50 mg ECT BID 7D | Number of Participants With Dose-Limiting Toxicity (DLT) | 1 participants |
Primary
Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14
Time frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed are participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alisertib 25mg PIC QD 21D | Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 2.1 ratio |
Primary
Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7
Time frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 2.5 ratio | Standard Deviation 0.6 |
| Alisertib 35 mg PIC QD 21D | Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 2.4 ratio | Standard Deviation 0.5 |
| Alisertib 35 mg PIC QD 14D | Peak/Trough Ratio for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 2.5 ratio | Standard Deviation 2.2 |
Primary
Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14
Time frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 4.1 ratio | — |
| Alisertib 35 mg PIC QD 21D | Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 5.4 ratio | Standard Deviation 1.9 |
| Alisertib 35 mg PIC QD 14D | Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 4.4 ratio | Standard Deviation 0.8 |
Primary
Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21
Time frame: Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis, with data available at the given time point. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 6.0 ratio | Standard Deviation 4.4 |
| Alisertib 35 mg PIC QD 21D | Peak/Trough Ratio for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 4.3 ratio | Standard Deviation 1.5 |
Primary
Terminal Half Life for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14
Time frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed are participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Alisertib 25mg PIC QD 21D | Terminal Half Life for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 11.7 h |
Primary
Terminal Half-Life (t1/2) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7
Time frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Terminal Half-Life (t1/2) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 13.3 h | — |
| Alisertib 35 mg PIC QD 21D | Terminal Half-Life (t1/2) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 19.9 h | Standard Deviation 10.7 |
| Alisertib 35 mg PIC QD 14D | Terminal Half-Life (t1/2) for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 18.4 h | Standard Deviation 13.9 |
Primary
Terminal Half-Life (t1/2) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21
Time frame: Cycle 1 Day 21 predose and at multiple time points (up to 6 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Terminal Half-Life (t1/2) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 20.5 h | Standard Deviation 7.3 |
| Alisertib 35 mg PIC QD 21D | Terminal Half-Life (t1/2) for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 19.5 h | Standard Deviation 6 |
Primary
Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 1
Time frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib 25mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | 3.9 h |
Primary
Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14
Time frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed are participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib 25mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 5.0 h |
Primary
Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1
Time frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 12 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 | 2.0 h | Full Range 39.7 |
| Alisertib 35 mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 | 2.2 h | Full Range 37.1 |
| Alisertib 35 mg PIC QD 14D | Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 1 | 2.0 h | Full Range 58.4 |
Primary
Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7
Time frame: Cycle 1 Day 7 predose and at multiple timepoints (up to 12 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 2.0 h | Full Range 39.7 |
| Alisertib 35 mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 2.2 h | Full Range 37.1 |
| Alisertib 35 mg PIC QD 14D | Tmax: Time of First Occurrence of Cmax for Alisertib as Enteric Coated Tablet (ECT) With Twice Daily for 7 Days (BID7D) Dosing at Day 7 | 2.0 h | Full Range 58.4 |
Primary
Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1
Time frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | 2.0 h | Full Range 34.8 |
| Alisertib 35 mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | 3.0 h | Full Range 58 |
| Alisertib 35 mg PIC QD 14D | Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | 2.0 h | Full Range 44.3 |
| Alisertib 45 mg PIC QD 14D | Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 1 | 2.9 h | Full Range 24.3 |
Primary
Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14
Time frame: Cycle 1 Day 14 predose and at multiple timepoints (up to 8 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 3.4 h | — |
| Alisertib 35 mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 2.0 h | Full Range 52.5 |
| Alisertib 35 mg PIC QD 14D | Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 14 Days (QD14D) Dosing at Day 14 | 2.0 h | Full Range 40.3 |
Primary
Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1
Time frame: Cycle 1 Day 1 predose and at multiple timepoints (up to 24 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib 25mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1 | 2.0 hours (h) |
| Alisertib 35 mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 1 | 2.0 hours (h) |
Primary
Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21
Time frame: Cycle 1 Day 21 predose and at multiple timepoints (up to 6 hours) postdose
Population: PK evaluable population included all participants for whom there were sufficient dosing and alisertib concentration time data to permit non-compartmental PK analysis. Here number of participants analyzed were participants evaluable for this outcome measure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib 25mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 2.0 h |
| Alisertib 35 mg PIC QD 21D | Tmax: Time of First Occurrence of Cmax for Alisertib as Pill in Capsule (PIC) With Once Daily for 21 Days (QD21D) Dosing at Day 21 | 2.0 h |
Secondary
Best Overall Response Rate Based on Investigator's Assessment
Best overall response rate is defined as the percentage of participants with complete response (CR) or partial response (PR) as assessed by the Investigator using International Working Group (IWG) Criteria. CR is defined as the disappearance of all evidence of disease and the definition for PR includes at least a 50% decrease in sum of the product of the diameters and no new lesions.
Time frame: Baseline and every 2 cycles up to Month 12 until disease progression, 30 days after end of treatment (up to 422 days)
Population: The response-evaluable population is defined as all participants who received at least 1 dose of alisertib and have measurable disease at baseline and have at least 1 post baseline response assessment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib 25mg PIC QD 21D | Best Overall Response Rate Based on Investigator's Assessment | 13 percentage of participants |
| Alisertib 35 mg PIC QD 21D | Best Overall Response Rate Based on Investigator's Assessment | 9 percentage of participants |
| Alisertib 35 mg PIC QD 14D | Best Overall Response Rate Based on Investigator's Assessment | 100 percentage of participants |
Secondary
Duration of Response (DOR)
DOR is defined as the time from the date of first documentation of a response (either CR or PR) to the date of first documentation of progressive disease (PD) according to International Working Group (IWG) criteria. CR is defined as the disappearance of all evidence of disease and the definition for PR includes at least a 50% decrease in sum of the product of the diameters and no new lesions. PD is defined as any new lesion or increase by \>50% of previously involved sites from nadir.
Time frame: Baseline and every 2 cycles up to Month 12 until disease progression, 30 days after end of treatment (up to 422 days)
Population: Participants from the Response-Evaluable Population who had a response of CR or PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib 25mg PIC QD 21D | Duration of Response (DOR) | 0.03 months |
| Alisertib 35 mg PIC QD 21D | Duration of Response (DOR) | 2.07 months |
| Alisertib 35 mg PIC QD 14D | Duration of Response (DOR) | 0.03 months |
Secondary
Number of Participants With Polymorphisms in Aurora A Kinase
Time frame: Cycle 1 Day 1 predose
Population: As per protocol amendment, no data was collected for polymorphisms in Aurora A Kinase.
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 participants 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. Not determined = blood sample was not evaluable.
Time frame: Cycle 1 Day 1 predose
Population: Safety population included all participants who received any amount of study drug. Data is presented for one arm because the data was collected prior to the participant receiving their assigned treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib 25mg PIC QD 21D | Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | wt/wt | 23 participants |
| Alisertib 25mg PIC QD 21D | Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | wt/*28 | 23 participants |
| Alisertib 25mg PIC QD 21D | Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | *28/*28 | 8 participants |
| Alisertib 25mg PIC QD 21D | Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | other/other | 1 participants |
| Alisertib 25mg PIC QD 21D | Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | Not Determined | 2 participants |
| Alisertib 25mg PIC QD 21D | Number of Participants With Polymorphisms in Gene Encoding Enzyme UGT1A1 | Missing | 1 participants |