Adenocarcinoma of the Prostate, Advanced Solid Tumors
Conditions
Brief summary
The purpose of this study is to evaluate the safety and tolerability of alisertib in combination with docetaxel as a treatment for participants with advanced solid tumors, including castration-resistant prostate cancer, who were deemed by the investigator to be medically appropriate candidates for docetaxel therapy.
Detailed description
The drug being tested in this study is called alisertib (MLN8237). Alisertib is being tested to treat people who have advanced solid tumors including castration-resistant prostate cancer. The study enrolled approximately 41 patients. Participants were enrolled to receive: • Alisertib 10-40 mg + docetaxel 60-75 mg/m\^2 All participants will receive alisertib (ECT) in dose escalating cohorts, orally, twice daily for 7 days followed by 14-day rest period in Cycle 1, 3 and onwards (21-day cycle) and orally twice daily from Day 3 to Day 7 followed by 14 day rest period in Cycle 2 \[dose held for pharmacokinetic (PK) collection\] along with docetaxel 75 mg/m\^2, intravenous (IV) infusion on Day 1 of each cycle for maximum of 12 months, or until the occurrence of progressive disease (PD), unmanageable AEs or withdrawal of consent. This multi-center trial is conducted in United States. The overall time to participate in this study was until there is evidence of disease progression or unacceptable treatment-related toxicity. Participants made multiple visits to the clinic, and were contacted every 12 weeks for up to 25.8 months after last dose of study drug for a follow-up assessment.
Interventions
DRUGAlisertib
Alisertib ECT
DRUGDocetaxel
Docetaxel IV infusion
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Each participant must meet all of the following inclusion criteria to be enrolled in the study: * 18 years or older * Histologically or cytologically confirmed advanced tumors and candidates for docetaxel treatment * Measurable or evaluable disease is required. Participants must have clinical evidence of progressive disease or persistent disease * Participants with castration-resistant prostate cancer (CRPC) are required to have * Pathologically confirmed adenocarcinoma of the prostate * Evidence of metastatic disease on bone scan or other imaging. Participants with prostate-specific antigen (PSA) elevation as the only manifestation of disease are not eligible. * Progressive disease after at least 1 hormonal treatment with documented testosterone levels less than 50 ng/dl * Concurrent use of an agent for testosterone suppression (e.g., luteinizing hormone-releasing hormone \[LHRH\] agonist) is required if the participants has not been surgically castrated * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Recovered to less than or equal to Grade 1 toxicity (CTCAE), to participant's baseline status (except alopecia) or deemed irreversible from the effects of prior cancer therapy and must have evidence of progressive or persistent disease * Adequate bone marrow, liver and renal function * Any use of opiates must be stable for at least 2 weeks prior to study entry * Female participants who are postmenopausal for at least 1 year OR are surgically sterile OR if of childbearing potential, agree to practice 2 effective methods of contraception at the same time * Male participants who agree to practice effective barrier contraception during the entire study and through 6 months after the last dose of study drug OR agree to abstain from heterosexual intercourse * Voluntary written consent * Willing to comply with scheduled visits, treatment plan, laboratory tests and other trial procedures * Suitable venous access for blood sampling
Exclusion criteria
Participants meeting any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | From enrollment through 30 days after the last dose of study drug (approximately up to 77 months) | An AE is considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events. A SAE 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 |
|---|---|---|
| AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2 | — |
| AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2 | — |
| Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2 | — |
| Cmax: Maximum Observed Plasma Concentration for Alisertib | Prior to dosing on Day 1 and Day 5 or 7 and at multiple time points (up to 12 hours) post-dose in Cycle 1 | — |
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib | Prior to dosing on Day 1 and Day 5 or 7 and at multiple time points (up to 12 hours) post-dose in Cycle 1 | — |
| AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Day 7 Over the Dosing Interval for Alisertib | Prior to dosing on Day 1 and Day 5 or 7 and at multiple time points (up to 12 hours) post-dose in Cycle 1 | — |
| Cmax: Maximum Observed Plasma Concentration for Docetaxel | Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2 | — |
| Overall Response Rate for Prostate Cancer Participants | Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months) | ORR is defined as percentage of participants who achieved CR or PR as assessed by either RECIST v 1.1 or PSA response by prostate cancer working group 2 (PCWG2) criteria. According to RECIST v 1.1, CR: disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: ≥30% decrease in sum of LD of target lesions in reference to Baseline sum LD. PSA response by PCWG2 is defined as PSA at least 50% decrease in PSA value from baseline for 2 consecutive evaluations. PCWG2 defines PSA progression as the date that a 25% or greater increase and an absolute increase of 2 ng/mL or more from the nadir is documented, which is confirmed by a second value obtained 3 or more weeks later. |
| Best Overall Response Rate Assessed by RECIST Criteria | Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months) | Best response rate is defined as the percentage of participants with CR, PR, CR+PR, stable disease (SD) and progressive disease (PD) as assessed by RECIST criteria 1.1 for target lesions and assessed by CT, PET or MRI. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). |
| Best Overall Response Rate Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria | Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months) | Best Response Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria PSA response is defined as at least 50% decrease in PSA value from baseline for 2 consecutive evaluations. |
| Duration of Response | Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months) | Duration of response is defined as the time from the date of first documentation of a response to the date of first documented progressive disease (PD), or censored at last SD or better. |
| Duration of Stable Disease (SD) | Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months) | Duration of SD is defined as the time from first dose to first PD, or censored at last SD or better. |
| Overall Response Rate (ORR) Assessed for Overall Participant Population | Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months) | ORR is defined as percentage of participants who achieved complete response (CR) or partial response (PR) as assessed by response evaluation criteria in solid tumors (RECIST) v 1.1. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as ≥30% decrease in sum of longest diameter (LD) of target lesions in reference to Baseline. RECIST-Evaluable Population is subset of safety population who had measurable disease by RECIST v 1.1 at baseline and had at least 1 post baseline response. prostate specific antigen (PSA)-Evaluable Population is subset of the safety population who had a baseline PSA reference value (\>5 ng/mL) and at least 12 weeks post-baseline PSA assessment for participants with no decline from baseline, or PSA progression within 12 weeks of treatment for participants with PSA decline from baseline. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 4 investigative sites in the United States from 17 August 2010 to 04 January 2017.
Pre-assignment details
Participants with a diagnosis of Advanced solid tumors, including castration-resistant prostate cancer were enrolled to receive alisertib Alisertib 10-40 mg + docetaxel 60-75 mg/m\^2 intravenous (IV) infusion and granulocyte colony stimulating factor (GCSF) in escalating dose cohorts.
Participants by arm
| Arm | Count |
|---|---|
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 Alisertib 10 mg, enteric-coated tablets (ECT), orally, twice daily for 7 days in Cycle 1, 3 and onwards; and orally twice daily from Day 3 to Day 7 in Cycle 2 followed by 14 day rest period along with docetaxel 75 mg/m\^2, intravenous infusion on Day 1 of each cycle (21-day cycle) for a maximum of 28 cycles, or until the occurrence of PD, unmanageable adverse events (AEs) or withdrawal of consent. | 6 |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 Alisertib 20 mg, ECT, orally, twice daily for 7 days in Cycle 1, 3 and onwards; and orally twice daily from Day 3 to Day 7 in Cycle 2 followed by 14 day rest period along with docetaxel 75 mg/m\^2, intravenous infusion on Day 1 of each cycle (21-day cycle) for a maximum of 34 cycles, or until the occurrence of PD, unmanageable AEs or withdrawal of consent. | 15 |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 Alisertib 30 mg, ECT, orally, twice daily for 7 days in Cycle 1, 3 and onwards; and orally twice daily from Day 3 to Day 7 in Cycle 2 followed by 14 day rest period along with docetaxel 75 mg/m\^2, intravenous infusion on Day 1 of each cycle (21-day cycle) for a maximum of 36 cycles, or until the occurrence of PD, unmanageable AEs or withdrawal of consent. | 5 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 Alisertib 30 mg, ECT, orally, twice daily for 5 days in Cycle 1, 3 and onwards; and orally twice daily from Day 3 to Day 7 in Cycle 2 followed by 14 day rest period along with docetaxel 75 mg/m\^2, intravenous infusion on Day 1 of each cycle (21-day cycle) for a maximum of 17 cycles, or until the occurrence of PD, unmanageable AEs or withdrawal of consent. | 3 |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 Alisertib 30 mg, ECT, orally, twice daily for 7 days in Cycle 1, 3 and onwards; and orally twice daily from Day 3 to Day 7 in Cycle 2 followed by 14 day rest period along with docetaxel 60 mg/m\^2, intravenous infusion on Day 1 of each cycle (21-day cycle) for a maximum of 15 cycles, or until the occurrence of PD, unmanageable AEs or withdrawal of consent. | 2 |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 Alisertib 30 mg, ECT, orally, twice daily for 5 days in Cycle 1, 3 and onwards; and orally twice daily from Day 3 to Day 7 in Cycle 2 followed by 14 day rest period along with docetaxel 60 mg/m\^2, intravenous infusion on Day 1 of each cycle (21-day cycle) for a maximum of 5 cycles, or until the occurrence of PD, unmanageable AEs or withdrawal of consent. | 4 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF Alisertib 30 mg, ECT, orally, twice daily for 5 days in Cycle 1, 3 and onwards; and orally twice daily from Day 3 to Day 7 in Cycle 2 followed by 14 day rest period along with docetaxel 75 mg/m\^2, intravenous infusion on Day 1 of each cycle (21-day cycle) and granulocyte colony stimulating factor (GCSF) as per standard of care for a maximum of 2 cycles, or until the occurrence of PD, unmanageable AEs or withdrawal of consent. | 2 |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF Alisertib 40 mg, ECT, orally, twice daily for 5 days in Cycle 1, 3 and onwards; and orally twice daily from Day 3 to Day 7 in Cycle 2 followed by 14 day rest period along with docetaxel 75 mg/m\^2, intravenous infusion on Day 1 of each cycle (21-day cycle) and granulocyte colony stimulating factor (GCSF) as per standard of care for a maximum of 5 cycles, or until the occurrence of PD, unmanageable AEs or withdrawal of consent. | 4 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 3 | 1 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Initiation of Alternative Therapy | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Ongoing Participants | 0 | 3 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Reason not Specified | 2 | 3 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 2 | 0 | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Total |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 63.7 years STANDARD_DEVIATION 5.2 | 61.5 years STANDARD_DEVIATION 13.1 | 60.2 years STANDARD_DEVIATION 16.75 | 61.3 years STANDARD_DEVIATION 8.62 | 56.5 years STANDARD_DEVIATION 2.12 | 54.8 years STANDARD_DEVIATION 18.73 | 52.5 years STANDARD_DEVIATION 26.16 | 62.3 years STANDARD_DEVIATION 25.71 | 60.4 years STANDARD_DEVIATION 14.07 |
| Body Surface Area (BSA) | 2.269 m^2 STANDARD_DEVIATION 0.2329 | 1.973 m^2 STANDARD_DEVIATION 0.2533 | 2.138 m^2 STANDARD_DEVIATION 0.3541 | 2.025 m^2 STANDARD_DEVIATION 0.4316 | 1.929 m^2 STANDARD_DEVIATION 0.1009 | 2.026 m^2 STANDARD_DEVIATION 0.242 | 1.635 m^2 STANDARD_DEVIATION 0.2005 | 2.046 m^2 STANDARD_DEVIATION 0.2945 | 2.034 m^2 STANDARD_DEVIATION 0.2878 |
| Height | 185.5 cm STANDARD_DEVIATION 11.02 | 170.5 cm STANDARD_DEVIATION 10.04 | 177.2 cm STANDARD_DEVIATION 12.13 | 171.0 cm STANDARD_DEVIATION 10.08 | 174.5 cm STANDARD_DEVIATION 0.71 | 172.5 cm STANDARD_DEVIATION 10.98 | 155.6 cm STANDARD_DEVIATION 8.08 | 174.9 cm STANDARD_DEVIATION 6.99 | 173.6 cm STANDARD_DEVIATION 11.32 |
| Race/Ethnicity, Customized Black or African American | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 1 participants | 2 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 participants | 5 participants | 0 participants | 0 participants | 0 participants | 1 participants | 1 participants | 0 participants | 7 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 6 participants | 10 participants | 5 participants | 3 participants | 1 participants | 3 participants | 1 participants | 4 participants | 33 participants |
| Race/Ethnicity, Customized Not Reported | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Other | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized White | 6 participants | 15 participants | 5 participants | 2 participants | 2 participants | 3 participants | 2 participants | 3 participants | 38 participants |
| Region of Enrollment United States | 6 participants | 15 participants | 5 participants | 3 participants | 2 participants | 4 participants | 2 participants | 4 participants | 41 participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 1 Participants | 1 Participants | 1 Participants | 1 Participants | 2 Participants | 1 Participants | 11 Participants |
| Sex: Female, Male Male | 6 Participants | 11 Participants | 4 Participants | 2 Participants | 1 Participants | 3 Participants | 0 Participants | 3 Participants | 30 Participants |
| Weight | 100.25 kg STANDARD_DEVIATION 15.842 | 82.73 kg STANDARD_DEVIATION 16.963 | 94.15 kg STANDARD_DEVIATION 25.623 | 87.73 kg STANDARD_DEVIATION 31.987 | 76.90 kg STANDARD_DEVIATION 8.344 | 85.97 kg STANDARD_DEVIATION 15.987 | 62.05 kg STANDARD_DEVIATION 11.95 | 87.05 kg STANDARD_DEVIATION 21.025 | 86.50 kg STANDARD_DEVIATION 19.55 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 14 / 15 | 5 / 5 | 3 / 3 | 2 / 2 | 4 / 4 | 2 / 2 | 4 / 4 |
| serious Total, serious adverse events | 3 / 6 | 10 / 15 | 3 / 5 | 2 / 3 | 1 / 2 | 3 / 4 | 2 / 2 | 2 / 4 |
Outcome results
Primary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE is considered any unfavorable and unintended sign, symptom, or disease associated with the use of the study drug, whether or not considered related to the study drug. Preexisting conditions that worsened during the study were reported as adverse events. A SAE 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 enrollment through 30 days after the last dose of study drug (approximately up to 77 months)
Population: Safety Population included all participants who received at least 1 dose of any study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 3 participants |
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 6 participants |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 8 participants |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 15 participants |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 3 participants |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 5 participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 3 participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 participants |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 1 participants |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 2 participants |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 4 participants |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 3 participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 2 participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 participants |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | SAEs | 2 participants |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | AEs | 4 participants |
Secondary
AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel
Time frame: Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2
Population: PK parameter population was defined as all participants who had sufficient dosing data and plasma alisertib or docetaxel concentration-time data to permit the calculation of any PK parameter. 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 10 mg (7D) + Docetaxel 75 mg/m^2 | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 2 Day 1 | 1918.0 hr*ng/mL | Geometric Coefficient of Variation 21.4 |
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 1 Day 1 | 2653.3 hr*ng/mL | Geometric Coefficient of Variation 68.1 |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 1 Day 1 | 2240.6 hr*ng/mL | Geometric Coefficient of Variation 23.9 |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 2 Day 1 | 2632.2 hr*ng/mL | Geometric Coefficient of Variation 28 |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 1 Day 1 | 2007.3 hr*ng/mL | Geometric Coefficient of Variation 15.7 |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 2 Day 1 | 2019.8 hr*ng/mL | Geometric Coefficient of Variation 10.1 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 1 Day 1 | 3570.0 hr*ng/mL | — |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 2 Day 1 | 4000.0 hr*ng/mL | — |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 2 Day 1 | 1785.4 hr*ng/mL | Geometric Coefficient of Variation 35.6 |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 1 Day 1 | 2130.0 hr*ng/mL | — |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 1 Day 1 | 1734.7 hr*ng/mL | Geometric Coefficient of Variation 9.6 |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 2 Day 1 | 1631.0 hr*ng/mL | Geometric Coefficient of Variation 9.9 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 1 Day 1 | 2600.0 hr*ng/mL | Geometric Coefficient of Variation 0 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 2 Day 1 | 3099.0 hr*ng/mL | Geometric Coefficient of Variation 14.3 |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 2 Day 1 | 3120.0 hr*ng/mL | — |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | AUC∞: Area Under the Plasma Concentration Curve From Time 0 to Infinity for Docetaxel | Cycle 1 Day 1 | 1730.9 hr*ng/mL | Geometric Coefficient of Variation 53.9 |
Secondary
AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel
Time frame: Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2
Population: PK parameter population was defined as all participants who had sufficient dosing data and plasma alisertib or docetaxel concentration-time data to permit the calculation of any PK parameter. 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 10 mg (7D) + Docetaxel 75 mg/m^2 | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 1 Day 1 | 2328.3 hr*ng/mL | Geometric Coefficient of Variation 69.5 |
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 2 Day 1 | 1750.8 hr*ng/mL | Geometric Coefficient of Variation 23.1 |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 1 Day 1 | 1925.7 hr*ng/mL | Geometric Coefficient of Variation 21.4 |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 2 Day 1 | 2416.4 hr*ng/mL | Geometric Coefficient of Variation 23.7 |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 1 Day 1 | 1750.1 hr*ng/mL | Geometric Coefficient of Variation 23.1 |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 2 Day 1 | 25.5 hr*ng/mL | Geometric Coefficient of Variation 2174.6 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 1 Day 1 | 2163.4 hr*ng/mL | Geometric Coefficient of Variation 52.8 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 2 Day 1 | 7811.5 hr*ng/mL | Geometric Coefficient of Variation 87.5 |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 1 Day 1 | 1830.0 hr*ng/mL | — |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 2 Day 1 | 1622.8 hr*ng/mL | Geometric Coefficient of Variation 35 |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 1 Day 1 | 1593.1 hr*ng/mL | Geometric Coefficient of Variation 14 |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 2 Day 1 | 1596.0 hr*ng/mL | Geometric Coefficient of Variation 19.9 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 2 Day 1 | 2895.7 hr*ng/mL | Geometric Coefficient of Variation 16.3 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 1 Day 1 | 2394.6 hr*ng/mL | Geometric Coefficient of Variation 2.7 |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 1 Day 1 | 1579.8 hr*ng/mL | Geometric Coefficient of Variation 45.4 |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | AUC(Last): Area Under the Plasma Concentration Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 2 Day 1 | 2510.0 hr*ng/mL | — |
Secondary
AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Day 7 Over the Dosing Interval for Alisertib
Time frame: Prior to dosing on Day 1 and Day 5 or 7 and at multiple time points (up to 12 hours) post-dose in Cycle 1
Population: PK parameter population was defined as all participants who had sufficient dosing data and plasma alisertib concentration-time data to permit the calculation of any PK parameter. 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 10 mg (7D) + Docetaxel 75 mg/m^2 | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Day 7 Over the Dosing Interval for Alisertib | Cycle 1 Day 1 | 1635.0 hr*nmol/L | Geometric Coefficient of Variation 28.3 |
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Day 7 Over the Dosing Interval for Alisertib | Cycle 1 Day 5/Day 7 | 3052.8 hr*nmol/L | Geometric Coefficient of Variation 42 |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Day 7 Over the Dosing Interval for Alisertib | Cycle 1 Day 5/Day 7 | 8546.0 hr*nmol/L | Geometric Coefficient of Variation 49.7 |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Day 7 Over the Dosing Interval for Alisertib | Cycle 1 Day 1 | 3303.0 hr*nmol/L | Geometric Coefficient of Variation 46.1 |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Day 7 Over the Dosing Interval for Alisertib | Cycle 1 Day 1 | 4387.5 hr*nmol/L | Geometric Coefficient of Variation 30.1 |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Day 7 Over the Dosing Interval for Alisertib | Cycle 1 Day 5/Day 7 | 13199.1 hr*nmol/L | Geometric Coefficient of Variation 60.8 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Day 7 Over the Dosing Interval for Alisertib | Cycle 1 Day 1 | 8013.7 hr*nmol/L | Geometric Coefficient of Variation 43.1 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | AUCτ: Area Under the Plasma Concentration-time Curve From Time 0 to Day 7 Over the Dosing Interval for Alisertib | Cycle 1 Day 5/Day 7 | 12630.0 hr*nmol/L | Geometric Coefficient of Variation 27.7 |
Secondary
Best Overall Response Rate Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria
Best Response Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria PSA response is defined as at least 50% decrease in PSA value from baseline for 2 consecutive evaluations.
Time frame: Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months)
Population: PSA-Evaluable Population is a subset of the safety population who had a baseline PSA reference value (\>5 ng/mL) and at least 12 weeks post-baseline PSA assessment for participants with no decline from baseline, or PSA progression within 12 weeks of treatment for participants with PSA decline from baseline.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria | ≥50% Reduction from Baseline | 67 percentage of participants |
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria | <50% Reduction from Baseline | 33 percentage of participants |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria | ≥50% Reduction from Baseline | 80 percentage of participants |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria | <50% Reduction from Baseline | 20 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria | ≥50% Reduction from Baseline | 100 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by PSA Response by Prostate Cancer Working Group 2 (PCWG2) Criteria | <50% Reduction from Baseline | 0 percentage of participants |
Secondary
Best Overall Response Rate Assessed by RECIST Criteria
Best response rate is defined as the percentage of participants with CR, PR, CR+PR, stable disease (SD) and progressive disease (PD) as assessed by RECIST criteria 1.1 for target lesions and assessed by CT, PET or MRI. CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PD: at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study).
Time frame: Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months)
Population: RECIST-Evaluable Population included a subset of the safety population who had measurable disease by RECIST v 1.1 at baseline and had at least 1 post baseline response assessment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Complete Response (CR) | 0 percentage of participants |
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Progressive Disease (PD) | 0 percentage of participants |
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Stable Disease (SD) | 50 percentage of participants |
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | CR+PR | 50 percentage of participants |
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Partial Response (PR) | 50 percentage of participants |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Partial Response (PR) | 11 percentage of participants |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Stable Disease (SD) | 67 percentage of participants |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Progressive Disease (PD) | 22 percentage of participants |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | CR+PR | 11 percentage of participants |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Complete Response (CR) | 0 percentage of participants |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Partial Response (PR) | 0 percentage of participants |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Progressive Disease (PD) | 0 percentage of participants |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Complete Response (CR) | 100 percentage of participants |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Stable Disease (SD) | 0 percentage of participants |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | CR+PR | 100 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | CR+PR | 50 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Progressive Disease (PD) | 50 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Complete Response (CR) | 0 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Partial Response (PR) | 50 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Stable Disease (SD) | 0 percentage of participants |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | CR+PR | 0 percentage of participants |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Complete Response (CR) | 0 percentage of participants |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Partial Response (PR) | 0 percentage of participants |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Stable Disease (SD) | 50 percentage of participants |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Progressive Disease (PD) | 50 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | CR+PR | 25 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Stable Disease (SD) | 0 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Partial Response (PR) | 25 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Complete Response (CR) | 0 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Best Overall Response Rate Assessed by RECIST Criteria | Progressive Disease (PD) | 75 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Best Overall Response Rate Assessed by RECIST Criteria | CR+PR | 0 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Best Overall Response Rate Assessed by RECIST Criteria | Complete Response (CR) | 0 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Best Overall Response Rate Assessed by RECIST Criteria | Partial Response (PR) | 0 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Best Overall Response Rate Assessed by RECIST Criteria | Progressive Disease (PD) | 100 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Best Overall Response Rate Assessed by RECIST Criteria | Stable Disease (SD) | 0 percentage of participants |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Best Overall Response Rate Assessed by RECIST Criteria | Progressive Disease (PD) | 0 percentage of participants |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Best Overall Response Rate Assessed by RECIST Criteria | Stable Disease (SD) | 50 percentage of participants |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Best Overall Response Rate Assessed by RECIST Criteria | Complete Response (CR) | 0 percentage of participants |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Best Overall Response Rate Assessed by RECIST Criteria | CR+PR | 50 percentage of participants |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Best Overall Response Rate Assessed by RECIST Criteria | Partial Response (PR) | 50 percentage of participants |
Secondary
Cmax: Maximum Observed Plasma Concentration for Alisertib
Time frame: Prior to dosing on Day 1 and Day 5 or 7 and at multiple time points (up to 12 hours) post-dose in Cycle 1
Population: PK parameter population was defined as all participants who had sufficient dosing data and plasma alisertib concentration-time data to permit the calculation of any PK parameter. 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 10 mg (7D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Alisertib | Cycle 1 Day 1 | 290.4 nmol/L | Geometric Coefficient of Variation 22.1 |
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Alisertib | Cycle 1 Day 5/Day 7 | 435.8 nmol/L | Geometric Coefficient of Variation 31 |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Alisertib | Cycle 1 Day 5/Day 7 | 1140.6 nmol/L | Geometric Coefficient of Variation 44.7 |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Alisertib | Cycle 1 Day 1 | 557.5 nmol/L | Geometric Coefficient of Variation 57.3 |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Alisertib | Cycle 1 Day 1 | 751.6 nmol/L | Geometric Coefficient of Variation 31.3 |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Alisertib | Cycle 1 Day 5/Day 7 | 1637.9 nmol/L | Geometric Coefficient of Variation 52.1 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Alisertib | Cycle 1 Day 1 | 1346.4 nmol/L | Geometric Coefficient of Variation 49.8 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Alisertib | Cycle 1 Day 5/Day 7 | 1766.3 nmol/L | Geometric Coefficient of Variation 40.1 |
Secondary
Cmax: Maximum Observed Plasma Concentration for Docetaxel
Time frame: Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2
Population: Pharmacokinetic (PK) parameter population was defined as all participants who had sufficient dosing data and plasma alisertib or docetaxel concentration-time data to permit the calculation of any PK parameter. 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 10 mg (7D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 1 Day 1 | 2392.7 ng/mL | Geometric Coefficient of Variation 60.2 |
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 2 Day 1 | 1825.1 ng/mL | Geometric Coefficient of Variation 25.9 |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 1 Day 1 | 1730.4 ng/mL | Geometric Coefficient of Variation 26.5 |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 2 Day 1 | 1957.0 ng/mL | Geometric Coefficient of Variation 23.4 |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 1 Day 1 | 1587.0 ng/mL | Geometric Coefficient of Variation 34.1 |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 2 Day 1 | 2146.6 ng/mL | Geometric Coefficient of Variation 19.4 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 1 Day 1 | 1717.6 ng/mL | Geometric Coefficient of Variation 51.9 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 2 Day 1 | 3299.9 ng/mL | Geometric Coefficient of Variation 0.9 |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 1 Day 1 | 3751.4 ng/mL | Geometric Coefficient of Variation 80.8 |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 2 Day 1 | 1649.7 ng/mL | Geometric Coefficient of Variation 19.1 |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 1 Day 1 | 1159.9 ng/mL | Geometric Coefficient of Variation 13.8 |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 2 Day 1 | 1061.6 ng/mL | Geometric Coefficient of Variation 24.8 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 2 Day 1 | 2504.6 ng/mL | Geometric Coefficient of Variation 28 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 1 Day 1 | 2232.9 ng/mL | Geometric Coefficient of Variation 19.8 |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 1 Day 1 | 1386.6 ng/mL | Geometric Coefficient of Variation 47 |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 2 Day 1 | 1627.8 ng/mL | Geometric Coefficient of Variation 17.2 |
Secondary
Duration of Response
Duration of response is defined as the time from the date of first documentation of a response to the date of first documented progressive disease (PD), or censored at last SD or better.
Time frame: Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months)
Population: Response-Evaluable population includes patients that are either RECIST-evaluable or PSA-evaluable. Here, number of participants analyzed are the participants who were responders. A responder that did not experience disease progression were censored at the last response assessment that is SD or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Duration of Response | 187 days |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Duration of Response | 342 days |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Duration of Response | 830 days |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Duration of Response | 176 days |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Duration of Response | 79 days |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Duration of Response | NA days |
Secondary
Duration of Stable Disease (SD)
Duration of SD is defined as the time from first dose to first PD, or censored at last SD or better.
Time frame: Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months)
Population: Response-Evaluable population includes patients that are either RECIST-evaluable or PSA-evaluable. Here, number of participants analyzed are the participants who had SD. For a participants that has not progressed, duration of SD is censored at the last response assessment that is SD or better.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Duration of Stable Disease (SD) | 253 days |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Duration of Stable Disease (SD) | NA days |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Duration of Stable Disease (SD) | 309 days |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Duration of Stable Disease (SD) | 134 days |
Secondary
Overall Response Rate for Prostate Cancer Participants
ORR is defined as percentage of participants who achieved CR or PR as assessed by either RECIST v 1.1 or PSA response by prostate cancer working group 2 (PCWG2) criteria. According to RECIST v 1.1, CR: disappearance of all target and non-target lesions and (if applicable) normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR: ≥30% decrease in sum of LD of target lesions in reference to Baseline sum LD. PSA response by PCWG2 is defined as PSA at least 50% decrease in PSA value from baseline for 2 consecutive evaluations. PCWG2 defines PSA progression as the date that a 25% or greater increase and an absolute increase of 2 ng/mL or more from the nadir is documented, which is confirmed by a second value obtained 3 or more weeks later.
Time frame: Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months)
Population: Response-Evaluable Population included participants who were either RECIST evaluable or PSA-evaluable. Here, number of participants analyzed are the enrolled participants who had castration-resistant prostate cancer (CRPC) and were evaluable by either RECIST or PSA response criteria.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Overall Response Rate for Prostate Cancer Participants | 50 percentage of participants |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Overall Response Rate for Prostate Cancer Participants | 20 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Overall Response Rate for Prostate Cancer Participants | 100 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Overall Response Rate for Prostate Cancer Participants | 0 percentage of participants |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Overall Response Rate for Prostate Cancer Participants | 100 percentage of participants |
Secondary
Overall Response Rate (ORR) Assessed for Overall Participant Population
ORR is defined as percentage of participants who achieved complete response (CR) or partial response (PR) as assessed by response evaluation criteria in solid tumors (RECIST) v 1.1. CR was defined as disappearance of all target and non-target lesions and normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined as ≥30% decrease in sum of longest diameter (LD) of target lesions in reference to Baseline. RECIST-Evaluable Population is subset of safety population who had measurable disease by RECIST v 1.1 at baseline and had at least 1 post baseline response. prostate specific antigen (PSA)-Evaluable Population is subset of the safety population who had a baseline PSA reference value (\>5 ng/mL) and at least 12 weeks post-baseline PSA assessment for participants with no decline from baseline, or PSA progression within 12 weeks of treatment for participants with PSA decline from baseline.
Time frame: Baseline up to Cycle 36 (21-day cycles) until disease progression, death or EOT (approximately up to 24.8 months)
Population: Response-Evaluable Population included participants who were either RECIST evaluable and/or PSA-evaluable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Overall Response Rate (ORR) Assessed for Overall Participant Population | 50 percentage of participants |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Overall Response Rate (ORR) Assessed for Overall Participant Population | 10 percentage of participants |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Overall Response Rate (ORR) Assessed for Overall Participant Population | 100 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Overall Response Rate (ORR) Assessed for Overall Participant Population | 50 percentage of participants |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Overall Response Rate (ORR) Assessed for Overall Participant Population | 0 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Overall Response Rate (ORR) Assessed for Overall Participant Population | 25 percentage of participants |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Overall Response Rate (ORR) Assessed for Overall Participant Population | 0 percentage of participants |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Overall Response Rate (ORR) Assessed for Overall Participant Population | 50 percentage of participants |
Secondary
Terminal Phase Elimination Half-life (T1/2) for Docetaxel
Time frame: Day 1 pre-dose and at multiple time points (up to 48 hours) post-dose in Cycles 1 and 2
Population: PK parameter population was defined as all participants who had sufficient dosing data and plasma alisertib or docetaxel concentration-time data to permit the calculation of any PK parameter. 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 10 mg (7D) + Docetaxel 75 mg/m^2 | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 1 Day 1 | 21.80 hr | Standard Deviation 4.339 |
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 2 Day 1 | 24.18 hr | Standard Deviation 2.05 |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 1 Day 1 | 22.88 hr | Standard Deviation 4.733 |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 2 Day 1 | 20.73 hr | Standard Deviation 5.845 |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 1 Day 1 | 24.00 hr | Standard Deviation 6.934 |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 2 Day 1 | 20.40 hr | Standard Deviation 2.121 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 1 Day 1 | 15.60 hr | — |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 2 Day 1 | 16.40 hr | — |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 1 Day 1 | 30.70 hr | — |
| Alisertib 30 mg (7D) + Docetaxel 60 mg/m^2 | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 2 Day 1 | 25.10 hr | Standard Deviation 2.546 |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 1 Day 1 | 16.34 hr | Standard Deviation 5.684 |
| Alisertib 30 mg (5D) + Docetaxel 60 mg/m^2 | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 2 Day 1 | 22.00 hr | Standard Deviation 2.404 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 2 Day 1 | 16.95 hr | Standard Deviation 0.636 |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 1 Day 1 | 19.25 hr | Standard Deviation 2.051 |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 1 Day 1 | 24.80 hr | Standard Deviation 6.444 |
| Alisertib 40 mg (5D) + Docetaxel 75 mg/m^2 + GCSF | Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 2 Day 1 | 26.00 hr | — |
Secondary
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib
Time frame: Prior to dosing on Day 1 and Day 5 or 7 and at multiple time points (up to 12 hours) post-dose in Cycle 1
Population: PK parameter population was defined as all participants who had sufficient dosing data and plasma alisertib concentration-time data to permit the calculation of any PK parameter. Here number analyzed is the number of participants with data available for analysis at the given time point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib | Cycle 1 Day 1 | 2.050 hr |
| Alisertib 10 mg (7D) + Docetaxel 75 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib | Cycle 1 Day 5/Day 7 | 3.510 hr |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib | Cycle 1 Day 5/Day 7 | 3.030 hr |
| Alisertib 20 mg (7D) + Docetaxel 75 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib | Cycle 1 Day 1 | 4.000 hr |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib | Cycle 1 Day 1 | 3.560 hr |
| Alisertib 30 mg (7D) + Docetaxel 75 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib | Cycle 1 Day 5/Day 7 | 2.030 hr |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib | Cycle 1 Day 1 | 1.500 hr |
| Alisertib 30 mg (5D) + Docetaxel 75 mg/m^2 | Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib | Cycle 1 Day 5/Day 7 | 1.975 hr |