Prostate Cancer
Conditions
Brief summary
This is an open-label, multicenter, Phase 1/2 study of TAK-700 in combination with docetaxel and prednisone that will evaluate the safety and pharmacokinetics (PK) of the combination and will allow estimation of prostate-specific antigen (PSA) response in men with metastatic castration-resistant prostate cancer (mCRPC).
Interventions
DRUGTAK-700
TAK-700 with docetaxel and prednisone on a continuous schedule.
DRUGDocetaxel
TAK-700 with docetaxel and prednisone on a continuous schedule.
DRUGPrednisone
TAK-700 with docetaxel and prednisone on a continuous schedule.
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Each patient must meet all of the following inclusion criteria: * Voluntary written consent * Male patients 18 years or older * Estimated life expectancy of 6 months or more * Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma * Radiograph-documented metastatic disease * Progressive disease * Prior surgical castration or concurrent use of an agent for medical castration * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Physical examination findings that are consistent with other study entry or
Exclusion criteria
and identified but not excluded chronic conditions * Even if surgically sterilized, patients must Practice effective barrier contraception during the entire study treatment period through 6 months after the last dose of study drug, OR Abstain from heterosexual intercourse * Any use of opiates must be stable for at least 2 weeks prior to study entry * Meet screening laboratory values as specified in protocol * Suitable venous access
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Best PSA Response | Cycle 2 Day 1 up to Cycle 12 Day 21 | Best PSA response was defined as the maximum PSA percent reduction from baseline at any time beyond Cycle 1. |
| Phase 2: Terminal Phase Elimination Half-life (T1/2) for Docetaxel | Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-end of docetaxel infusion; Cycle 2 Day 1: pre-dose and at multiple time points (up to 8 hours) post-end of docetaxel infusion | — |
| Phase 2: Cmax, ss: Maximum Observed Plasma Concentration at Steady State for Orteronel | Cycle 1 Day 21: pre-dose and at multiple time points (up to 8 hours) post-dose for orteronel; Cycle 2 Day 1: pre-dose and at multiple time points (up to 8 hours) post-dose for orteronel | — |
| Phase 2: AUC 0-tau: Area Under the Plasma Concentration Versus Time Curve Zero to the Time of the End of the Dosing Interval for Orteronel | Cycle 1 Day 21: pre-dose and at multiple time points (up to 8 hours) post-dose for orteronel; Cycle 2 Day 1: pre-dose and at multiple time points (up to 8 hours) post-dose for orteronel | — |
| Phase 2: Percentage of Participants With Prostate-specific Antigen (PSA) Response of 30 Percent (%), 50%, and 90% | Cycle 4 Day 21 | PSA response rates (PSA-30, PSA-50, and PSA-90) were defined as greater than or equal to (\>=) 30%, 50%, and 90% reductions, respectively, from baseline in PSA concentration. |
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) or Serious Adverse Events (SAE) | Baseline up to 30 days after last dose of study drug (Day of last dose for Phase 1: Cycle 84 Day 21; Phase 2: Cycle 48 Day 21) | — |
| Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Baseline up to 30 days after last dose of study drug (Day of last dose for Phase 1: Cycle 84 Day 21; Phase 2: Cycle 48 Day 21) | — |
| Number of Participants With TEAEs Related to Vital Signs | Baseline up to 30 days after last dose of study drug (Day of last dose for Phase 1: Cycle 84 Day 21; Phase 2: Cycle 48 Day 21) | — |
| Number of Participants With TEAEs Related to Electrocardiogram (ECG) | Baseline up to 30 days after last dose of study drug (Day of last dose for Phase 1: Cycle 84 Day 21; Phase 2: Cycle 48 Day 21) | — |
| Phase 2: Cmax: Maximum Observed Plasma Concentration for Docetaxel | Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-end of docetaxel infusion; Cycle 2 Day 1: pre-dose and at multiple time points (up to 8 hours) post-end of docetaxel infusion | — |
| Phase 2: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-end of docetaxel infusion; Cycle 2 Day 1: pre-dose and at multiple time points (up to 8 hours) post-end of docetaxel infusion | — |
| Phase 2: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Docetaxel | Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-end of docetaxel infusion; Cycle 2 Day 1: pre-dose and at multiple time points (up to 8 hours) post-end of docetaxel infusion | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 2: Time to Radiographic Disease Progression | Baseline until disease progression or death, whichever occurred first (up to approximately 25.4 months) | Time to Radiographic Disease Progression was defined as (date of Radiographic Disease progression) - (date of first dose of drug) + 1. Radiographic disease progression is defined as the presence of progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.1) criteria and/or bone scan progression determined according to second Prostate Cancer Clinical Trials Working Group (PCWG2) bone scan criteria. |
| Phase 2: Percentage of Participants With Objective Measurable Disease Response | Baseline until disease progression or death, whichever occurred first (up to approximately 25.4 months) | Percentage of participants with objective measurable disease response based assessment of complete response (CR), partial response (PR), stable disease or PD according to RECIST (Version 1.1). A CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to less than (\<)10 millimeter (mm). A PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of longest diameters of non-lymph node lesions and of the short diameter(s) or short axis of lymph nodes. |
| Phase 2: Change From Baseline in Circulating Tumor Cells (CTCs) | Cycle 2 Day 1, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, Cycle 17 Day 1, Cycle 21 Day 1, End of treatment (approximately up to Cycle 48), Last assessment (30 days after last dose of study drug, approximately up to 1038 days) | Baseline is defined as the last scheduled observed measurement prior to the first dose of drug. |
| Phase 2: Time to PSA Progression | Baseline until disease progression or death, whichever occurred first (up to approximately 25.4 months) | Time to PSA progression was defined as (date of PSA progression) - (date of first dose of drug) + 1, where PSA progression was defined as: For participants whose PSA concentrations never declined before the end of Cycle 4 of treatment: a) \>=25% increase over the baseline level and an increase in absolute PSA concentration \>=2 ng/mL; For participants who initially experienced a PSA decline: a) \>=25% increase in PSA above the nadir concentration and an increase in absolute PSA concentration \>=2 ng/mL. |
Countries
United States
Participant flow
Recruitment details
Participants took part in the study at 10 investigative sites in the United States from 22 July 2010 to 03 March 2016.
Pre-assignment details
Male participants with a historical diagnosis of metastatic-castration resistant prostate cancer (mCRPC) were enrolled in this 2 part study to receive orteronel (TAK-700) along with docetaxel 75 milligram per square meter (mg/m\^2) and prednisone 5 milligram (mg) twice daily (BID).
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone Orteronel (TAK-700) 200 mg, tablets, orally, twice daily starting from Day 1 along with docetaxel 75 mg/m\^2, infusion, intravenously over 1 hour on Day 1 and prednisone 5 mg, tablets, orally, twice daily from Day 8 up to Day 21 of each treatment cycle. Cycle 1 of Phase 1 consisted of a 28-day treatment period and subsequent cycles consisted of 21-day treatment periods. | 6 |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone Orteronel (TAK-700) 400 mg, tablets, orally, twice daily starting from Day 1 along with docetaxel 75 mg/m\^2, infusion, intravenously over 1 hour on Day 1 and prednisone 5 mg, tablets , orally, twice daily from Day 8 up to Day 21 of each treatment cycle. Cycle 1 of Phase 1 consisted of a 28-day treatment period and subsequent cycles consisted of 21-day treatment periods. | 8 |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone Orteronel (TAK-700) 400 mg, tablets, orally, twice daily starting from Cycle 1 Day 15, then given continuously along with docetaxel 75 mg/m\^2, infusion, intravenously over 1 hour on Day 1 and prednisone 5 mg, tablets, orally, twice daily from Day 1 up to Day 21 of each 21-day treatment cycle until disease progression or end of treatment (EOT). | 23 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 | 2 |
| Overall Study | Other | 0 | 3 | 2 |
| Overall Study | Prostate-specificAntigen(PSA)progression | 0 | 0 | 1 |
| Overall Study | Radiographic disease progression | 3 | 2 | 8 |
| Overall Study | Symptomatic deterioration | 0 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 4 |
Baseline characteristics
| Characteristic | Total | Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone |
|---|---|---|---|---|
| Age, Continuous | 66.6 years STANDARD_DEVIATION 8.8 | 66.2 years STANDARD_DEVIATION 9.21 | 65.3 years STANDARD_DEVIATION 7.76 | 69.7 years STANDARD_DEVIATION 9.2 |
| Body mass index (BMI) | 31.044 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.6762 | 31.599 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.2488 | 30.589 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 5.9713 | 29.525 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 7.5049 |
| Height | 178.38 centimeter STANDARD_DEVIATION 7.018 | 179.57 centimeter STANDARD_DEVIATION 6.684 | 179.39 centimeter STANDARD_DEVIATION 5.452 | 172.47 centimeter STANDARD_DEVIATION 8.15 |
| Race/Ethnicity, Customized Black or African American | 5 Participants | 2 Participants | 2 Participants | 1 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 35 Participants | 22 Participants | 7 Participants | 6 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 2 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 32 Participants | 21 Participants | 6 Participants | 5 Participants |
| Region of Enrollment United States | 37 Participants | 23 Participants | 8 Participants | 6 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 37 Participants | 23 Participants | 8 Participants | 6 Participants |
| Weight | 99.07 kilogram STANDARD_DEVIATION 20.557 | 101.83 kilogram STANDARD_DEVIATION 17.527 | 98.61 kilogram STANDARD_DEVIATION 20.296 | 89.08 kilogram STANDARD_DEVIATION 30.972 |
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 | 6 / 6 | 8 / 8 | 23 / 23 |
| serious Total, serious adverse events | 5 / 6 | 5 / 8 | 16 / 23 |
Outcome results
Primary
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) or Serious Adverse Events (SAE)
Time frame: Baseline up to 30 days after last dose of study drug (Day of last dose for Phase 1: Cycle 84 Day 21; Phase 2: Cycle 48 Day 21)
Population: The safety analysis set included all participants who were enrolled and received at least 1 dose of orteronel.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) or Serious Adverse Events (SAE) | SAE | 5 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) or Serious Adverse Events (SAE) | TEAE | 6 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) or Serious Adverse Events (SAE) | SAE | 5 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) or Serious Adverse Events (SAE) | TEAE | 8 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) or Serious Adverse Events (SAE) | SAE | 16 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE) or Serious Adverse Events (SAE) | TEAE | 23 participants |
Primary
Number of Participants With TEAEs Related to Electrocardiogram (ECG)
Time frame: Baseline up to 30 days after last dose of study drug (Day of last dose for Phase 1: Cycle 84 Day 21; Phase 2: Cycle 48 Day 21)
Population: The safety analysis set included all participants who were enrolled and received at least 1 dose of orteronel.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Electrocardiogram (ECG) | Overall | 1 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Electrocardiogram (ECG) | Angina pectoris | 1 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Electrocardiogram (ECG) | Overall | 0 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Electrocardiogram (ECG) | Angina pectoris | 0 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Electrocardiogram (ECG) | Overall | 1 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Electrocardiogram (ECG) | Angina pectoris | 1 participants |
Primary
Number of Participants With TEAEs Related to Hematology and Serum Chemistry
Time frame: Baseline up to 30 days after last dose of study drug (Day of last dose for Phase 1: Cycle 84 Day 21; Phase 2: Cycle 48 Day 21)
Population: The safety analysis set included all participants who were enrolled and received at least 1 dose of orteronel.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Neutropenia | 3 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Aspartate aminotransferase increased | 0 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hypomagnesaemia | 1 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hyponatraemia | 1 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Anaemia | 2 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Leukopenia | 0 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Leukocytosis | 0 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Neutrophil count decreased | 1 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Blood bilirubin increased | 0 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Blood creatinine increased | 1 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | White blood cell count decreased | 0 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Gamma-glutamyltransferase increased | 0 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Blood alkaline phosphatase increased | 0 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Alanine aminotransferase increased | 0 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hyperglycaemia | 3 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hypophosphataemia | 0 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hyperkalaemia | 0 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Leukocytosis | 0 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Neutrophil count decreased | 2 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hyperglycaemia | 4 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Blood bilirubin increased | 1 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hyponatraemia | 1 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Blood creatinine increased | 0 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | White blood cell count decreased | 3 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hyperkalaemia | 3 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Gamma-glutamyltransferase increased | 0 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hypophosphataemia | 3 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Neutropenia | 4 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Blood alkaline phosphatase increased | 0 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hypomagnesaemia | 2 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Alanine aminotransferase increased | 0 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Anaemia | 0 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Aspartate aminotransferase increased | 0 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Leukopenia | 1 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hypophosphataemia | 2 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Leukocytosis | 3 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hyperkalaemia | 0 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Leukopenia | 4 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Neutrophil count decreased | 4 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Neutropenia | 8 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Alanine aminotransferase increased | 2 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Blood bilirubin increased | 1 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Aspartate aminotransferase increased | 2 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hyperglycaemia | 4 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Blood creatinine increased | 2 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hyponatraemia | 2 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Blood alkaline phosphatase increased | 3 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | White blood cell count decreased | 6 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Anaemia | 6 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Hypomagnesaemia | 3 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Hematology and Serum Chemistry | Gamma-glutamyltransferase increased | 4 participants |
Primary
Number of Participants With TEAEs Related to Vital Signs
Time frame: Baseline up to 30 days after last dose of study drug (Day of last dose for Phase 1: Cycle 84 Day 21; Phase 2: Cycle 48 Day 21)
Population: The safety analysis set included all participants who were enrolled and received at least 1 dose of orteronel.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Vital Signs | Hypotension | 1 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Vital Signs | Hypertension | 3 participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Vital Signs | Accelerated hypertension | 0 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Vital Signs | Hypotension | 0 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Vital Signs | Hypertension | 2 participants |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Vital Signs | Accelerated hypertension | 0 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Vital Signs | Hypertension | 1 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Vital Signs | Accelerated hypertension | 1 participants |
| Phase 2: Orteronel 400 mg BID + Docetaxel + Prednisone | Number of Participants With TEAEs Related to Vital Signs | Hypotension | 1 participants |
Primary
Phase 2: AUC 0-tau: Area Under the Plasma Concentration Versus Time Curve Zero to the Time of the End of the Dosing Interval for Orteronel
Time frame: Cycle 1 Day 21: pre-dose and at multiple time points (up to 8 hours) post-dose for orteronel; Cycle 2 Day 1: pre-dose and at multiple time points (up to 8 hours) post-dose for orteronel
Population: The PK-evaluable population included participants who had sufficient dosing data and plasma concentration-time data to permit calculation of at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: AUC 0-tau: Area Under the Plasma Concentration Versus Time Curve Zero to the Time of the End of the Dosing Interval for Orteronel | 18000 ng*hr/mL | Geometric Coefficient of Variation 14.6 |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Phase 2: AUC 0-tau: Area Under the Plasma Concentration Versus Time Curve Zero to the Time of the End of the Dosing Interval for Orteronel | 871 ng*hr/mL | Geometric Coefficient of Variation 44.9 |
Comparison: ANOVA with dose level as a fixed effect and participant as a random effect.90% CI: [0.955, 1.195]
Primary
Phase 2: AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Docetaxel
Time frame: Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-end of docetaxel infusion; Cycle 2 Day 1: pre-dose and at multiple time points (up to 8 hours) post-end of docetaxel infusion
Population: Data was not calculated since no participant was available for analysis.
Primary
Phase 2: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel
Time frame: Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-end of docetaxel infusion; Cycle 2 Day 1: pre-dose and at multiple time points (up to 8 hours) post-end of docetaxel infusion
Population: The PK-evaluable population included participants who had sufficient dosing data and plasma concentration-time data to permit calculation of at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | 1180 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 43.7 |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Phase 2: AUClast: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Docetaxel | 1270 nanogram*hour per milliliter (ng*hr/mL) | Geometric Coefficient of Variation 25 |
Comparison: ANOVA with dose level as a fixed effect and participant as a random effect.90% CI: [0.793, 1.455]
Primary
Phase 2: Best PSA Response
Best PSA response was defined as the maximum PSA percent reduction from baseline at any time beyond Cycle 1.
Time frame: Cycle 2 Day 1 up to Cycle 12 Day 21
Population: The PSA-evaluable population included all participants with a baseline PSA evaluation and at least 1 PSA evaluation beyond Cycle 1, or participants with baseline PSA evaluation without a beyond-cycle-1 PSA evaluation due to PSA progression, disease progression, unacceptable AE, or death.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Best PSA Response | -61.72 percent change | Standard Deviation 51.609 |
Primary
Phase 2: Cmax: Maximum Observed Plasma Concentration for Docetaxel
Time frame: Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-end of docetaxel infusion; Cycle 2 Day 1: pre-dose and at multiple time points (up to 8 hours) post-end of docetaxel infusion
Population: The pharmacokinetic (PK)-evaluable population included participants who had sufficient dosing data and plasma concentration-time data to permit calculation of at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Cmax: Maximum Observed Plasma Concentration for Docetaxel | 1330 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 41.6 |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Phase 2: Cmax: Maximum Observed Plasma Concentration for Docetaxel | 1600 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 25.9 |
Comparison: ANOVA with dose level as a fixed effect and participant as a random effect.90% CI: [0.87, 1.666]
Primary
Phase 2: Cmax, ss: Maximum Observed Plasma Concentration at Steady State for Orteronel
Time frame: Cycle 1 Day 21: pre-dose and at multiple time points (up to 8 hours) post-dose for orteronel; Cycle 2 Day 1: pre-dose and at multiple time points (up to 8 hours) post-dose for orteronel
Population: PK set where Cmax,ss data was available. The PK-evaluable population included participants who had sufficient dosing data and plasma concentration-time data to permit calculation of at least 1 PK parameter.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Cmax, ss: Maximum Observed Plasma Concentration at Steady State for Orteronel | 2660 ng/mL | Geometric Coefficient of Variation 38.8 |
| Phase 1: Orteronel 400 mg BID + Docetaxel + Prednisone | Phase 2: Cmax, ss: Maximum Observed Plasma Concentration at Steady State for Orteronel | 3000 ng/mL | Geometric Coefficient of Variation 27.1 |
Comparison: ANOVA with dose level as a fixed effect and participant as a random effect.90% CI: [0.802, 1.417]
Primary
Phase 2: Percentage of Participants With Prostate-specific Antigen (PSA) Response of 30 Percent (%), 50%, and 90%
PSA response rates (PSA-30, PSA-50, and PSA-90) were defined as greater than or equal to (\>=) 30%, 50%, and 90% reductions, respectively, from baseline in PSA concentration.
Time frame: Cycle 4 Day 21
Population: The PSA-evaluable population included all participants with a baseline PSA evaluation and at least 1 PSA evaluation beyond Cycle 1, or participants with baseline PSA evaluation without a beyond-cycle-1 PSA evaluation due to PSA progression, disease progression, unacceptable adverse event (AE), or death.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Percentage of Participants With Prostate-specific Antigen (PSA) Response of 30 Percent (%), 50%, and 90% | PSA-30 | 68 percentage of participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Percentage of Participants With Prostate-specific Antigen (PSA) Response of 30 Percent (%), 50%, and 90% | PSA-50 | 59 percentage of participants |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Percentage of Participants With Prostate-specific Antigen (PSA) Response of 30 Percent (%), 50%, and 90% | PSA-90 | 23 percentage of participants |
Primary
Phase 2: Terminal Phase Elimination Half-life (T1/2) for Docetaxel
Time frame: Cycle 1 Day 1: pre-dose and at multiple time points (up to 24 hours) post-end of docetaxel infusion; Cycle 2 Day 1: pre-dose and at multiple time points (up to 8 hours) post-end of docetaxel infusion
Population: Data was not calculated since no participant was available for analysis.
Secondary
Phase 2: Change From Baseline in Circulating Tumor Cells (CTCs)
Baseline is defined as the last scheduled observed measurement prior to the first dose of drug.
Time frame: Cycle 2 Day 1, Cycle 5 Day 1, Cycle 9 Day 1, Cycle 13 Day 1, Cycle 17 Day 1, Cycle 21 Day 1, End of treatment (approximately up to Cycle 48), Last assessment (30 days after last dose of study drug, approximately up to 1038 days)
Population: Safety analysis set where baseline and post-baseline assessments were available. The safety analysis set included all participants who were enrolled and received at least 1 dose of orteronel.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Change From Baseline in Circulating Tumor Cells (CTCs) | Baseline (n=21) | 47.9 milliliter (mL) | Standard Deviation 108.85 |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Change From Baseline in Circulating Tumor Cells (CTCs) | Change at Cycle 13 Day 1 (n=7) | -11.3 milliliter (mL) | Standard Deviation 27.72 |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Change From Baseline in Circulating Tumor Cells (CTCs) | Change at Cycle 17 Day 1 (n=5) | -18.8 milliliter (mL) | Standard Deviation 31.93 |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Change From Baseline in Circulating Tumor Cells (CTCs) | Change at Cycle 21 Day 1 (n=1) | -5.0 milliliter (mL) | — |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Change From Baseline in Circulating Tumor Cells (CTCs) | Change at End of treatment (n=11) | -40.2 milliliter (mL) | Standard Deviation 66.43 |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Change From Baseline in Circulating Tumor Cells (CTCs) | Change at Cycle 2 Day 1 (n=12) | -11.9 milliliter (mL) | Standard Deviation 24.57 |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Change From Baseline in Circulating Tumor Cells (CTCs) | Change at Cycle 5 Day 1 (n=16) | -39.0 milliliter (mL) | Standard Deviation 80.35 |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Change From Baseline in Circulating Tumor Cells (CTCs) | Change at Cycle 9 Day 1 (n=6) | -25.5 milliliter (mL) | Standard Deviation 35.07 |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Change From Baseline in Circulating Tumor Cells (CTCs) | Change at Last assessment (n=18) | -35.0 milliliter (mL) | Standard Deviation 76.3 |
Secondary
Phase 2: Percentage of Participants With Objective Measurable Disease Response
Percentage of participants with objective measurable disease response based assessment of complete response (CR), partial response (PR), stable disease or PD according to RECIST (Version 1.1). A CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have had reduction in short axis to less than (\<)10 millimeter (mm). A PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of longest diameters of non-lymph node lesions and of the short diameter(s) or short axis of lymph nodes.
Time frame: Baseline until disease progression or death, whichever occurred first (up to approximately 25.4 months)
Population: The RECIST-evaluable population was defined as all participants with measurable disease by RECIST (Version 1.1) at baseline, and with at least 1 postbaseline tumor response assessment (RECIST, Version 1.1).
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Percentage of Participants With Objective Measurable Disease Response | Partial response | 70 percentage of participants | — |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Percentage of Participants With Objective Measurable Disease Response | Stable Disease | 30 percentage of participants | — |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Percentage of Participants With Objective Measurable Disease Response | Complete response | 0 percentage of participants | 51.609 |
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Percentage of Participants With Objective Measurable Disease Response | Progressive Disease | 0 percentage of participants | — |
Secondary
Phase 2: Time to PSA Progression
Time to PSA progression was defined as (date of PSA progression) - (date of first dose of drug) + 1, where PSA progression was defined as: For participants whose PSA concentrations never declined before the end of Cycle 4 of treatment: a) \>=25% increase over the baseline level and an increase in absolute PSA concentration \>=2 ng/mL; For participants who initially experienced a PSA decline: a) \>=25% increase in PSA above the nadir concentration and an increase in absolute PSA concentration \>=2 ng/mL.
Time frame: Baseline until disease progression or death, whichever occurred first (up to approximately 25.4 months)
Population: The safety analysis set included all participants who were enrolled and received at least 1 dose of orteronel.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Time to PSA Progression | 203 days | 95% Confidence Interval 51.609 |
Secondary
Phase 2: Time to Radiographic Disease Progression
Time to Radiographic Disease Progression was defined as (date of Radiographic Disease progression) - (date of first dose of drug) + 1. Radiographic disease progression is defined as the presence of progressive disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) (Version 1.1) criteria and/or bone scan progression determined according to second Prostate Cancer Clinical Trials Working Group (PCWG2) bone scan criteria.
Time frame: Baseline until disease progression or death, whichever occurred first (up to approximately 25.4 months)
Population: The safety analysis set included all participants who were enrolled and received at least 1 dose of orteronel.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Phase 1: Orteronel 200 mg BID + Docetaxel + Prednisone | Phase 2: Time to Radiographic Disease Progression | 393 days | 95% Confidence Interval 51.609 |