Metastatic Castration-Resistant Prostate Cancer
Conditions
Keywords
mCRPC, CDK4, CDK6, CDK4/6, CDK4&6 inhibitor, CDK4/6 inhibitor, LY2835219, CYCLONE 1, CYCLONE1
Brief summary
The study will evaluate how safe and effective abemaciclib is when given to participants whose metastatic prostate cancer progresses after they had received several previous treatments.
Interventions
DRUGAbemaciclib
Administered orally
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participant must have metastatic prostate cancer for which castration (medical or surgical) is no longer effective (castration-resistant). * Participant must have disease spread to soft tissue that is measurable. * Participant must have documented evidence of progressive disease by PSA test or imaging. * Participant must have previously received at least one of the following treatment: abiraterone acetate, apalutamide, darolutamide or enzalutamide. * Participant must have previously received chemotherapy with docetaxel and cabazitaxel. * Participant must be willing and amenable to undergo a biopsy of tumor tissue (or able to provide adequate archived tumor tissue sample) and to provide blood for research. * Participant must have good physical functioning ability and adequate organ function.
Exclusion criteria
* Participant must not have received more than 3 therapy regimens for metastatic castration-resistant prostate cancer (NOTE: GnRHa, first-generation antiandrogens (flutamide, nilutamide, or bicalutamide), diethylstilbestrol (DES) (or other estrogens), corticosteroids, ketoconazole, and bone loss-prevention will not count as systemic therapy regimens. * Participants must not have previously received abemaciclib or any cyclin-dependent kinase (CDK)4 and/or CDK6 inhibitors. * Participants must not have serious and/or uncontrolled preexisting medical condition(s) including but not limited to severe renal impairment, severe hepatic impairment, interstitial lung disease (ILD)/pneumonitis, severe dyspnea at rest or requiring oxygen therapy or other serious preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study. * Participants must not have, or suspected to have, brain metastasis. * Participants must not have untreated spinal cord compression, evidence of spinal metastases with risk of spinal compression or structurally unstable bone lesions suggesting impending fracture.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Confirmed Objective Response (Objective Response Rate [ORR]) | From Date of First Dose until Objective Progression (Up To 12.8 Months) | ORR is defined as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR) in soft tissue per response evaluation criteria in solid tumors (RECIST) version 1.1 and do not have concurrent bone progression per Prostate Cancer Clinical Trials Working Group 3 (PCWG3), as assessed by the investigator. ORR = (participants with confirmed CR and no bone progression) + (participants with confirmed PR and no bone progression) x 100 / all treated participants. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From Date of First Dose until Date of Death from Any Cause (Up To 28 Months) | OS time is measured from the date of first dose to the date of death from any cause. If the participant was alive or lost to follow-up at the time of data analysis, OS data were censored on the last date the participant was known to be alive. |
| Duration of Response (DoR) | CR or PR to Disease Progression or Death Due to Any Cause (Up to 12 Months) | DoR is measured only for confirmed responders (participants with a confirmed soft tissue best overall response of CR or PR per RECIST 1.1 no concurrent bone progression per PCWG3). It is measured from the date of first evidence of soft tissue CR or PR to the earliest date of investigator-assessed radiographic progression or death from any cause, whichever is earlier. |
| Percentage of Participants Achieving CR, PR or Stable Disease (SD) (Disease Control Rate [DCR]) | From Date of First Dose until Measured Progressive Disease or Death Due to Any Cause (Up To 12.8 Months) | The DCR is defined as the percentage of participants with confirmed soft tissue best overall response of CR, PR, or stable disease (SD) per RECIST 1.1, and do not have concurrent bone disease progression per PCWG3. |
| Time to Prostate-Specific Antigen (PSA) Progression | From Date of First Dose until Confirmed PSA Progression (Up To 12.8 Months) | Time to PSA progression is defined as the time from the date of treatment initiation to the date of first observation of PSA progression. The PSA progression is defined as a greater than or equal to (\>=) 25 percentage (%) increase and an absolute increase of \>=2 nanogram/milliliter (ng/mL) above the nadir (or baseline value if baseline is the smallest on study), which is confirmed by a second value obtained 3 or more weeks later. |
| Percentage of Participants Who Achieved Prostate-Specific Antigen (PSA) Response (PSA Response Rate) | From Date of First Dose until Confirmed PSA Progression (Up To 12.8 Months) | The PSA response rate is defined as the percentage of participants with a reduction in PSA level ≥50% from baseline, confirmed with a second assessment conducted at least 3 weeks later. |
| Radiographic Progression-Free Survival (rPFS) | From Date of First Dose until Objective Progression or Death from Any Cause (Up To 12.8 Months) | The rPFS time is measured from the date of first dose to the earliest date of investigator-assessed radiographic progression per RECIST 1.1 for soft tissue and PCWG3 criteria for bone, or death from any cause, whichever occurred first. Participants who have neither progressed nor died will be censored at the day of their last radiographic tumor assessment (if available) or date of first dose if no post initiation (i.e., postbaseline) radiographic assessment is available. |
| Pharmacokinetics (PK): Maximum Plasma Concentration at Steady State (Cmax,ss) of Abemaciclib | Cycle (C) 1 Day (D) 1: Post dose; C1 D15, C2D1, C2D15, C3D1: Pre dose | PK: Cmax,ss of abemaciclib is reported. The cycle length was 28 days. |
| PK: Minimum/Trough Concentration at Steady State (Cmin,ss) of Abemaciclib | C1 D1: Post dose; C1 D15, C2D1, C2D15, C3D1: Pre dose | PK: Cmin,ss of abemaciclib is reported. |
| PK: Maximum Plasma Concentration at Steady State (Cmax,ss) of Abemaciclib Metabolites (Total Active Species) | C1 D1: Post dose; C1 D15, C2D1, C2D15, C3D1: Pre dose | PK: Cmax,ss of abemaciclib metabolites (Total Active Species) is reported. |
| PK: Minimum/Trough Concentration at Steady State (Cmin,ss) of Abemaciclib Metabolites (Total Active Species) | C1 D1: Post dose; C1 D15, C2D1, C2D15, C3D1: Pre dose | PK: Cmin,ss of abemaciclib metabolites (Total Active Species) is reported. |
| Percentage of Participants With Expression of Ki-67 Proliferation Marker by Immunohistochemistry (IHC) | Baseline | Percentage of participants with expression of Ki-67 proliferation marker at baseline by immunohistochemistry. Baseline expression of the Ki-67 proliferation marker was evaluated by IHC utilizing a 20% or higher score to define high Ki-67 expression. The percentage of Ki-67 positive cells was defined by the number of non-apoptotic tumor cells with unequivocal brown nuclear staining (intensities ≥1 using a 0-3 scale) over the total number of non-apoptotic tumor cells. Unit of Measure is percentage of participants with low or high baseline Ki-67 expression. |
| Time to Symptomatic Progression | From Date of First Dose until Symptomatic Progression (Up to 12.8 Months) | Time to symptomatic progression is defined as the time from first dose to any of the following (whichever occurred earlier): 1) symptomatic skeletal event, defined as symptomatic fracture, surgery, or radiation to bone, or spinal cord compression; 2) pain progression or worsening of disease-related symptoms requiring initiation of a new systemic anticancer therapy; and 3) development of clinically significant symptoms due to locoregional tumor progression requiring surgical intervention or radiation therapy. For participants who were not known to have symptomatic progression at the time of data analysis, data were censored on the last date at which no symptomatic progression was indicated. |
Countries
France, Spain, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 200 mg Abemaciclib Twice Daily Participants received 200 mg abemaciclib administered orally twice daily on a continuous dosing schedule (28-day cycle) until symptomatic and/or radiographic progression, unacceptable toxicity, or until another discontinuation criterion is met. | 44 |
| Total | 44 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Off Treatment on Post-Treatment-Discontinuation Follow-up | 3 |
| Overall Study | Sponsor Decision | 2 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | 200 mg Abemaciclib Twice Daily |
|---|---|
| Age, Continuous | 68.3 years STANDARD_DEVIATION 9.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 41 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 14 Participants |
| Race (NIH/OMB) White | 27 Participants |
| Region of Enrollment France | 14 participants |
| Region of Enrollment Spain | 27 participants |
| Region of Enrollment United States | 3 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 31 / 44 |
| other Total, other adverse events | 42 / 44 |
| serious Total, serious adverse events | 18 / 44 |
Outcome results
Primary
Percentage of Participants With Confirmed Objective Response (Objective Response Rate [ORR])
ORR is defined as the percentage of participants with a confirmed complete response (CR) or confirmed partial response (PR) in soft tissue per response evaluation criteria in solid tumors (RECIST) version 1.1 and do not have concurrent bone progression per Prostate Cancer Clinical Trials Working Group 3 (PCWG3), as assessed by the investigator. ORR = (participants with confirmed CR and no bone progression) + (participants with confirmed PR and no bone progression) x 100 / all treated participants.
Time frame: From Date of First Dose until Objective Progression (Up To 12.8 Months)
Population: All participants who received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 200 mg Abemaciclib Twice Daily | Percentage of Participants With Confirmed Objective Response (Objective Response Rate [ORR]) | 6.8 percentage of participants |
Secondary
Duration of Response (DoR)
DoR is measured only for confirmed responders (participants with a confirmed soft tissue best overall response of CR or PR per RECIST 1.1 no concurrent bone progression per PCWG3). It is measured from the date of first evidence of soft tissue CR or PR to the earliest date of investigator-assessed radiographic progression or death from any cause, whichever is earlier.
Time frame: CR or PR to Disease Progression or Death Due to Any Cause (Up to 12 Months)
Population: All randomized participants who received at least one dose of the study drug and had CR or PR responses. The median was not achieved due to insufficient sample data.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 200 mg Abemaciclib Twice Daily | Duration of Response (DoR) | NA months |
Secondary
Overall Survival (OS)
OS time is measured from the date of first dose to the date of death from any cause. If the participant was alive or lost to follow-up at the time of data analysis, OS data were censored on the last date the participant was known to be alive.
Time frame: From Date of First Dose until Date of Death from Any Cause (Up To 28 Months)
Population: All participants who received at least one dose of the study drug. Participants censored = 13.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 200 mg Abemaciclib Twice Daily | Overall Survival (OS) | 8.38 months |
Secondary
Percentage of Participants Achieving CR, PR or Stable Disease (SD) (Disease Control Rate [DCR])
The DCR is defined as the percentage of participants with confirmed soft tissue best overall response of CR, PR, or stable disease (SD) per RECIST 1.1, and do not have concurrent bone disease progression per PCWG3.
Time frame: From Date of First Dose until Measured Progressive Disease or Death Due to Any Cause (Up To 12.8 Months)
Population: All participants who received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 200 mg Abemaciclib Twice Daily | Percentage of Participants Achieving CR, PR or Stable Disease (SD) (Disease Control Rate [DCR]) | 45.5 percentage of participants |
Secondary
Percentage of Participants Who Achieved Prostate-Specific Antigen (PSA) Response (PSA Response Rate)
The PSA response rate is defined as the percentage of participants with a reduction in PSA level ≥50% from baseline, confirmed with a second assessment conducted at least 3 weeks later.
Time frame: From Date of First Dose until Confirmed PSA Progression (Up To 12.8 Months)
Population: All participants who received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 200 mg Abemaciclib Twice Daily | Percentage of Participants Who Achieved Prostate-Specific Antigen (PSA) Response (PSA Response Rate) | 4.6 percentage of participants |
Secondary
Percentage of Participants With Expression of Ki-67 Proliferation Marker by Immunohistochemistry (IHC)
Percentage of participants with expression of Ki-67 proliferation marker at baseline by immunohistochemistry. Baseline expression of the Ki-67 proliferation marker was evaluated by IHC utilizing a 20% or higher score to define high Ki-67 expression. The percentage of Ki-67 positive cells was defined by the number of non-apoptotic tumor cells with unequivocal brown nuclear staining (intensities ≥1 using a 0-3 scale) over the total number of non-apoptotic tumor cells. Unit of Measure is percentage of participants with low or high baseline Ki-67 expression.
Time frame: Baseline
Population: All participants with evaluable tumor tissue specimens
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| 200 mg Abemaciclib Twice Daily | Percentage of Participants With Expression of Ki-67 Proliferation Marker by Immunohistochemistry (IHC) | Low baseline Ki-67 expression | 25.8 Percentage of participants |
| 200 mg Abemaciclib Twice Daily | Percentage of Participants With Expression of Ki-67 Proliferation Marker by Immunohistochemistry (IHC) | High baseline Ki-67 expression | 74.2 Percentage of participants |
Secondary
Pharmacokinetics (PK): Maximum Plasma Concentration at Steady State (Cmax,ss) of Abemaciclib
PK: Cmax,ss of abemaciclib is reported. The cycle length was 28 days.
Time frame: Cycle (C) 1 Day (D) 1: Post dose; C1 D15, C2D1, C2D15, C3D1: Pre dose
Population: All participants who received at least one dose of study drug had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 200 mg Abemaciclib Twice Daily | Pharmacokinetics (PK): Maximum Plasma Concentration at Steady State (Cmax,ss) of Abemaciclib | 223 nanogram per milliliter (ng/ mL) | Geometric Coefficient of Variation 47 |
Secondary
PK: Maximum Plasma Concentration at Steady State (Cmax,ss) of Abemaciclib Metabolites (Total Active Species)
PK: Cmax,ss of abemaciclib metabolites (Total Active Species) is reported.
Time frame: C1 D1: Post dose; C1 D15, C2D1, C2D15, C3D1: Pre dose
Population: All participants who received at least one dose of study drug had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 200 mg Abemaciclib Twice Daily | PK: Maximum Plasma Concentration at Steady State (Cmax,ss) of Abemaciclib Metabolites (Total Active Species) | 1.7 micromolar per liter (µmol/L) | Geometric Coefficient of Variation 79 |
Secondary
PK: Minimum/Trough Concentration at Steady State (Cmin,ss) of Abemaciclib
PK: Cmin,ss of abemaciclib is reported.
Time frame: C1 D1: Post dose; C1 D15, C2D1, C2D15, C3D1: Pre dose
Population: All participants who received at least one dose of study drug had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 200 mg Abemaciclib Twice Daily | PK: Minimum/Trough Concentration at Steady State (Cmin,ss) of Abemaciclib | 176 ng/mL | Geometric Coefficient of Variation 37 |
Secondary
PK: Minimum/Trough Concentration at Steady State (Cmin,ss) of Abemaciclib Metabolites (Total Active Species)
PK: Cmin,ss of abemaciclib metabolites (Total Active Species) is reported.
Time frame: C1 D1: Post dose; C1 D15, C2D1, C2D15, C3D1: Pre dose
Population: All participants who received at least one dose of study drug had evaluable PK data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 200 mg Abemaciclib Twice Daily | PK: Minimum/Trough Concentration at Steady State (Cmin,ss) of Abemaciclib Metabolites (Total Active Species) | 1.5 µmol/L | Geometric Coefficient of Variation 80 |
Secondary
Radiographic Progression-Free Survival (rPFS)
The rPFS time is measured from the date of first dose to the earliest date of investigator-assessed radiographic progression per RECIST 1.1 for soft tissue and PCWG3 criteria for bone, or death from any cause, whichever occurred first. Participants who have neither progressed nor died will be censored at the day of their last radiographic tumor assessment (if available) or date of first dose if no post initiation (i.e., postbaseline) radiographic assessment is available.
Time frame: From Date of First Dose until Objective Progression or Death from Any Cause (Up To 12.8 Months)
Population: All participants who received at least one dose of the study drug. Participants censored = 11.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 200 mg Abemaciclib Twice Daily | Radiographic Progression-Free Survival (rPFS) | 2.7 months |
Secondary
Time to Prostate-Specific Antigen (PSA) Progression
Time to PSA progression is defined as the time from the date of treatment initiation to the date of first observation of PSA progression. The PSA progression is defined as a greater than or equal to (\>=) 25 percentage (%) increase and an absolute increase of \>=2 nanogram/milliliter (ng/mL) above the nadir (or baseline value if baseline is the smallest on study), which is confirmed by a second value obtained 3 or more weeks later.
Time frame: From Date of First Dose until Confirmed PSA Progression (Up To 12.8 Months)
Population: All participants who received at least one dose of the study drug. Participants censored = 31.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 200 mg Abemaciclib Twice Daily | Time to Prostate-Specific Antigen (PSA) Progression | 6.5 months |
Secondary
Time to Symptomatic Progression
Time to symptomatic progression is defined as the time from first dose to any of the following (whichever occurred earlier): 1) symptomatic skeletal event, defined as symptomatic fracture, surgery, or radiation to bone, or spinal cord compression; 2) pain progression or worsening of disease-related symptoms requiring initiation of a new systemic anticancer therapy; and 3) development of clinically significant symptoms due to locoregional tumor progression requiring surgical intervention or radiation therapy. For participants who were not known to have symptomatic progression at the time of data analysis, data were censored on the last date at which no symptomatic progression was indicated.
Time frame: From Date of First Dose until Symptomatic Progression (Up to 12.8 Months)
Population: All participants who received at least one dose of the study drug. Participants censored = 28.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 200 mg Abemaciclib Twice Daily | Time to Symptomatic Progression | 4.1 months |