Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, Recurrent Prostate Carcinoma, Stage IV Prostate Cancer AJCC v7
Conditions
Brief summary
This phase I/II trial studies the side effects and best dose of cabazitaxel when given together with enzalutamide in treating patients with prostate cancer that has spread to other places in the body (metastatic) and has not responded to treatment with hormones or no longer responds to treatment with hormones (hormone-resistant). Drugs used in chemotherapy, such as cabazitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Androgen can cause the growth of prostate cancer cells. Hormone therapy using enzalutamide may fight prostate cancer by blocking the use of androgen by the tumor cells. Giving cabazitaxel together with enzalutamide may work better in treating metastatic, hormone-resistant prostate cancer.
Detailed description
PRIMARY OBJECTIVES: I. To determine the safety and tolerability of combination treatment with enzalutamide and cabazitaxel (as determined by percent dose limiting toxicities \[DLT\], where DLT \< 17% is consistent with it being a tolerable combination). II. To determine the efficacy of treatment with the hormonal agent enzalutamide and the chemotherapy cabazitaxel in combination in men with metastatic castration-resistant prostate cancer (CRPC) (as determined by percent of patients achieving \>= 90% prostate specific antigen \[PSA\] declines following initiation of treatment). SECONDARY OBJECTIVES: I. To further define the anticancer effect and safety profile of the combination of enzalutamide and cabazitaxel. Ia. Collect toxicity data (description of adverse events). Ib. Determine PSA response (percent of patients who achieve \>= 50% PSA decline and \>= 30% PSA decline). Ic. Examine pharmacokinetic (PK) data of cabazitaxel to characterize enzalutamide and cabazitaxel pharmacokinetic blood levels. Id. Determine tumor response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for measurable disease and Prostate Cancer Working Group 2 criteria for non-measurable (bone) disease. Ie. Determine overall survival. EXPLORATORY OBJECTIVES: I. To determine baseline (and at progression) biological tumor characteristics to evaluate for possible biomarkers indicative or predictive of response: apoptosis by cleaved caspase 3; androgen signaling axis (including but not limited to: androgen receptor expression, androgen receptor splice variants, and intratumoral androgen levels), and glucocorticoid receptor. II. To collect circulating tumor cells (CTCs) and determine the degree to which tumor characteristics (delineated above) are shared by the CTCs. III. To collect plasma and serum pre-treatment and at progression for assessment of circulating micro-ribonucleic acid (RNA)s and other circulating markers. IV. To collect buffy coat to evaluate for steroid transporters. OUTLINE: This is a dose de-escalation study of cabazitaxel. Patients receive cabazitaxel intravenously (IV) over 1 hour on day 1 and enzalutamide orally (PO) once daily (QD) on days 1-21 (days 2-21 of cycle 1). Patients also receive prednisone PO twice daily (BID) as standard of care with cabazitaxel. Cycles repeat every 21 days for 6-10 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue enzalutamide PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 28 days and then every 6 months for up to 5 years.
Interventions
DRUGCabazitaxel
Given IV
DRUGEnzalutamide
Given PO
OTHERLaboratory Biomarker Analysis
Correlative studies
OTHERPharmacological Study
Correlative studies
DRUGPrednisone
Given PO
Sponsors
OHSU Knight Cancer Institute
Oregon Health and Science University
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
* Metastatic CRPC * Willing to provide a tumor sample via biopsy from a metastatic site of disease to be collected at screening if safe and feasible per discretion of treating investigator; adequate archival metastatic tissue can be used, if available, in lieu of baseline biopsy if done when patient had CRPC; patients without a site amenable to biopsy and lack of archival tissue may still join the study * Evidence of prostate cancer progression by any of the following criteria: radiographic or PSA criteria, or symptomatic progression related to prostate cancer * Castrate testosterone levels (\< 50 ng/dL) achieved by orchiectomy or maintenance on a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist * Histologic confirmation of original prostate cancer diagnosis per institutional standard; life expectancy of greater than 6 months * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Leukocytes \>= 3,000/mm\^3 * Absolute neutrophil count \>= 1,500/mm\^3 * Platelets \>= 100,000/mm\^3 * Total bilirubin within normal institutional limits (or \< 2 X the upper limit of normal in those with Gilbert's disease) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 1.5 X institutional upper limit of normal * Creatinine within less than the institutional upper limit of normal * Creatinine clearance \>= 45 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal * Subject agrees to use a double barrier method of birth control during the course of study treatment period with enzalutamide and/or cabazitaxel treatment and for at least 3 months after the study is discontinued * A double-barrier method of contraception involves the use of a condom in combination with 1 of the following: contraceptive sponge, diaphragm, or cervical ring with spermicidal gel or foam * Subject who has had a vasectomy at least 6 months prior to starting study treatment period and those whose female sexual partner(s) are more than 55 years of age and postmenopausal for at least 2 years or surgically sterile (tubal ligation, hysterectomy, or bilateral oophorectomy) agree to use at least a condom * Ability to understand, and the willingness to sign, a written informed consent document, as well as comply with study requirements * Must have appropriate wash out (\> 6 half-lives) of androgen receptor antagonists, 5 alpha reductase inhibitors or ketoconazole prior to the start of cycle 1; if the agent is not in the table below, the washout should be 2 weeks * Bicalutamide; approximate half-life: 6 days; washout period required: 36 days * Flutamide; approximate half-life: 6 hours; washout period required: 36 hours * Nilutamide approximate half-life: 4 days; washout period required: 24 days * Finasteride; approximate half-life: 8 hours; washout period required: 48 hours * Aminoglutethimide; approximate half-life: 15 hours; washout period required: 4 days * Ketoconazole; approximate half-life: 8 hours; washout period required: 48 hours
Exclusion criteria
* Prior chemotherapy for mCRPC prostate cancer; chemotherapy given neoadjuvantly, adjuvantly, or for hormone sensitive metastatic disease is permitted as long as the cancer did not progress on chemotherapy AND \> 6 months have elapsed * Patients may not have received any other investigational agents within the last 14 days at the time of treatment start * Patients may not have received enzalutamide or ARN-509 (another androgen receptor antagonist) in the past * Patients may not have received cabazitaxel in the past * Subject has clinical signs suggestive of high or imminent risks for pathological fracture, spinal cord compression and/or cauda equina syndrome * History of severe hypersensitivity reaction (\>= grade 3) to docetaxel, polysorbate 80 containing drugs, or any of the capsule components of enzalutamide, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene * Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 family 3, subfamily A, polypeptide 4/5 (3A4/5); (a one-week wash-out period is necessary for patients who are already on these treatments) * Uncontrolled, intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled diabetes, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Subject has a history of seizure or any condition that may predispose to seizure including, but not limited to, underlying brain injury, stroke in the past 6 months, primary brain tumors, brain metastases, prior seizures * Subject has a history of unexplained loss of consciousness or transient ischemic attack within 12 months of treatment start * Subject is unwilling to stop using herbal supplements that can affect the PSA, such as saw palmetto or prostate cancer (PC)-SPES * Subject has another active malignancy other than non-melanomatous skin cancer (unless it is metastatic) or superficial bladder cancer * Must not have a gastrointestinal condition that would interfere with absorption * Subjects may not be on other therapies that affect hormone levels, such as estrogens, testosterones, ketoconazole during this study; however, megestrol for hot flashes is permitted
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Dose Limiting ToxicitiesGgraded by National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (Phase I) | Up to 42 days | The percentage of participants will be reported with 95% confidence interval using exact method. |
| PSA Response 1, Defined as >= 90% PSA Decline From Baseline | Baseline to time of >= 90% PSA decline, assessed up to 68 weeks | The percentage of participants with a \>= 90% PSA decline from baseline will be reported with 95% confidence interval using exact method. 'PSA response' is based on Prostate Cancer Working Group 2's (PCWG2) recommendations, which do not offer a specific definition as no single degree of decline has been established. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Adverse Events Graded by National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 | Up to 28 days after the last dose of study medication | Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval using exact method. |
| Overall Survival | Up to 5 years | Descriptive statistical analysis will be conducted. The median overall survival will be estimated with 95% confidence interval (if available). Kaplan-Meier plot will be used to graphically illustrate the overall survival distribution. |
| Pharmacokinetic Parameters of Cabazitaxel: Max Plasma Concentration (Cmax) | Day 1 at 0.5, 1, 1.5, 2, 4, 8, and 24 hours after the start of cabazitaxel infusion of cycles 1 and 2 (each cycle is 21 days) | Mean plasma concentration (Cmax) will be plotted over time for cabazitaxel (day 1, cycle 1) and cabazitaxel co-administered with enzalutamide (day 1, cycle 2). Noncompartmental pharmacokinetic analysis will be performed on individual concentration-time data to calculate maximum concentration from 0 hours to last measurable concentration and to infinity, and half-life, for cabazitaxel administered alone or coadministered with enzalutamide. |
| Pharmacokinetic Parameters of Cabazitaxel: Mean Area Under the Curve (AUC) | Day 1 at 0.5, 1, 1.5, 2, 4, 8, and 24 hours after the start of cabazitaxel infusion of cycles 1 and 2 (each cycle is 21 days) | Mean area under the curve (AUC) will be plotted over time for cabazitaxel (day 1, cycle 1) and cabazitaxel co-administered with enzalutamide (day1, cycle 2). Noncompartmental pharmacokinetic analysis will be performed on individual concentration-time data to calculate AUC from 0 hours to last measurable concentration for cabazitaxel administered alone or coadministered with enzalutamide. |
| Pharmacokinetic Parameters of Cabazitaxel: Mean Cabazitaxel Half-Life | Day 1 at 0.5, 1, 1.5, 2, 4, 8, and 24 hours after the start of cabazitaxel infusion of cycles 1 and 2 (each cycle is 21 days) | Mean cabazitaxel half-life will be plotted over time for cabazitaxel (day 1, cycle 1) and cabazitaxel co-administered with enzalutamide (day1, cycle 2). Noncompartmental pharmacokinetic analysis will be performed on individual concentration-time data to calculate half-life from 0 hours to last measurable concentration for cabazitaxel administered alone or coadministered with enzalutamide. |
| PSA Response 2, Defined as >= 50% PSA Decline From Baseline | Baseline to time of >= 50% PSA decline, assessed up to 68 weeks | The percentage of participants with a \>= 50% PSA decline from baseline will be reported with 95% confidence interval using exact method. 'PSA response' is based on Prostate Cancer Working Group 2's (PCWG2) recommendations, which do not offer a specific definition as no single degree of decline has been established. |
| PSA Response 3, Defined as >= 30% PSA Decline From Baseline | Baseline to time of >= 30% PSA decline, assessed up to 68 weeks | The percentage of participants with a \>= 30% PSA decline from baseline will be reported with 95% confidence interval using exact method. 'PSA response' is based on Prostate Cancer Working Group 2's (PCWG2) recommendations, which do not offer a specific definition as no single degree of decline has been established. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORJulie N Graff
OHSU Knight Cancer Institute
Participant flow
Recruitment details
Phase I accrual occurred between November 2015 and April 2016. Phase II accrual occurred between January 2017 and March 2019. The last follow-up date is anticipated to be December 2023.
Pre-assignment details
One participant withdrew before receiving study treatment and was therefore excluded from safety and efficacy analysis.
Participants by arm
| Arm | Count |
|---|---|
| Phase I - Treatment (Cabazitaxel, Enzalutamide) Patients receive 25 mg/m2 cabazitaxel IV over 1 hour on day 1 and enzalutamide PO QD on days 1-21 (days 2-21 of cycle 1). Patients also receive prednisone PO BID as standard of care with cabazitaxel. Cycles repeat every 21 days for 6-10 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue enzalutamide PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.
Cabazitaxel: Given IV
Enzalutamide: Given PO
Laboratory Biomarker Analysis: Correlative studies
Pharmacological Study: Correlative studies
Prednisone: Given PO | 3 |
| Phase II - Treatment (Cabazitaxel, Enzalutamide) Patients receive 25 mg/m2 cabazitaxel IV over 1 hour on day 1 and enzalutamide PO QD on days 1-21 (days 2-21 of cycle 1). Patients also receive prednisone PO BID as standard of care with cabazitaxel. Cycles repeat every 21 days for 6-10 cycles in the absence of disease progression or unacceptable toxicity. Patients may continue enzalutamide PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. | 33 |
| Total | 36 |
Baseline characteristics
| Characteristic | Phase II - Treatment (Cabazitaxel, Enzalutamide) | Total | Phase I - Treatment (Cabazitaxel, Enzalutamide) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 26 Participants | 28 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 8 Participants | 1 Participants |
| Age, Continuous | 69 years | 69 years | 66 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 31 Participants | 3 Participants |
| Region of Enrollment United States | 33 participants | 36 participants | 3 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 33 Participants | 36 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 0 / 33 |
| other Total, other adverse events | 3 / 3 | 33 / 33 |
| serious Total, serious adverse events | 2 / 3 | 10 / 33 |
Outcome results
Primary
Percentage of Participants With Dose Limiting ToxicitiesGgraded by National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (Phase I)
The percentage of participants will be reported with 95% confidence interval using exact method.
Time frame: Up to 42 days
Population: Patients with metastatic CRPC. Phase I patients who received at least two cycles of study drugs will be evaluable for DLT analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Treatment (Cabazitaxel, Enzalutamide) | Percentage of Participants With Dose Limiting ToxicitiesGgraded by National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0 (Phase I) | 0.0 percentage of participants |
Primary
PSA Response 1, Defined as >= 90% PSA Decline From Baseline
The percentage of participants with a \>= 90% PSA decline from baseline will be reported with 95% confidence interval using exact method. 'PSA response' is based on Prostate Cancer Working Group 2's (PCWG2) recommendations, which do not offer a specific definition as no single degree of decline has been established.
Time frame: Baseline to time of >= 90% PSA decline, assessed up to 68 weeks
Population: Phase I and Phase II participants with mCRPC who received at least one cycle of study drugs. For efficacy outcomes, Phase I and II arms were combined as participants in each arm received identical treatments of 25 mg/m2 cabazitaxel q3 weeks plus enzalutamide 160 mg QD. Per protocol, dose limiting toxicities (DLTs) identified during Phase I informed the dose of cabazitaxel in Phase II. No DLTs were identified during Phase I, and the study proceeded to Phase II at the identical dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Treatment (Cabazitaxel, Enzalutamide) | PSA Response 1, Defined as >= 90% PSA Decline From Baseline | 55.6 percentage of subjects |
Comparison: One-sample binomial test with null hypothesis that the percentage of participants with PSA response 1 is equal to 25%.p-value: <0.01two-sided exact binomial test
Secondary
Incidence of Adverse Events Graded by National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0
Descriptive statistical analysis will be conducted. The proportion estimate will be reported with 95% confidence interval using exact method.
Time frame: Up to 28 days after the last dose of study medication
Secondary
Overall Survival
Descriptive statistical analysis will be conducted. The median overall survival will be estimated with 95% confidence interval (if available). Kaplan-Meier plot will be used to graphically illustrate the overall survival distribution.
Time frame: Up to 5 years
Secondary
Pharmacokinetic Parameters of Cabazitaxel: Max Plasma Concentration (Cmax)
Mean plasma concentration (Cmax) will be plotted over time for cabazitaxel (day 1, cycle 1) and cabazitaxel co-administered with enzalutamide (day 1, cycle 2). Noncompartmental pharmacokinetic analysis will be performed on individual concentration-time data to calculate maximum concentration from 0 hours to last measurable concentration and to infinity, and half-life, for cabazitaxel administered alone or coadministered with enzalutamide.
Time frame: Day 1 at 0.5, 1, 1.5, 2, 4, 8, and 24 hours after the start of cabazitaxel infusion of cycles 1 and 2 (each cycle is 21 days)
Secondary
Pharmacokinetic Parameters of Cabazitaxel: Mean Area Under the Curve (AUC)
Mean area under the curve (AUC) will be plotted over time for cabazitaxel (day 1, cycle 1) and cabazitaxel co-administered with enzalutamide (day1, cycle 2). Noncompartmental pharmacokinetic analysis will be performed on individual concentration-time data to calculate AUC from 0 hours to last measurable concentration for cabazitaxel administered alone or coadministered with enzalutamide.
Time frame: Day 1 at 0.5, 1, 1.5, 2, 4, 8, and 24 hours after the start of cabazitaxel infusion of cycles 1 and 2 (each cycle is 21 days)
Secondary
Pharmacokinetic Parameters of Cabazitaxel: Mean Cabazitaxel Half-Life
Mean cabazitaxel half-life will be plotted over time for cabazitaxel (day 1, cycle 1) and cabazitaxel co-administered with enzalutamide (day1, cycle 2). Noncompartmental pharmacokinetic analysis will be performed on individual concentration-time data to calculate half-life from 0 hours to last measurable concentration for cabazitaxel administered alone or coadministered with enzalutamide.
Time frame: Day 1 at 0.5, 1, 1.5, 2, 4, 8, and 24 hours after the start of cabazitaxel infusion of cycles 1 and 2 (each cycle is 21 days)
Secondary
PSA Response 2, Defined as >= 50% PSA Decline From Baseline
The percentage of participants with a \>= 50% PSA decline from baseline will be reported with 95% confidence interval using exact method. 'PSA response' is based on Prostate Cancer Working Group 2's (PCWG2) recommendations, which do not offer a specific definition as no single degree of decline has been established.
Time frame: Baseline to time of >= 50% PSA decline, assessed up to 68 weeks
Population: Phase I and Phase II participants with mCRPC who received at least one cycle of study drugs. For efficacy outcomes, Phase I and II arms were combined as participants in each arm received identical treatments of 25 mg/m2 cabazitaxel q3 weeks plus enzalutamide 160 mg QD. Per protocol, dose limiting toxicities (DLTs) identified during Phase I informed the dose of cabazitaxel in Phase II. No DLTs were identified during Phase I, and the study proceeded to Phase II at the identical dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Treatment (Cabazitaxel, Enzalutamide) | PSA Response 2, Defined as >= 50% PSA Decline From Baseline | 77.8 percentage of subjects |
Secondary
PSA Response 3, Defined as >= 30% PSA Decline From Baseline
The percentage of participants with a \>= 30% PSA decline from baseline will be reported with 95% confidence interval using exact method. 'PSA response' is based on Prostate Cancer Working Group 2's (PCWG2) recommendations, which do not offer a specific definition as no single degree of decline has been established.
Time frame: Baseline to time of >= 30% PSA decline, assessed up to 68 weeks
Population: Phase I and Phase II participants with mCRPC who received at least one cycle of study drugs. For efficacy outcomes, Phase I and II arms were combined as participants in each arm received identical treatments of 25 mg/m2 cabazitaxel q3 weeks plus enzalutamide 160 mg QD. Per protocol, dose limiting toxicities (DLTs) identified during Phase I informed the dose of cabazitaxel in Phase II. No DLTs were identified during Phase I, and the study proceeded to Phase II at the identical dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I - Treatment (Cabazitaxel, Enzalutamide) | PSA Response 3, Defined as >= 30% PSA Decline From Baseline | 80.6 percentage of subjects |