Castration Levels of Testosterone, Castration-Resistant Prostate Carcinoma, Metastatic Prostate Carcinoma, PSA Progression, Stage IV Prostate Adenocarcinoma AJCC v7
Conditions
Brief summary
This phase II trials studies the side effects and how well ESK981 works in treating patients with castration-resistant prostate cancer that has spread to other places in the body. ESK981 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed description
PRIMARY OBJECTIVES: I. To determine the PSA \>= 50% response rate (PSA50) from baseline using the Prostate Cancer Working Group 3 (PCWG3) criteria to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981 (ESK981) as a single agent in men with castration-resistant prostate cancer (CRPC) who have progressed on enzalutamide (an oral androgen-receptor inhibitor) and/or abiraterone acetate (an androgen synthesis inhibitor). II. To assess the safety and tolerability of ESK981 as a single agent. SECONDARY OBJECTIVES: I. To determine the time to PSA response to ESK981 in metastatic CRPC patients. II. To determine the duration of PSA response to ESK981 in metastatic CRPC patients. III. To determine PSA progression rates and PSA progression free survival (PFS), as defined by the PCWG3 criteria. TERTIARY OBJECTIVES: I. To assess exploratory biomarkers from blood and tumor biopsies. OUTLINE: Patients receive pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981 orally (PO) once daily (QD) for 5 days (Monday-Friday). Treatment repeats for up to 8 weeks in the absence of disease progression or unacceptable toxicity. If treatment is successful after 8 weeks, patients may receive up to 6 months of pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981. After completion of study treatment, patients are followed up periodically.
Interventions
DRUGESK981
Treatment with ESK981 for patients with metastatic castrate resistant prostate cancer
Sponsors
National Cancer Institute (NCI)
Barbara Ann Karmanos Cancer Institute
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
* Have signed an informed consent document indicating that the subject understands the purpose of and procedures required for the study and are willing to participate in the study * Be willing/able to adhere to the prohibitions and restrictions specified in this protocol * Eastern Cooperative Group (ECOG) performance status =\< 1 * Patient must have evidence of castrate resistant prostate cancer as evidenced by a confirmed rising PSA (per PCWG3 criteria) and a castrate serum testosterone level (i.e. =\< 50 mg/dL) * Documented histologically confirmed adenocarcinoma of the prostate * Metastatic prostate cancer (M1) as documented by appropriate medical imaging (i.e. computed tomography \[CT\]-scan, positron emission tomography \[PET\] scan or bone scan) * Treatment failure of either abiraterone and/or enzalutamide as evidenced by a confirmed rising PSA (per PCWG3 criteria) and a castrate serum testosterone level (i.e. =\< 50 mg/dL) while receiving treatment with either abiraterone and/or enzalutamide * Willingness to use contraception by a method that is deemed effective by the Investigator throughout the treatment period and for at least 30 days following the last dose of therapy * Willingness and ability to comply with study procedures and follow-up examination * Able to swallow and retain oral medication
Exclusion criteria
* Current systemic therapy (other than a gonadotrophin releasing hormone \[GnRH\] agonist/antagonist) for CRPC including: * CYP-17 inhibitors (e.g. ketoconazole, abiraterone) * Antiandrogens (e.g. bicalutamide, nilutamide) * Second generation antiandrogens (e.g. enzalutamide, ARN-509, Galeterone) * Immunotherapy (e.g. sipuleucel-T, ipilimumab) * Chemotherapy (e.g. docetaxel, cabazitaxel) * Greater than 2 lines of prior systemic therapy for CRPC * Prior chemotherapy (e.g. docetaxel, cabazitaxel) for CRPC; prior docetaxel administered in the castrate-sensitive space is allowed * Prior radiopharmaceutical therapy (e.g. radium-223, strontium-89, samarium-153, etc.) within the past year * Have any condition that, in the opinion of the investigator, would compromise the well-being of the subject or the study or prevent the subject from meeting or performing study requirements * Absolute neutrophil count (ANC) less than 1500/mm\^3 * Platelet count less than 100000/mm\^3 * Hemoglobin less than 9 g/dL * Bilirubin greater than 1.5 times the upper limit of normal (ULN) * Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 2.0 times the ULN in the absence of known hepatic metastases, or ALT or AST greater than 3.0 times the ULN in the presence of known hepatic metastases * The patient has a serum creatinine value greater than 1.5 mg/dL * The patient has active brain metastases * The patient is currently on warfarin or heparin therapy * The patient has any pre-existing coagulopathy, recent hemoptysis, gross hematuria, or gastrointestinal bleeding, and a history of a clinically significant cardiovascular or cerebrovascular event within 12 months prior to study entry * The patient has uncontrolled hypertension defined as a blood pressure measurement greater than 150 mm Hg systolic or 90 mm Hg diastolic with medication * The patient has received any investigational drug within the past 4 weeks * The patient has previously been enrolled in the study or received ESK981 * The patient has known hypersensitivity to gelatin or lactose monohydrate * The patient has taken a medication known to be a potent inducer of CYP1A2, CYP2C8, or CYP3A4 within 4 weeks prior to the first dose of study drug * The patient has taken a medication known to be a potent inhibitor of CYP1A2, CYP2C8, or CYP3A4 within 2 weeks prior to the first dose of study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PSA Decline of >= 50% (PSA50) From Baseline | Up to 1 year | PSA decline of \>= 50% (PSA50) from baseline using Prostate Cancer Working Group 3 (PCWG3) definition with point estimate and (1-sided Wilson type 90% lower) confidence interval (CI) estimates. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Duration of PSA Response (RD) | From start of PSA50 until PSA progression, assessed up to 1 year | Will be summarized with the Kaplan-Meier (K-M) survivorship estimate. A graph of the K-M curve for RD will be generated along with the Hall-Wellner 90% confidence band, and a display of the number of patients at risk at several time points, below the X-axis. Summary statistics (6-month rate, 12-month rate, median, etc.) will be calculated from the K-M life table, each one with its respective 80% CI. |
| PSA Progression Free Survival (PFS) | Date that a 25% or greater increase and an absolute increase of 2.0 ng/mL or more from the nadir is documented and confirmed by a second value obtained 3 or more weeks later, assessed up to 1 year | Will be summarized with the Kaplan-Meier (K-M) survivorship estimate. A graph of the K-M curve for PFS will be generated along with the Hall-Wellner 90% confidence band, and a display of the number of patients at risk at several time points, below the X-axis. Summary statistics (6-month rate, 12-month rate, median, etc.) will be calculated from the K-M life table, each one with its respective 80% CI. |
| Time to PSA Response | From treatment start until the first documented occurrence of PSA50, assessed up to 1 year | Will be used to summarize the time to PSA response. These descriptives will include sample size (N), median, mean, standard deviation (SD), interquartile range (IQR), minimum, and maximum. |
Other
| Measure | Time frame | Description |
|---|---|---|
| ETS/Kinase Gene Fusions | Up to 1 year | Will examine the association of somatic and germline mutations with exceptional response/resistance to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981. |
| Immunohistochemistry (IHC) of Protein Markers | Up to 1 year | Ki67, Receptor, CD31, NG2, desmin, PDGFR1/2, VEGFR1/2 immunohistochemistry graded 0, 1, 2, 3 |
| Metastatic Kinome Activity Profiles as Predictive Biomarkers | Up to 1 year | Description of immunohistochemistry of the kinases, graded 0,1,2,3 |
| DNA Sequencing of Prostate Tumor | Up to 1 year | copy number, Loss of heterozygosity, mutation, amplification, graded 0,1 |
| Androgen Receptor (AR) Signaling | Up to 1 year | Will examine the association of somatic and germline mutations with exceptional response/resistance to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981. |
| Circulating and Disseminated Tumor Cells as Pharmacodynamic Biomarkers | Up to 1 year | Number of Circulating and disseminated tumor cells per 7.5ml as a pharmacodynamic biomarker. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Treatment ESK981 Patients receive pan-VEGFR/TIE2 (Vascular Endothelial Growth Factor Receptor/angopoeitin receptor2) tyrosine kinase inhibitor CEP-11981 PO QD for 5 days (Monday-Friday). Treatment repeats for up to 8 weeks in the absence of disease progression or unacceptable toxicity. If treatment is successful after 8 weeks, patients may receive up to 6 months of pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981.
ESK981: Treatment with ESK981 for patients with metastatic castrate resistant prostate cancer | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | Treatment ESK981 |
|---|---|
| Age, Continuous | 71 years |
| Gleason Score Gleason Score 6 | 1 Participants |
| Gleason Score Gleason Score 7 | 3 Participants |
| Gleason Score Gleason Score 8~10 | 6 Participants |
| Gleason Score Gleason Score unknown | 3 Participants |
| Performance Status PS = 0 | 0 Participants |
| Performance Status PS = 1 | 13 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 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 | 0 Participants |
| Race (NIH/OMB) White | 9 Participants |
| Region of Enrollment United States | 13 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 10 / 13 |
| other Total, other adverse events | 13 / 13 |
| serious Total, serious adverse events | 5 / 13 |
Outcome results
Primary
PSA Decline of >= 50% (PSA50) From Baseline
PSA decline of \>= 50% (PSA50) from baseline using Prostate Cancer Working Group 3 (PCWG3) definition with point estimate and (1-sided Wilson type 90% lower) confidence interval (CI) estimates.
Time frame: Up to 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment ESK981 | PSA Decline of >= 50% (PSA50) From Baseline | 7.7 percentage of participants |
Secondary
Duration of PSA Response (RD)
Will be summarized with the Kaplan-Meier (K-M) survivorship estimate. A graph of the K-M curve for RD will be generated along with the Hall-Wellner 90% confidence band, and a display of the number of patients at risk at several time points, below the X-axis. Summary statistics (6-month rate, 12-month rate, median, etc.) will be calculated from the K-M life table, each one with its respective 80% CI.
Time frame: From start of PSA50 until PSA progression, assessed up to 1 year
Population: patients who achieved a 50% reduction in PSA from baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment ESK981 | Duration of PSA Response (RD) | 1.9 months |
Secondary
PSA Progression Free Survival (PFS)
Will be summarized with the Kaplan-Meier (K-M) survivorship estimate. A graph of the K-M curve for PFS will be generated along with the Hall-Wellner 90% confidence band, and a display of the number of patients at risk at several time points, below the X-axis. Summary statistics (6-month rate, 12-month rate, median, etc.) will be calculated from the K-M life table, each one with its respective 80% CI.
Time frame: Date that a 25% or greater increase and an absolute increase of 2.0 ng/mL or more from the nadir is documented and confirmed by a second value obtained 3 or more weeks later, assessed up to 1 year
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Treatment ESK981 | PSA Progression Free Survival (PFS) | 0.9 months |
Secondary
Time to PSA Response
Will be used to summarize the time to PSA response. These descriptives will include sample size (N), median, mean, standard deviation (SD), interquartile range (IQR), minimum, and maximum.
Time frame: From treatment start until the first documented occurrence of PSA50, assessed up to 1 year
Population: patients who achieved a 50% reduction in PSA from baseline
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Treatment ESK981 | Time to PSA Response | 10.0 months |
Other Pre-specified
Androgen Receptor (AR) Signaling
Will examine the association of somatic and germline mutations with exceptional response/resistance to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981.
Time frame: Up to 1 year
Population: Measure not taken
Other Pre-specified
Circulating and Disseminated Tumor Cells as Pharmacodynamic Biomarkers
Number of Circulating and disseminated tumor cells per 7.5ml as a pharmacodynamic biomarker.
Time frame: Up to 1 year
Population: Measure not taken
Other Pre-specified
DNA Sequencing of Prostate Tumor
copy number, Loss of heterozygosity, mutation, amplification, graded 0,1
Time frame: Up to 1 year
Population: Measure not taken
Other Pre-specified
ETS/Kinase Gene Fusions
Will examine the association of somatic and germline mutations with exceptional response/resistance to pan-VEGFR/TIE2 tyrosine kinase inhibitor CEP-11981.
Time frame: Up to 1 year
Population: Measure not taken
Other Pre-specified
Immunohistochemistry (IHC) of Protein Markers
Ki67, Receptor, CD31, NG2, desmin, PDGFR1/2, VEGFR1/2 immunohistochemistry graded 0, 1, 2, 3
Time frame: Up to 1 year
Population: Measure not taken
Other Pre-specified
Metastatic Kinome Activity Profiles as Predictive Biomarkers
Description of immunohistochemistry of the kinases, graded 0,1,2,3
Time frame: Up to 1 year
Population: Measure not taken