Recruitment

Recruitment Status
Active, not recruiting

Inclusion Criteria

Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels,
Albumin > 30 g/L (3.0 g/dL) at the Screening visit,
Creatinine < 1.5 mg/dL at the Screening visit,
...
Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels,
Albumin > 30 g/L (3.0 g/dL) at the Screening visit,
Creatinine < 1.5 mg/dL at the Screening visit,
Age ≥ 18 years.
Willing to abstain from procreative sex or partake in appropriate form of contraception. For the purpose of this study, condom use or abstinence will be required.
Patients with clinically localized adenocarcinoma of the prostate who are scheduled to undergo radical prostatectomy (RP) with curative intent and have the following clinico-pathologic features: (1) Gleason score sum ≥ 4+3 or any Gleason 5, (2) PSA > 20, (3) clinical stage ≥ T3a (staging by MRI is allowed).
Adenocarcinoma of the prostate with planned RP with curative intent as part of standard of care management plan.
Left ventricular ejection fraction (LVEF) ≥ LLN by ECHO or MUGA,
Patient is a candidate for radical prostatectomy.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
Absolute neutrophil count > 1,500/µL, or platelet count > 100,000/µL, or hemoglobin > 5.6 mmol/L (9 g/dL) at the Screening visit,
Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) within the normal range at the Screening visit,
Estimated life expectancy of ≥ 6 months,
Willing and able to give informed consent.
INR < 1.3 (or < 3 if on warfarin or other anticoagulants) at the Screening visit,
Tumor accessible to biopsy.

Exclusion Criteria

History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes),
Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%,
History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes).
...
History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes),
Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%,
History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes).
Use of an investigational agent within 4 weeks of enrollment,
History of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke, significant brain trauma) at any time in the past,
Hospitalization within 30 days of enrollment,
Uncontrolled angina within 3 months,
Known cardiac metastases.
Evidence of new optic disc cupping
Bradycardia as indicated by a heart rate of < 50 beats per minute on the Screening ECG,
Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted).
Any history of congestive heart failure of any NYHA class for patients assigned to Group 2 (trametinib arm).
Evidence of a coagulopathy,
Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 30 days of enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days of enrollment,
Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids greater than the equivalent of 10 mg of prednisone per day within 4 weeks of enrollment,
Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease within last 3 months),
History of interstitial lung disease or pneumonitis,
LVEF < LLN
Evidence of new visual field defects
Presence of a comorbid disease or medical condition that would impair the ability of the patient to receive or comply with the study protocol,
Any non-adenocarcinoma histologic component,
Use of any medications known to affect the serum androgen levels or the PSA,
History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months,
Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHG and/or diastolic > 90 mmHG which cannot be controlled by anti-hypertensive therapy,
Unwillingness to engage in adequate contraception,
Prior use of androgen deprivation therapy or radiation therapy,
Any condition or reason that, in the opinion of the Investigator, interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of safety data.
Allergy/sensitivity to any study drug (degarelix, enzalutamide, trametinib, dasatinib), or drugs chemically related to study drug, or excipients or to dimethylsulfoxide.
History of loss of consciousness or transient ischemic attack within past 12 months,
QTC ≥ 480 milliseconds,
Known or suspected brain metastasis or active leptomeningeal disease or spinal cord compression.
Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury (mmHg) at the Screening visit,
Intraocular pressure > 21 mm Hg
History of another malignancy within the previous 5 years other than curatively treated non-melanoma skin cancer,
Prior use of degarelix, enzalutamide, trametinib, or dasatinib in any context,
Patient receiving therapeutic anticoagulation.
Any prior treatment for prostate cancer,
Any evidence of lymphatic or hematogenous metastases,
Patients with intra-cardiac defibrillators or permanent pacemakers,

Summary

Conditions
Prostate Cancer
Type
Interventional
Phase
Phase 2
Design
  • Allocation: Randomized
  • Intervention Model: Parallel Assignment
  • Masking: None (Open Label)
  • Primary Purpose: Treatment

Participation Requirements

Age
Between 18 years and 125 years
Gender
Only males

Description

Most prostate cancers respond to hormone therapy, also known as chemical castration. Unfortunately, castration resistance may occur in certain prostate cancers. Castration resistance or hormone refractory prostate cancer means that the cancer continues to progress as seen by progressively rising PSA...

Most prostate cancers respond to hormone therapy, also known as chemical castration. Unfortunately, castration resistance may occur in certain prostate cancers. Castration resistance or hormone refractory prostate cancer means that the cancer continues to progress as seen by progressively rising PSA and/or or an increase in tumor mass on bone scan, X-ray, CT scan or MRI despite previous hormonal therapy. The researchers are interested in understanding mechanisms of castration resistance in prostate cancer by analyzing prostate tissue before radical prostatectomy (from prostate biopsy tissue) and after radical prostatectomy (whole prostate specimen). They will look at the "molecular signature" of prostate cancer cells after hormone therapy to identify the key steps that the cancer cells undergo to become resistant to hormone therapy. In addition, the researchers will use other medications in addition to hormone therapy in order to block some of the key biochemical steps that are thought to mediate treatment resistance. This research will provide crucial information for the development of therapies that can improve the clinical outcome of patients with advanced prostate cancer.

Inclusion Criteria

Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels,
Albumin > 30 g/L (3.0 g/dL) at the Screening visit,
Creatinine < 1.5 mg/dL at the Screening visit,
...
Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels,
Albumin > 30 g/L (3.0 g/dL) at the Screening visit,
Creatinine < 1.5 mg/dL at the Screening visit,
Age ≥ 18 years.
Willing to abstain from procreative sex or partake in appropriate form of contraception. For the purpose of this study, condom use or abstinence will be required.
Patients with clinically localized adenocarcinoma of the prostate who are scheduled to undergo radical prostatectomy (RP) with curative intent and have the following clinico-pathologic features: (1) Gleason score sum ≥ 4+3 or any Gleason 5, (2) PSA > 20, (3) clinical stage ≥ T3a (staging by MRI is allowed).
Adenocarcinoma of the prostate with planned RP with curative intent as part of standard of care management plan.
Left ventricular ejection fraction (LVEF) ≥ LLN by ECHO or MUGA,
Patient is a candidate for radical prostatectomy.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
Absolute neutrophil count > 1,500/µL, or platelet count > 100,000/µL, or hemoglobin > 5.6 mmol/L (9 g/dL) at the Screening visit,
Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) within the normal range at the Screening visit,
Estimated life expectancy of ≥ 6 months,
Willing and able to give informed consent.
INR < 1.3 (or < 3 if on warfarin or other anticoagulants) at the Screening visit,
Tumor accessible to biopsy.

Exclusion Criteria

History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes),
Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%,
History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes).
...
History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes),
Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or patients with history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram or multi-gated acquisition scan performed within 3 months results in a left ventricular ejection fraction that is ≥ 45%,
History of RVO or CSR, or predisposing factors to RVO or CSR (e.g. uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes).
Use of an investigational agent within 4 weeks of enrollment,
History of seizure or any condition that may predispose to seizure (e.g., prior cortical stroke, significant brain trauma) at any time in the past,
Hospitalization within 30 days of enrollment,
Uncontrolled angina within 3 months,
Known cardiac metastases.
Evidence of new optic disc cupping
Bradycardia as indicated by a heart rate of < 50 beats per minute on the Screening ECG,
Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects with laboratory evidence of cleared HBV and HCV infection will be permitted).
Any history of congestive heart failure of any NYHA class for patients assigned to Group 2 (trametinib arm).
Evidence of a coagulopathy,
Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 30 days of enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days of enrollment,
Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids greater than the equivalent of 10 mg of prednisone per day within 4 weeks of enrollment,
Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease within last 3 months),
History of interstitial lung disease or pneumonitis,
LVEF < LLN
Evidence of new visual field defects
Presence of a comorbid disease or medical condition that would impair the ability of the patient to receive or comply with the study protocol,
Any non-adenocarcinoma histologic component,
Use of any medications known to affect the serum androgen levels or the PSA,
History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months,
Treatment refractory hypertension defined as a blood pressure of systolic > 140 mmHG and/or diastolic > 90 mmHG which cannot be controlled by anti-hypertensive therapy,
Unwillingness to engage in adequate contraception,
Prior use of androgen deprivation therapy or radiation therapy,
Any condition or reason that, in the opinion of the Investigator, interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of safety data.
Allergy/sensitivity to any study drug (degarelix, enzalutamide, trametinib, dasatinib), or drugs chemically related to study drug, or excipients or to dimethylsulfoxide.
History of loss of consciousness or transient ischemic attack within past 12 months,
QTC ≥ 480 milliseconds,
Known or suspected brain metastasis or active leptomeningeal disease or spinal cord compression.
Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury (mmHg) at the Screening visit,
Intraocular pressure > 21 mm Hg
History of another malignancy within the previous 5 years other than curatively treated non-melanoma skin cancer,
Prior use of degarelix, enzalutamide, trametinib, or dasatinib in any context,
Patient receiving therapeutic anticoagulation.
Any prior treatment for prostate cancer,
Any evidence of lymphatic or hematogenous metastases,
Patients with intra-cardiac defibrillators or permanent pacemakers,

Tracking Information

NCT #
NCT01990196
Collaborators
  • Medivation, Inc.
  • GlaxoSmithKline
  • Prostate Cancer Foundation
  • Astellas Pharma Inc
  • Novartis
Investigators
  • Principal Investigator: Robert Reiter, M.D. University of California, Los Angeles
  • Robert Reiter, M.D. University of California, Los Angeles
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