Androgen Receptor Antagonist ARN509 and Leuprolide Acetate in Treating Patients with Prostate Cancer before Surgery
This phase II trial studies how well androgen receptor antagonist ARN-509 and leuprolide acetate work in treating patients with prostate cancer before surgery. Hormone therapy using androgen receptor antagonist ARN-509 and leuprolide acetate may fight prostate cancer by lowering the amount of androgen the body makes and / or blocking the use of androgen by the tumor cells.
- Adenocarcinoma of the prostate with histological or cytological confirmation without neuroendocrine differentiation or small cell histology and with G 4+3 or higher, and PSA >= 10, and >= T2b, for whom radical prostatectomy has been recommended and who choose to undergo radical prostatectomy
- A minimum tissue requirement of >= 3 core biopsies with tumor involvement and at least 50% tumor involvement in one of the core biopsies is required
- Have an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- Hemoglobin of >= 10 g/dL, independent of transfusion and/or growth factors within 3 months prior to randomization
- Platelet count of >= 100 k/mL independent of transfusion and/or growth factors within 3 months prior to randomization
- Serum albumin >= 3.0 g/dL
- Serum creatinine < 2.0 times the upper limit of normal (ULN) (or a calculated creatinine clearance >= 60 mL/min)
- Serum potassium >= 3.5 mmol/L
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN
- Total serum bilirubin levels < 1.5 x ULN (note: in subjects with Gilbert’s syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is =< 1.5 x ULN, subject may be eligible)
- Be capable of swallowing study agents whole as a tablet
- Be willing/able to adhere to the prohibitions and restrictions specified in this protocol
- 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
- Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to study entry
- Agrees to use a condom (even men with vasectomies) and another effective method of birth control if he is having sex with a woman of childbearing potential or agrees to use a condom if he is having sex with a woman who is pregnant while on study drug and for 3 months following the last dose of study drug; must also agree not to donate sperm during the study and for 3 months following the last dose of study drug
- The use of any prior hormones including luteinizing hormone–releasing hormone (LHRH) agonists, LHRH antagonists, antiandrogens such as bicalutamide, flutamide and nilutamide, and/or the use of 5-alpha reductase inhibitors, PCSPES (or PC-x product), megestrol acetate, or estrogen containing nutraceuticals within 6 months of study treatment initiation
- Prior radiation therapy, immunotherapy, chemotherapy or other investigational therapy given for prostate cancer
- "Currently active" second malignancy other than non-melanoma skin cancers or non-muscle invasive transitional cell carcinoma of bladder; patients are not considered to have a "currently active" malignancy if they have completed therapy and are now considered (by their physician) to be at less than 30% risk for relapse
- History of seizure or condition that may pre-dispose to seizure (including but not limited to prior stroke, transient ischemic attack, loss of consciousness within 1 year prior to randomization, brain arteriovenous malformation; or intracranial masses such as schwannomas and meningiomas that are causing edema or mass effect)
- Current systemic steroid therapy (inhaled or topical steroids are also not allowed)
- Have received treatment with any form of therapy with CYP17 inhibitory activity such as ketoconazole, aminoglutethimide, or an antiandrogen such as bicalutamide within 6 months of study treatment initiation
- 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 within 6 months of enrollment
- Active infection (eg, human immunodeficiency virus [HIV] or viral hepatitis)
- Have uncontrolled hypertension; subjects with a history of hypertension are permitted in the study provided their blood pressure is controlled by anti-hypertensive therapy
- Have a known history of pituitary or adrenal dysfunction
- Have clinically significant heart disease as evidenced by severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (e.g., pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to randomization
- Have a history of gastric bypass surgery or severe malabsorption that may interfere with the absorption of the study agents
- Be taking or require the use of prohibited medications
- 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
Locations & Contacts
Contact: Jorge A. Garcia
Trial Objectives and Outline
I. To evaluate the differential effect of neo-adjuvant leuprolide acetate (leuprolide) and androgen receptor antagonist ARN-509 (ARN-509) on dihydrotestosterone (DHT) concentration in benign prostate tissue based on HSD3B1 genotype.
I. To evaluate the differential effect of neoadjuvant leuprolide and ARN-509 on other androgen (testosterone [T], dehydroepiandrosterone [DHEA], androstenediol, 5 alpha-androstanedione [5 alpha-dione], androstenedione [AD], androsterone and 5 alpha-androstanediol) concentrations in benign and malignant prostate tissue based on HSD3B1 genotype.
II. To compare the level of DHT, T, DHEA, androstenediol, 5 alpha-dione, AD, androsterone and 5 alpha-androstanediol between normal and malignant prostate tissue after neoadjuvant treatment with leuprolide and ARN-509.
III. To determine the safety of the combination of leuprolide and ARN-509 administered prior to radical prostatectomy.
IV. To evaluate prostate-specific antigen (PSA), FKBP5, TMPRSS2, EZH2, H3K27 and UBE2C tissue expression (via immunohistochemistry [IHC] and quantitative polymerase chain reaction [qPCR]) in benign and malignant prostate tissue after treatment with leuprolide and ARN-509.
Patients receive leuprolide acetate intramuscularly (IM) once on day -28 and androgen receptor antagonist ARN-509 orally (PO) starting on day -28 until radical prostatectomy in the absence of disease progression or unaccepted toxicity.
After completion of study treatment, patients are followed up for 28 days.
Trial Phase & Type
Case Comprehensive Cancer Center
Jorge A. Garcia
Secondary IDs NCI-2016-01612
Clinicaltrials.gov ID NCT02770391