Apalutamide and Leuprolide in Intermediate and High-risk Prostate Cancer

Phase 2

Completed

• Conditions: Prostate Cancer
• Interventions: Drug: Leuprolide acetate; Drug: Apalutamide; Procedure: Radical prostatectomy

• Registration Number: NCT02770391
• Lead Sponsor: Case Comprehensive Cancer Center

Brief Summary

This is a research study to test an investigational drug (Not FDA approved), Apalutamide given in combination with Leuprolide acetate (FDA approved) in men diagnosed with high-risk prostate cancer who have already selected to have surgery to remove their prostate gland as part of their treatment plan. The main purpose of this study is to determine how tumors make androgens (male hormones), which makes these tumors more aggressive and resistant to hormonal therapy and how a short period of treatment with Apalutamide and leuprolide acetate prior to surgery can affect the production of these hormones in normal and malignant prostate tissue.

Detailed Description

Primary Objective: To evaluate the differential effect of neo-adjuvant leuprolide and Apalutamide on dihydrotestosterone (DHT) concentration in benign prostate tissue based on HSD3B1 genotype.

Secondary Objective(s): To evaluate the differential effect of neoadjuvant leuprolide and Apalutamide on other androgen (testosterone (T), dehydroepiandrosterone (DHEA), androstenediol, 5α-androstanedione (5α-dione), androstenedione (AD), androsterone and 5α-androstanediol) concentrations in benign and malignant prostate tissue based on HSD3B1 genotype.

To compare the level of DHT, T, DHEA, androstenediol, 5α-dione, AD, androsterone and 5α-androstanediol between normal and malignant prostate tissue after neoadjuvant treatment with leuprolide and Apalutamide

To determine the safety of the combination of Leuprolide and Apalutamide administered prior to radical prostatectomy

To evaluate prostatic 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 Apalutamide.

Study Timeline

• Study First Submitted: 2016-05-05
• Study First Submitted QC: 2016-05-10
• Study First Posted: 2016-05-12
• Study Start: 2016-10-17
• Primary Completion: 2020-04-29
• Study Completion: 2020-04-29
• Disposition First Submitted: 2021-03-24
• Disposition First Submitted QC: 2021-03-24
• Disposition First Posted: 2021-03-29
• Results First Submitted: 2022-01-28
• Status Verified: 2022-05
• Results First Submitted QC: 2022-05-25
• Last Update Submitted: 2022-05-25
• Results First Posted: 2022-06-21
• Last Update Posted: 2022-06-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 54

Inclusion Criteria

• 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 ≥ 100k/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 × ULN, measure direct and indirect bilirubin and if direct bilirubin is ≤1.5 × 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.

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Exclusion Criteria

• 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, prostate cancer (PC) Spes (or PC-x product), Megestrol Acetate, or estrogen containing nutriceuticals 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, at the discretion of the treating physician
• 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 as listed
• 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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Apalutamide + Leuprolide Acetate	Leuprolide acetate	All participating patients will receive a single dose of leuprolide 7.5 mg intramuscularly (IM) in addition to Apalutamide 240 mg orally daily for four weeks prior to radical prostatectomy (RP). Treatment will be started on day (-28) ± 3 from the scheduled RP date to minimize the variability of treatment duration. Apalutamide may be continued up to and including the day before
Apalutamide + Leuprolide Acetate	Radical prostatectomy	All participating patients will receive a single dose of leuprolide 7.5 mg intramuscularly (IM) in addition to Apalutamide 240 mg orally daily for four weeks prior to radical prostatectomy (RP). Treatment will be started on day (-28) ± 3 from the scheduled RP date to minimize the variability of treatment duration. Apalutamide may be continued up to and including the day before
Apalutamide + Leuprolide Acetate	Apalutamide	All participating patients will receive a single dose of leuprolide 7.5 mg intramuscularly (IM) in addition to Apalutamide 240 mg orally daily for four weeks prior to radical prostatectomy (RP). Treatment will be started on day (-28) ± 3 from the scheduled RP date to minimize the variability of treatment duration. Apalutamide may be continued up to and including the day before

Primary Outcome Measures

Name	Time	Method
Dihydrotestosterone (DHT) Concentration in Benign Prostate Tissue After a Combination Drug Treatment Based on Genotype Status	Up to 28 Days	To evaluate the differential effect of neo-adjuvant leuprolide and ARN-509 on dihydrotestosterone (DHT) concentration in benign prostate tissue based on HSD3B1 genotype.
Dihydrotestosterone (DHT) Concentration in Malignant Prostate Tissue After a Combination Drug Treatment Based on Genotype Status	Up to 28 Days	To evaluate the differential effect of neo-adjuvant leuprolide and ARN-509 on dihydrotestosterone (DHT) concentration in malignant prostate tissue based on HSD3B1 genotype.

Secondary Outcome Measures

Name	Time	Method
PSA, FKBP5, TMPRSS2, EZH2, H3K27, and UBE2C Expression (Via IHC) in Malignant Prostate Tissue After Neoadjuvant Leuprolide and Apalutamide Based on Genotype Status.	Up to 28 Days	To evaluate PSA, FKBP5, TMPRSS2, EZH2, H3K27, and UBE2C tissue expression (via IHC) in malignant prostate tissue after treatment with Leuprolide and Apalutamide.
Other Androgens Concentration in Benign Prostate Tissue After Neo-adjuvant Leuprolide and Apalutamide Based on Genotype Status.	Up to 28 Days	To evaluate the differential effect of neoadjuvant leuprolide and ARN-509 on other androgens (testosterone (T), dehydroepiandrosterone (DHEA), androstenediol, 5?-androstanedione (5?-dione), androstenedione (AD), androsterone and 5?-androstanediol) concentration in benign prostate tissue based on HSD3B1 genotype.
Other Androgens (DHT, T, DHEA, Androstenediol, 5α-dione, AD, Androsterone and 5α-androstanediol) Concentration in Malignant Prostate Tissue After Neo-adjuvant Leuprolide and Apalutamide Based on Genotype Status.	Up to 28 Days	To evaluate the effect of neoadjuvant ARN-509 on other androgens (DHT, T, DHEA, androstenediol, 5?-dione, AD, androsterone and 5?-androstanediol) concentration in malignant prostate tissue after neoadjuvant leuprolide and ARN-509.
To Compare the Level of DHT, T, DHEA, Androstenediol, 5alpha-dione, AD, Androsterone and 5alpha-androstanediol Between Normal and Malignant Prostate Tissue After Neoadjuvant Leuprolide and ARN-509.	Up to 28 Days	To compare the level of DHT, T, DHEA, androstenediol, 5alpha-dione, AD, androsterone and 5alpha-androstanediol between normal and malignant prostate tissue after neoadjuvant leuprolide and ARN-509.
PSA, FKBP5, TMPRSS2, EZH2, H3K27, and UBE2C Expression (Via qPCR) in Malignant Prostate Tissue After Neoadjuvant Leuprolide and Apalutamide Based on Genotype Status.	Up to 28 Days	To evaluate PSA, FKBP5, TMPRSS2, EZH2, H3K27, and UBE2C tissue expression (via qPCR) in malignant prostate tissue after treatment with Leuprolide and Apalutamide.
PSA, FKBP5, TMPRSS2, EZH2, H3K27, and UBE2C Expression (Via qPCR) in Benign Prostate Tissue After Neoadjuvant Leuprolide and Apalutamide Based on Genotype Status.	Up to 28 Days	To evaluate PSA, FKBP5, TMPRSS2, EZH2, H3K27 and UBE2C tissue expression (via qPCR) in benign prostate tissue after treatment with Leuprolide and Apalutamide.
PSA, FKBP5, TMPRSS2, EZH2, H3K27, and UBE2C Expression (Via IHC) in Benign Prostate Tissue After Neoadjuvant Leuprolide and Apalutamide Based on Genotype Status.	Up to 28 Days	To evaluate PSA, FKBP5, TMPRSS2, EZH2, H3K27 and UBE2C tissue expression (via IHC) in benign prostate tissue after treatment with Leuprolide and Apalutamide.

Trial Locations

Locations (1)

Cleveland Clinic, Case Comprehensive Cancer Center; 🇺🇸 Cleveland, Ohio, United States