Enzalutamide/Leuprolide +/- Abiraterone/Pred in Prostate

• ClinicalTrials.gov Identifier: NCT02268175
• Recruitment Status: Active, not recruiting
• First Posted: October 20, 2014
• Last Update Posted: May 27, 2019
• Sponsor: Dana-Farber Cancer Institute
• Collaborator: Medivation, Inc.
• Information provided by (Responsible Party): Mary-Ellen Taplin, MD, Dana-Farber Cancer Institute

Study Description

Brief Summary:

This study is comparing the effectiveness of enzalutamide with or without abiraterone acetate for men with high-risk, localized prostate cancer.

Condition or disease	Intervention/treatment	Phase
Prostate Adenocarcinoma; Prostate Cancer; High Risk Prostate Cancer	Drug: Enzalutamide; Drug: Abiraterone Acetate; Drug: Prednisone; Drug: Leuprolide Acetate	Phase 2

Detailed Description:

In this research study, the investigators are comparing the effectiveness of enzalutamide with or without abiraterone acetate for men with high-risk, localized prostate cancer.

Abiraterone acetate with prednisone and enzalutamide are currently FDA-approved for use in the treatment of patients with metastatic castration-resistant prostate cancer, however they are investigational for the treatment of localized prostate cancer. Abiraterone acetate works by decreasing the production of male sex hormones, which cause prostate cancer growth. Enzalutamide works by blocking the effects of male sex hormones, which cause prostate cancer growth.

The FDA (the U.S. Food and Drug Administration) has not approved the combination of enzalutamide and abiraterone acetate as neoadjuvant therapy for high risk prostate cancer undergoing prostatectomy but each drug has been approved for the treatment of more advanced prostate cancer.

Participants will be randomized to one of two study arms. Randomization means that the participant is put into a group by chance. It is like flipping a coin. Neither participant nor the research doctor will choose what group participants are randomized to.

The names of the study medications involved in this study are:

• Enzalutamide
• Abiraterone Acetate
• Prednisone
• Leuprolide Acetate

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 75 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Randomized Study of Enzalutamide+Leuprolide Versus Enzalutamide+Leuprolide+Abiraterone Acetate+Prednisone as Neoadjuvant Therapy for HIgh-Risk Prostate Cancer Undergoing Prostatectomy
• Study Start Date: October 2014
• Estimated Primary Completion Date: May 2019
• Estimated Study Completion Date: February 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: ARM 1; Participants will be randomized in a 2:1 ratio to neoadjuvant treatment (ARM 1) or (ARM 2). Participants will receive the assigned study treatment per cycle; Enzalutamide- Once daily at prespecified dose, orally; Abiraterone Acetate- Once daily at prespecified dose, orally; Prednisone-Once daily at prespecified dose, orally; Leuprolide Acetate-Intermuscular injection at prespecified dose and duration	Drug: Enzalutamide; 160 mg (four 40 mg capsules), oral, once daily, 28 days (4 weeks) 6 cycles maximum. Can be taken with or without food.; Other Name: XTANDI; Drug: Abiraterone Acetate; 1000 mg (four 250 mg tablets), oral, once daily, 28 days (4 weeks) 6 cycles maximum. No food should be consumed for at least two hours before the dose and for at least one hour after the dose.; Other Name: Zytiga; Drug: Prednisone; 5 mg, oral, once daily, 28 days (4 weeks) 6 cycles maximum.Take with food, preferred to be taken in the morning .; Drug: Leuprolide Acetate; Either 7.5 mg monthly or 22.5 mg every three months, Intramuscular, monthly or every three months.; Other Names: - Lupron Depot-3 Month; - Lupron Depot-4 Month; - Lupron Depot; - Lupron; - Viadur
Experimental: ARM 2; Participants will be randomized in a 2:1 ratio to neoadjuvant treatment (ARM 1) or (ARM 2). Participants will receive the assigned study treatment per cycle.; Enzalutamide- once daily at prespecified dose, orally; Leuprolide Acetate- Intermuscular injection at prespecified dose and duration	Drug: Enzalutamide; 160 mg (four 40 mg capsules), oral, once daily, 28 days (4 weeks) 6 cycles maximum. Can be taken with or without food.; Other Name: XTANDI; Drug: Leuprolide Acetate; Either 7.5 mg monthly or 22.5 mg every three months, Intramuscular, monthly or every three months.; Other Names: - Lupron Depot-3 Month; - Lupron Depot-4 Month; - Lupron Depot; - Lupron; - Viadur

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants with pCR and MRD [ Time Frame: 2 Years ]
   Fisher's exact test

Secondary Outcome Measures :

1. Percentage of participants with pCR at RP [ Time Frame: 2 Years ]
2. Percentage of Participants with favorable RCB at RB [ Time Frame: 2 Years ]
3. Percentage of Participants with cribriform or intraductal spread at RP [ Time Frame: 2 Years ]
4. Percentage of participants with positive surgical margins extracapsular extension, positive seminal vesicles, and positive lymph [ Time Frame: 2 Years ]
   To evaluate the frequency of positive surgical margins, extracapsular extension, positive seminal vesicles, and positive lymph nodes at time of RP following treatment with ARM 1 compared to ARM 2.
5. Percentage of participants with PSA [ Time Frame: Baseline, Day 169 ]
6. Time to biochemical recurrence [ Time Frame: 2 Years ]
   Kaplan Meier method and comparison between arms will be conducted by the log-rank test.
7. Number of Participants with Serious and Non-Serious Adverse Events [ Time Frame: 24 Weeks ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Male greater than or equal 18 years of age.
• Histologically confirmed adenocarcinoma of the prostate without histological variants (including overt neuroendocrine differentiation, small cell neuroendocrine carcinoma features, sarcomatoid features, pure ductal adenocarcinoma, squamous or transitional cell carcinoma).
• Must have tissue available from the pre-treatment diagnostic biopsy (tissue blocks if possible; if not possible, 10 unstained slides from each positive core sample for a total of 30 slides).
• Must have three core biopsies involved with cancer (a minimum of 6 core biopsies must be obtained). Prostate biopsy must be within three months from screening.

• Participants must have the following features:

  • Intermediate-risk disease defined as Gleason 4+3=7 disease OR
  • High-risk disease defined as Gleason 8-10 OR PSA > 20 ng/dL OR T3 disease (by prostate MRI)
• No evidence of metastatic or nodal disease as determined by radionuclide bone scans CT/MRI.
• Participants must be candidates for RP and considered surgically resectable by urologic evaluation.
• ECOG performance status 0 to 1 (Appendix A).

• Participants must have normal organ and marrow function as defined below:

  • WBC ≥ 3,000/mcL
  • ANC ≥ 1,500/mcL
  • Platelets ≥ 100,000/mcL
  • Serum potassium ≥ 3.5 mmol/L
  • AST, ALT, and total bilirubin ≤ 1.5 x Institutional ULN
  • Calculated creatinine clearance ≥ 60 mL/min
  • PTT ≤ 60, INR ≤ 1.5 x Institutional ULN unless on warfarin therapy (investigator would need to determine if safe for participant to stop warfarin prior to biopsy and warfarin therapy)
  • Controlled blood pressure defined as a systolic blood pressure ≤ 140 mmHg and diastolic blood pressure ≤ 90 mmHg on no more than three anti-hypertensive agents. Drug formulations containing two or more anti-hypertensive agents will be counted based on the number of active agents in each formulation.

Exclusion Criteria:

• Prior hormone therapy for prostate cancer including orchiectomy, antiandrogens (including first-generation antiandrogens, enzalutamide, ARN-509 and others), CYP17 inhibitors (including abiraterone, TAK-700, galeterone, ketoconazole, and others), estrogens, LHRH agonist/antagonists. Prior therapy with 5α-reductace inhibitors is allowed. LHRH therapy allowed if begun within 4 weeks of day 1.
• Prior chemotherapy, radiation therapy, or immunotherapy for prostate cancer.
• Prior systemic treatment with an azole drug within four weeks of screening visit.
• Hypogonadism or severe androgen deficiency as defined by screening serum testosterone < 200 ng/dL.
• Clinically significant cardiovascular disease including:

• Acute coronary syndrome within 6 months of screening visit;

  • Hypotension defined as a systolic blood pressure < 86 mmHg;
  • Bradycardia defined as a heart rate of < 50 beats per minute, unless pharmaceutically induced and thus reversible (i.e. beta blockers);
  • Uncontrolled angina (requiring escalating doses of nitrates) within 3 months of screening visit;
  • Congestive heart failure NYHA Class III or IV or subjects with a history of congestive heart failure NYHA Class III or IV, unless screening ECHO results in left ventricular ejection fraction that ≥ 45%;
  • History of clinically significant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation, torsades de pointes);
  • Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on screening EKG > 470 msec;
  • History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place;
• History of seizure or any condition or concurrent medication that may predispose to seizure.
• Thromboembolism within 6 months of screening visit.
• Severe hepatic impairment (Child-Pugh Class C).
• Active or symptomatic viral hepatitis or chronic liver disease.
• History of pituitary or adrenal dysfunction.
• GI disorders which may interfere with the absorption of the study drug.
• Pre-existing condition that warrants long-term corticosteroid use.
• Concomitant use of medications that may alter pharmacokinetics of abiraterone or enzalutamide.
• Individuals with a history of a different malignancy are ineligible except for the following circumstances: 1) individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy, or 2) individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: non-muscle invasive bladder cancer, basal cell or squamous cell carcinoma of the skin.
• Major surgery or radiation therapy within 30 days of screening.

Contacts and Locations

Locations

United States, Maryland

Johns Hopkins University

Baltimore, Maryland, United States, 21231

United States, Massachusetts

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States, 02115

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02115

United States, Washington

University of Washington

Seattle, Washington, United States, 98109

Sponsors and Collaborators

Dana-Farber Cancer Institute

Medivation, Inc.

Investigators

• Principal Investigator: Mary-Ellen Taplin, MD; Dana-Farber Cancer Institute

More Information

• Responsible Party: Mary-Ellen Taplin, MD, Principal Investigator, Dana-Farber Cancer Institute
• ClinicalTrials.gov Identifier: NCT02268175 History of Changes
• Other Study ID Numbers: 14-283
• First Posted: October 20, 2014
• Last Update Posted: May 27, 2019
• Last Verified: May 2019

Keywords provided by Mary-Ellen Taplin, MD, Dana-Farber Cancer Institute:

prostate adenocarcinoma; advanced prostate cancer; high risk prostate cancer

Additional relevant MeSH terms:

Prostatic Neoplasms; Adenocarcinoma; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Prednisone; Leuprolide; Abiraterone Acetate; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Hormone Antagonists; Cytochrome P-450 Enzyme Inhibitors; Fertility Agents, Female; Fertility Agents; Reproductive Control Agents