A Study of Androgen Annihilation in High-Risk Biochemically Relapsed Prostate Cancer

Prostate Cancer Clinical Trial

Official title:

A Phase 3 Study of Androgen Annihilation in High-Risk Biochemically Relapsed Prostate Cancer

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03009981
• Other study ID #: AFT-19
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: March 6, 2017
• Est. completion date: January 1, 2025

Study information

• Verified date: March 2023
• Source: Alliance Foundation Trials, LLC.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized, open-label, three-arm, phase 3 study in men with biochemically recurrent prostate cancer and PSA doubling time ≤ 9 months at the time of study entry.

Description:

Patients will be stratified by PSA doubling time (< 3 months vs. 3-9 months) and randomized in 1:1:1 fashion to one of three treatment arms: (1) Control arm consisting of LHRH analogue monotherapy (degarelix or leuprolide), (2) Experimental arm consisting of apalutamide in combination with LHRH analogue, and (3) Experimental arm consisting of apalutamide, abiraterone acetate + prednisone, and LHRH analogue. Patients will be treated for a maximum duration of 52 weeks and then enter follow up phase until the time of PSA progression, development of metastasis, or patient withdrawal from study, whichever occurs first. Patients with PSA progression will be followed long term until the development of castration resistance, first metastasis, and death.

The primary endpoint of the study is PSA progression-free survival in the intent-to-treat patient population. PSA progression during the 52-week treatment period is defined as a rising PSA confirmed on repeat measurement, and at least 25% and 2 ng/mL above nadir or baseline, whichever is lower. PSA progression during follow up defined as PSA > 0.2 ng/mL confirmed by repeat measurement at least 2 weeks later. Secondary study endpoints include PSA progression-free survival in testosterone-evaluable population, 36-month PSA progression-free survival rate in both intent-to-treat and testosterone-evaluable populations, time to testosterone recovery, time to castration resistance, metastasis-free survival, quality of life, and safety. Each experimental arm will be compared against the control arm in pair-wise fashion. The study is not powered to detect differences in primary or secondary endpoints between the two experimental arms.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 504
• Est. completion date: January 1, 2025
• Est. primary completion date: July 1, 2024
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologically confirmed prostate adenocarcinoma

• Prior radical prostatectomy

• Biochemically recurrent prostate cancer with PSA doubling time = 9 months at the time of study entry. Calculation of PSA doubling time should include the use of all available PSA values obtained within past 6-12 months prior to randomization, with a minimum of 3 values separated by at least 2 weeks apart. PSA values obtained prior to therapeutic interventions (e.g. salvage radiation) will be excluded. PSA doubling time to be estimated using Memorial Sloan Kettering Cancer Center online calculator (https://www.mskcc.org/nomograms/prostate/psa-doubling-time)

• Prior adjuvant or salvage radiation or not a candidate for radiation based upon clinical assessment of disease characteristics and patient co-morbidities.

• Screening PSA > 0.5 ng/mL

• No definitive evidence of metastases on screening CT or MRI of abdomen/pelvis and radionuclide whole body bone scan per the judgment of the investigator. Abdominal and/or pelvic lymph nodes measuring 2 cm or less in short axis diameter are allowed. Lesions identified on other imaging modalities (e.g. PSMA or choline PET) that are not visualized on CT and/or MRI or radionuclide bone scan are allowed. Equivocal lesions on bone scan should be followed up with additional imaging as clinically indicated.

• Screening serum testosterone > 150 ng/dL

• Eastern Cooperative Oncology Group (ECOG) Performance Status grade 0 or 1

• Age = 18 years

• Medications known to lower the seizure threshold must be discontinued or substituted at least 4 weeks prior to cycle 1 day 1

• 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 after receiving the last dose of study drug.

• Adequate organ function as defined by the following laboratory values at screening:

• Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) < 2.5 x upper limit of normal (ULN)

• Total serum bilirubin =1.5 x ULN. 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)

• Serum potassium = 3.5 mmol/L. Supplementation and re-screening is allowed.

• Estimated creatinine clearance > 45 ml/min using Cockroft-Gault equation

• Platelets = 100,000/microliter independent of transfusion and/or growth factors within 3 months prior to randomization

• Hemoglobin = 9.0 g/dL independent of transfusion and/or growth factors within 3 months prior to randomization

• Serum albumin = 3.0 g/dL

Exclusion Criteria:

• Prior androgen deprivation therapy and/or first generation anti-androgen (e.g. bicalutamide, nilutamide, flutamide) for biochemically recurrent prostate cancer. Prior ADT and/or first generation anti-androgen in the (neo)adjuvant and/or salvage setting before, during, and/or following radiation or surgery is allowed provided last effective dose of ADT and/or first-generation anti-androgen is > 9 months prior to date of randomization and total duration of prior therapy is = 36 months.

• Prior treatment with CYP17 inhibitor (e.g. ketoconazole, abiraterone acetate, galeterone) or second generation androgen receptor antagonist including apalutamide or enzalutamide

• Prior chemotherapy for prostate cancer except if administered in neoadjuvant or adjuvant setting

• Use of 5-alpha reductase inhibitor within 42 days prior to cycle 1 day 1

• Use of investigational agent within 28 days prior to randomization

• Use of other prohibited medications within 7 days prior to cycle 1 day 1 on study (Arms B and C only)

• Prior bilateral orchiectomy

• Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1year to randomization, brain arteriovenous malformation, Schwannoma, meningioma, or other benign CNS or meningeal disease which may require treatment with surgery or radiation therapy)

• Uncontrolled hypertension

• Gastrointestinal disorder affecting absorption or the ability to swallow tablets

• Baseline severe hepatic impairment (Child-Pugh Class B & C)

• Intercurrent illness that is not controlled such as active infection, psychiatric illness/social situations that would limit compliance with study requirements

• Any chronic medical condition requiring a higher dose of corticosteroid than equivalent of 5 mg prednisone/prednisolone once daily

Related Conditions & MeSH terms

• Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• Apalutamide
Take apalutamide 240 mg (four 60 mg tablets) orally once daily, starting on C1D1 and continuing throughout 52-week treatment period.
• LHRH Analogue
Patients will receive a LHRH analogue therapy of either Degarelix OR Leuprolide with bicalutamide. Degarelix: Patients will receive subcutaneous injections every 28 days (+/- 3 days). Patients will receive a loading dose of 240 mg (two 120 mg injections) on C1D1, followed by maintenance dose of 80 mg on Day 1 of subsequent cycles. Leuprolide: Patients treated with leuprolide will receive a 7.5 mg IM injection on C1D1. Patients in arm A ONLY will take this in combination with bicalutamide 50 mg orally once daily starting on C1D1 and continuing for 28 days through completion of cycle 1. Starting on C2D1, patients will continue on one of the following two treatments at investigator discretion: Leuprolide 7.5 mg IM injection on Day 1 of subsequent cycles without concurrent bicalutamide. OR: Leuprolide 22.5 mg IM injection at the following visits without concurrent bicalutamide: C2D1, C5D1, C8D1, and C11D1.
• Abiraterone Acetate
Take abiraterone acetate 1000 mg (four 250 mg tablets) orally once daily, starting on C1D1 and continuing throughout 52-week treatment period.
• Prednisone
Take two prednisone 5 mg tablets daily, starting on C1D1 and continuing throughout the 52-week treatment period. Following completion of treatment period, patients will taper off prednisone per institutional guidelines. Suggested tapering plan: prednisone 5 mg daily for 7 days, then 2.5 mg daily for 7 days before discontinuing.

Locations

Country	Name	City	State
United States	Pali Momi Medical Center	'Aiea	Hawaii
United States	New Mexico Oncology Hematology Consultants	Albuquerque	New Mexico
United States	University of New Mexico Comprehensive Cancer Center	Albuquerque	New Mexico
United States	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Eastern Maine Medical Center	Brewer	Maine
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	VA Western New York	Buffalo	New York
United States	Dayton Physicians Miami Valley South	Centerville	Ohio
United States	University of North Carolina Hospital	Chapel Hill	North Carolina
United States	Novant Health Presbyterian Medical Center	Charlotte	North Carolina
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Sharp Memorial Hospital	Chula Vista	California
United States	The Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Memorial Sloan Kettering Cancer Center	Commack	New York
United States	New Hampshire Oncology & Hematology	Concord	New Hampshire
United States	City of Hope National Medical Center	Duarte	California
United States	Northshore University Health System	Evanston	Illinois
United States	Palo Alto Medical Foundation	Fremont	California
United States	VA Central California Health Care System	Fresno	California
United States	Memorial Sloan Kettering Cancer Center	Harrison	New York
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	New Hampshire Oncology & Hematology	Hooksett	New Hampshire
United States	University of Texas MD Anderson Cancer Center	Houston	Texas
United States	New England Cancer Specialists	Kennebunk	Maine
United States	Sharp Memorial Hospital	La Mesa	California
United States	Memorial Medical Center- Cancer Center	Las Cruces	New Mexico
United States	Nevada Cancer Research Foundation	Las Vegas	Nevada
United States	Marshfield Clinic Cancer Center	Marshfield	Wisconsin
United States	Loyola University	Maywood	Illinois
United States	Memorial Sloan Kettering Cancer Center	Middletown	New Jersey
United States	Dana Farber Cancer Institute	Milford	Massachusetts
United States	Froedtert Hospital/Medical College of Wisconsin	Milwaukee	Wisconsin
United States	University of Minnesota	Minneapolis	Minnesota
United States	Atlantic Health System/Morristown Medical Center	Morristown	New Jersey
United States	Palo Alto Medical Foundation	Mountain View	California
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Montefiore Medical Center	New York	New York
United States	Weill Cornell Medical Ctr - New York Presbyterian Hospital	New York	New York
United States	Nebraska Methodist Hospital	Omaha	Nebraska
United States	Palo Alto Medical Foundation	Palo Alto	California
United States	The Mayo Clinic - Phoenix	Phoenix	Arizona
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Providence Portland Medical Center	Portland	Oregon
United States	Quincy Medical Group	Quincy	Illinois
United States	Adventist Health St. Helena/St. Helena Hospital/Martin O'Neil Cancer Center	Saint Helena	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota
United States	VA Salisbury	Salisbury	North Carolina
United States	Sharp Memorial Hospital	San Diego	California
United States	University of California San Diego - Moores Cancer Center	San Diego	California
United States	University of California San Francisco	San Francisco	California
United States	Palo Alto Medical Foundation	Santa Cruz	California
United States	Christus St. Vincent's Regional Cancer Center	Santa Fe	New Mexico
United States	New England Cancer Specialists	Scarborough	Maine
United States	Dana Farber Cancer Institute	South Weymouth	Massachusetts
United States	Spartanburg Medical Center/Gibbs Cancer Center	Spartanburg	South Carolina
United States	Palo Alto Medical Foundation	Sunnyvale	California
United States	SUNY Upstate Medical University	Syracuse	New York
United States	The Toledo Clinic	Toledo	Ohio
United States	New England Cancer Specialists	Topsham	Maine
United States	Oklahoma Cancer Specialists and Research Institute	Tulsa	Oklahoma
United States	Carle Cancer Center	Urbana	Illinois
United States	Georgetown University Medical Center	Washington	District of Columbia
United States	MedStar Washington Hospital Center	Washington	District of Columbia
United States	Cancer Center of Kansas	Wichita	Kansas
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Alliance Foundation Trials, LLC.	Janssen Research & Development, LLC

Country where clinical trial is conducted

United States, 

References & Publications (6)

Gershon RC, Rothrock N, Hanrahan R, Bass M, Cella D. The use of PROMIS and assessment center to deliver patient-reported outcome measures in clinical research. J Appl Meas. 2010;11(3):304-14. — View Citation

Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Reuter VE. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and Bladder Tumours. Eur Urol. 2016 Jul;70(1):106-119. doi: 10.1016/j.eururo.2016.02.028. Epub 2016 Mar 17. — View Citation

Qu Y, Dai B, Ye D, Kong Y, Chang K, Jia Z, Yang X, Zhang H, Zhu Y, Shi G. Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer. Sci Rep. 2015 Jan 7;5:7654. doi: 10.1038/srep07654. — View Citation

Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015 Jan-Feb;65(1):5-29. doi: 10.3322/caac.21254. Epub 2015 Jan 5. — View Citation

Zelefsky MJ, Ben-Porat L, Scher HI, Chan HM, Fearn PA, Fuks ZY, Leibel SA, Venkatraman ES. Outcome predictors for the increasing PSA state after definitive external-beam radiotherapy for prostate cancer. J Clin Oncol. 2005 Feb 1;23(4):826-31. doi: 10.1200/JCO.2005.02.111. — View Citation

Zietman AL, Chung CS, Coen JJ, Shipley WU. 10-year outcome for men with localized prostate cancer treated with external radiation therapy: results of a cohort study. J Urol. 2004 Jan;171(1):210-4. doi: 10.1097/01.ju.0000100980.13364.a6. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PSA progression-free survival in the intent-to-treat population	To compare PSA progression-free survival in each of the experimental arms (LHRH analogue + apalutamide; LHRH analogue + apalutamide +abiraterone acetate) versus the control arm (LHRH analogue) among all randomized patients (intent-to-treat population).	36 months
Secondary	PSA progression-free survival in the testosterone-evaluable population	Compare PSA progression-free survival in testosterone-evaluable population in each experimental arm versus the control arm. Testosterone-evaluable population includes all patients who achieve serum testosterone recovery to > 50 ng/dL with subsequent PSA measurements sufficient for evaluation	36 months
Secondary	PSA progression-free survival in both the intent-to-treat and testosterone-evaluable populations	To compare the 36-month PSA progression-free survival rate in each experimental arm versus the control arm in both the intent-to-treat and testosterone-evaluable populations.	36 months
Secondary	Serum testosterone	To compare the time to recovery of serum testosterone to greater than 50 ng/dL in each experimental arm versus the control arm.	12 months
Secondary	Time to castration resistance	To compare the time to castration resistance in each experimental arm versus the control arm.	6 years
Secondary	Metastasis-Free Survival	To compare metastasis-free survival in each experimental arm versus the control arm.	6 years
Secondary	Overall Survival	To compare overall survival in each experimental arm versus the control arm.	6 years
Secondary	Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	To characterize the safety profile in each treatment arm	6 years
Secondary	Quality of life Expanded Prostate Cancer Index Composite (EPIC)	Expanded Prostate Cancer Index Composite (EPIC)	72 months
Secondary	Quality of life Hot Flash Daily Interference Scale (HFRDIS)	Hot Flash Daily Interference Scale (HFRDIS)	72 months
Secondary	Quality of life EQ-5D-5L	EQ-5D-5L	72 months
Secondary	Quality of life PROMIS Fatigue	PROMIS Fatigue	72 months
Secondary	Quality-adjusted survival	To compare the quality-adjusted survival (overall survival multiplied by utility score) of patients in each experimental arm versus the control arm.	72 months