Clinical trial NCT03009981: A Study of Androgen Annihilation in High-Risk Biochemically Relapsed Prostate Cancer
Official title: A Phase 3 Study of Androgen Annihilation in High-Risk Biochemically Relapsed Prostate Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Prostate Cancer
Keywords: PSA
Degarelix
Apalutamide
Abiraterone Acetate
Radical Prostatectomy
Bicalutamide
Leuprolide
Lupron
Lead sponsor: Alliance Foundation Trials, LLC.
Sponsor class: OTHER
Collaborators: name: Janssen Research & Development, LLC
First posted: 2017-01-04
Enrollment: 504
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: PSA progression-free survival in the intent-to-treat population
timeFrame: 36 months
Secondary outcomes:
measure: PSA progression-free survival in the testosterone-evaluable population
timeFrame: 36 months
measure: PSA progression-free survival in both the intent-to-treat and testosterone-evaluable populations
timeFrame: 36 months
measure: Serum testosterone
timeFrame: 12 months
measure: Time to castration resistance
timeFrame: 6 years
measure: Metastasis-Free Survival
timeFrame: 6 years
measure: Overall Survival
timeFrame: 6 years
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 6 years
measure: Quality of life Expanded Prostate Cancer Index Composite (EPIC)
timeFrame: 72 months
measure: Quality of life Hot Flash Daily Interference Scale (HFRDIS)
timeFrame: 72 months
measure: Quality of life EQ-5D-5L
timeFrame: 72 months
measure: Quality of life PROMIS Fatigue
timeFrame: 72 months
measure: Quality-adjusted survival
timeFrame: 72 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: The Mayo Clinic - Phoenix
state: Arizona
city: Chula Vista
country: United States
facility: Sharp Memorial Hospital
state: California
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Fremont
country: United States
facility: Palo Alto Medical Foundation
state: California
city: Fresno
country: United States
facility: VA Central California Health Care System
state: California
city: La Mesa
country: United States
facility: Sharp Memorial Hospital
state: California
city: Mountain View
country: United States
facility: Palo Alto Medical Foundation
state: California
city: Palo Alto
country: United States
facility: Palo Alto Medical Foundation
state: California
city: Saint Helena
country: United States
facility: Adventist Health St. Helena/St. Helena Hospital/Martin O'Neil Cancer Center
state: California
city: San Diego
country: United States
facility: University of California San Diego - Moores Cancer Center
state: California
city: San Diego
country: United States
facility: Sharp Memorial Hospital
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Santa Cruz
country: United States
facility: Palo Alto Medical Foundation
state: California
city: Sunnyvale
country: United States
facility: Palo Alto Medical Foundation
state: California
city: Washington
country: United States
facility: Georgetown University Medical Center
state: District of Columbia
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: 'Aiea
country: United States
facility: Pali Momi Medical Center
state: Hawaii
city: Honolulu
country: United States
facility: University of Hawaii Cancer Center
state: Hawaii
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Chicago
country: United States
facility: University of Chicago Comprehensive Cancer Center
state: Illinois
city: Evanston
country: United States
facility: Northshore University Health System
state: Illinois
city: Maywood
country: United States
facility: Loyola University
state: Illinois
city: Quincy
country: United States
facility: Quincy Medical Group
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Wichita
country: United States
facility: Cancer Center of Kansas
state: Kansas
city: Brewer
country: United States
facility: Eastern Maine Medical Center
state: Maine
city: Kennebunk
country: United States
facility: New England Cancer Specialists
state: Maine
city: Scarborough
country: United States
facility: New England Cancer Specialists
state: Maine
city: Topsham
country: United States
facility: New England Cancer Specialists
state: Maine
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Milford
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: South Weymouth
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis Park
country: United States
facility: Metro Minnesota Community Oncology Research Consortium
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: Nebraska Methodist Hospital
state: Nebraska
city: Las Vegas
country: United States
facility: Nevada Cancer Research Foundation
state: Nevada
city: Concord
country: United States
facility: New Hampshire Oncology & Hematology
state: New Hampshire
city: Hooksett
country: United States
facility: New Hampshire Oncology & Hematology
state: New Hampshire
city: Basking Ridge
country: United States
facility: Memorial Sloan Kettering Basking Ridge
state: New Jersey
city: Middletown
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New Jersey
city: Morristown
country: United States
facility: Atlantic Health System/Morristown Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: New Mexico Oncology Hematology Consultants
state: New Mexico
city: Albuquerque
country: United States
facility: University of New Mexico Comprehensive Cancer Center
state: New Mexico
city: Las Cruces
country: United States
facility: Memorial Medical Center- Cancer Center
state: New Mexico
city: Santa Fe
country: United States
facility: Christus St. Vincent's Regional Cancer Center
state: New Mexico
city: Buffalo
country: United States
facility: VA Western New York
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Commack
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medical Ctr - New York Presbyterian Hospital
state: New York
city: New York
country: United States
facility: Montefiore Medical Center
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina Hospital
state: North Carolina
city: Charlotte
country: United States
facility: Novant Health Presbyterian Medical Center
state: North Carolina
city: Salisbury
country: United States
facility: VA Salisbury
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Sciences
state: North Carolina
city: Centerville
country: United States
facility: Dayton Physicians Miami Valley South
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Comprehensive Cancer Center
state: Ohio
city: Toledo
country: United States
facility: The Toledo Clinic
state: Ohio
city: Tulsa
country: United States
facility: Oklahoma Cancer Specialists and Research Institute
state: Oklahoma
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Spartanburg
country: United States
facility: Spartanburg Medical Center/Gibbs Cancer Center
state: South Carolina
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Marshfield
country: United States
facility: Marshfield Clinic Cancer Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Froedtert Hospital/Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: Alliance Foundation Trials, LLC.
name: Suzanne George, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of California, San Francisco
name: Rahul Aggarwal, MD
role: STUDY_CHAIR
References:
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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.
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.
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.
citation: 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.