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

• Sponsor: Alliance Foundation Trials, LLC. (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03009981
• Collaborator: Janssen Research & Development, LLC (Industry)
• Enrollment: 504
• Locations: 69
• Arms: 3
• Anticipated Duration (Months): 81.9
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: Apalutamide; Drug: LHRH Analogue; Drug: Abiraterone Acetate; Drug: Prednisone	Phase 3

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.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 504 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Study of Androgen Annihilation in High-Risk Biochemically Relapsed Prostate Cancer
• Actual Study Start Date: Mar 6, 2017
• Anticipated Primary Completion Date: Jan 1, 2024
• Anticipated Study Completion Date: Jan 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A: Degarelix Monotherapy OR Leuprolide/Bicalutamide Patients will receive degarelix OR leuprolide with bicalutamide.	Drug: 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.; Other Names: Degarelix (Firmagon) Leuprolide (Lupron) and Bicalutamide
Experimental: Arm B: Degarelix/Apalutamide Patients will receive apalutamide and either degarelix OR leuprolide. Patients on this arm will NOT take bicalutamide at any point in the treatment course.	Drug: Apalutamide; Take apalutamide 240 mg (four 60 mg tablets) orally once daily, starting on C1D1 and continuing throughout 52-week treatment period.; Other Names: Erleada ; Drug: 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.; Other Names: Degarelix (Firmagon) Leuprolide (Lupron) and Bicalutamide
Experimental: Arm C: Degarelix/Apalutamide/Abiraterone/Prednisone Patients will receive apalutamide and abiraterone acetate, in addition to either degarelix OR leuprolide. Patients on this arm will NOT take bicalutamide at any point in the treatment course.	Drug: Apalutamide; Take apalutamide 240 mg (four 60 mg tablets) orally once daily, starting on C1D1 and continuing throughout 52-week treatment period.; Other Names: Erleada ; Drug: 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.; Other Names: Degarelix (Firmagon) Leuprolide (Lupron) and Bicalutamide ; Drug: Abiraterone Acetate; Take abiraterone acetate 1000 mg (four 250 mg tablets) orally once daily, starting on C1D1 and continuing throughout 52-week treatment period.; Other Names: Zytiga ; Drug: 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.; Other Names: Deltasone

Outcome Measures

Primary Outcome Measures

1. PSA progression-free survival in the intent-to-treat population [36 months]

   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).

Secondary Outcome Measures

1. PSA progression-free survival in the testosterone-evaluable population [36 months]

   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

2. PSA progression-free survival in both the intent-to-treat and testosterone-evaluable populations [36 months]

   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.

3. Serum testosterone [12 months]

   To compare the time to recovery of serum testosterone to greater than 50 ng/dL in each experimental arm versus the control arm.

4. Time to castration resistance [6 years]

   To compare the time to castration resistance in each experimental arm versus the control arm.

5. Metastasis-Free Survival [6 years]

   To compare metastasis-free survival in each experimental arm versus the control arm.

6. Overall Survival [6 years]

   To compare overall survival in each experimental arm versus the control arm.

7. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [6 years]

   To characterize the safety profile in each treatment arm

8. Quality of life Expanded Prostate Cancer Index Composite (EPIC) [72 months]

   Expanded Prostate Cancer Index Composite (EPIC)

9. Quality of life Hot Flash Daily Interference Scale (HFRDIS) [72 months]

   Hot Flash Daily Interference Scale (HFRDIS)

10. Quality of life EQ-5D-5L [72 months]

    EQ-5D-5L

11. Quality of life PROMIS Fatigue [72 months]

    PROMIS Fatigue

12. Quality-adjusted survival [72 months]

    To compare the quality-adjusted survival (overall survival multiplied by utility score) of patients in each experimental arm versus the control arm.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Mayo Clinic - Phoenix	Phoenix	Arizona	United States	85054
2	Sharp Memorial Hospital	Chula Vista	California	United States	91911
3	City of Hope National Medical Center	Duarte	California	United States	91010
4	Palo Alto Medical Foundation	Fremont	California	United States	94538
5	VA Central California Health Care System	Fresno	California	United States	93703
6	Sharp Memorial Hospital	La Mesa	California	United States	91942
7	Palo Alto Medical Foundation	Mountain View	California	United States	94040
8	Palo Alto Medical Foundation	Palo Alto	California	United States	94301
9	Adventist Health St. Helena/St. Helena Hospital/Martin O'Neil Cancer Center	Saint Helena	California	United States	94574
10	University of California San Diego - Moores Cancer Center	San Diego	California	United States	92093
11	Sharp Memorial Hospital	San Diego	California	United States	92123
12	University of California San Francisco	San Francisco	California	United States	94158
13	Palo Alto Medical Foundation	Santa Cruz	California	United States	95065
14	Palo Alto Medical Foundation	Sunnyvale	California	United States	94086
15	Georgetown University Medical Center	Washington	District of Columbia	United States	20007
16	MedStar Washington Hospital Center	Washington	District of Columbia	United States	20007
17	Pali Momi Medical Center	'Aiea	Hawaii	United States	96701
18	University of Hawaii Cancer Center	Honolulu	Hawaii	United States	96813
19	Rush University Medical Center	Chicago	Illinois	United States	606012
20	University of Chicago Comprehensive Cancer Center	Chicago	Illinois	United States	60637
21	Northshore University Health System	Evanston	Illinois	United States	60201
22	Loyola University	Maywood	Illinois	United States	60153
23	Quincy Medical Group	Quincy	Illinois	United States	62301
24	Carle Cancer Center	Urbana	Illinois	United States	61801
25	Cancer Center of Kansas	Wichita	Kansas	United States	67214
26	Eastern Maine Medical Center	Brewer	Maine	United States	04412
27	New England Cancer Specialists	Kennebunk	Maine	United States	04043
28	New England Cancer Specialists	Scarborough	Maine	United States	04074
29	New England Cancer Specialists	Topsham	Maine	United States	04086
30	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
31	Dana Farber Cancer Institute	Milford	Massachusetts	United States	01757
32	Dana Farber Cancer Institute	South Weymouth	Massachusetts	United States	02190
33	University of Minnesota	Minneapolis	Minnesota	United States	55455
34	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota	United States	55416
35	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
36	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
37	Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
38	New Hampshire Oncology & Hematology	Concord	New Hampshire	United States	03301
39	New Hampshire Oncology & Hematology	Hooksett	New Hampshire	United States	03106
40	Memorial Sloan Kettering Basking Ridge	Basking Ridge	New Jersey	United States	07920
41	Memorial Sloan Kettering Cancer Center	Middletown	New Jersey	United States	07748
42	Atlantic Health System/Morristown Medical Center	Morristown	New Jersey	United States	07962
43	New Mexico Oncology Hematology Consultants	Albuquerque	New Mexico	United States	87109
44	University of New Mexico Comprehensive Cancer Center	Albuquerque	New Mexico	United States	87131
45	Memorial Medical Center- Cancer Center	Las Cruces	New Mexico	United States	88011
46	Christus St. Vincent's Regional Cancer Center	Santa Fe	New Mexico	United States	87505
47	VA Western New York	Buffalo	New York	United States	14215
48	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
49	Memorial Sloan Kettering Cancer Center	Commack	New York	United States	11725
50	Memorial Sloan Kettering Cancer Center	Harrison	New York	United States	11533
51	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
52	Weill Cornell Medical Ctr - New York Presbyterian Hospital	New York	New York	United States	10065
53	Montefiore Medical Center	New York	New York	United States	10461
54	SUNY Upstate Medical University	Syracuse	New York	United States	13210
55	University of North Carolina Hospital	Chapel Hill	North Carolina	United States	27514
56	Novant Health Presbyterian Medical Center	Charlotte	North Carolina	United States	28204
57	VA Salisbury	Salisbury	North Carolina	United States	28144
58	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
59	Dayton Physicians Miami Valley South	Centerville	Ohio	United States	45459
60	The Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
61	The Toledo Clinic	Toledo	Ohio	United States	43623
62	Oklahoma Cancer Specialists and Research Institute	Tulsa	Oklahoma	United States	74146
63	Providence Portland Medical Center	Portland	Oregon	United States	97213
64	Oregon Health & Science University	Portland	Oregon	United States	97239
65	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15232
66	Spartanburg Medical Center/Gibbs Cancer Center	Spartanburg	South Carolina	United States	29303
67	University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
68	Marshfield Clinic Cancer Center	Marshfield	Wisconsin	United States	54449
69	Froedtert Hospital/Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Alliance Foundation Trials, LLC.
• Janssen Research & Development, LLC

Investigators

• Principal Investigator: Monica Bertagnolli, MD, Alliance Foundation Trials, LLC.
• Study Chair: Rahul Aggarwal, MD, University of California, San Francisco

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• 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. Review.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: Alliance Foundation Trials, LLC.
• ClinicalTrials.gov Identifier: NCT03009981
• Other Study ID Numbers: AFT-19
• First Posted: Jan 4, 2017
• Last Update Posted: Aug 23, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Alliance Foundation Trials, LLC.: PSA; Degarelix; Apalutamide; Abiraterone Acetate; Radical Prostatectomy; Bicalutamide; Leuprolide; Lupron
• Additional relevant MeSH terms: Prostatic Neoplasms; Prednisone; Leuprolide; Abiraterone Acetate; Bicalutamide

Study Results

No Results Posted as of Aug 23, 2022