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A Phase II Neoadjuvant Study of Apalutamide, Abiraterone Acetate, Prednisone, Degarelix and Indomethacin in Men With Localized Prostate Cancer Pre-prostatectomy

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ClinicalTrials.gov Identifier: NCT02849990
Recruitment Status : Active, not recruiting
First Posted : July 29, 2016
Last Update Posted : February 22, 2019
Sponsor:
Collaborators:
Janssen Scientific Affairs, LLC
National Cancer Institute (NCI)
Information provided by (Responsible Party):
University of Washington

Brief Summary:
This phase II trial studies how well apalutamide, abiraterone acetate, prednisone, degarelix, and indomethacin work in treating patients with prostate cancer that has spread from where it started to nearby tissue or lymph nodes before surgery. Androgen can cause the growth of tumor cells. Hormone therapy using apalutamide, abiraterone acetate, prednisone, degarelix, and indomethacin may fight prostate cancer by lowering the amount of androgen the body makes and/or blocking the use of androgen by the tumor cells.

Condition or disease Intervention/treatment Phase
Stage III Prostate Adenocarcinoma AJCC v7 Stage III Prostate Cancer AJCC v7 Stage IV Prostate Adenocarcinoma AJCC v7 Stage IV Prostate Cancer AJCC v7 Drug: Abiraterone Acetate Drug: Apalutamide Drug: Degarelix Drug: Indomethacin Other: Laboratory Biomarker Analysis Drug: Prednisone Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. The rate of the pathologic complete response (pCR) (i.e. no evidence of residual tumor) as assessed on prostatectomy specimens following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin.

SECONDARY OBJECTIVES:

I. To determine the negative margin rate as assessed on prostatectomy specimens following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin.

II. To determine the rate of near pCR (i.e. =< 5 mm of residual tumor) as assessed on prostatectomy specimens following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin.

III. To determine the rate of pathologic T3 disease as assessed on prostatectomy specimens following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin.

IV. To determine the rate of nodal metastases as assessed on surgical lymph node specimens following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin.

V. To determine the apoptotic index (i.e. percentage of tumor cells undergoing apoptosis) as determined by cleaved caspase-3 immunohistochemistry following 3-months (12 weeks) of neoadjuvant apalutamide, abiraterone acetate, degarelix and indomethacin.

VI. To determine the proportion of men who receive adjuvant radiation therapy within 1-year of prostatectomy.

VII. To determine the biochemical (i.e. prostate-specific antigen [PSA]) progression free survival estimate two years after the last patient has accrued (i.e. confirmed PSA post-radical prostatectomy >= 0.2 ng/mL).

VIII. To determine the overall survival estimate two years after the last patient has accrued.

IX. Safety as assessed by the incidence and severity of adverse events and serious adverse events graded according to the National Cancer Institute - Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

X. Exploratory biomarker assessment.

OUTLINE:

Patients receive apalutamide and abiraterone acetate orally (PO) daily, prednisone PO twice per day (BID) and indomethacin PO three times per day (TID). Patients also receive degarelix subcutaneously (SC) on day 1 and every 4 weeks for 3 doses. Treatment continues for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo prostatectomy on day 85.

After completion of study treatment, patients are followed up at 28, 113, 450 and 815 days.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 22 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Neoadjuvant Study of Apalutamide, Abiraterone Acetate, Prednisone, Degarelix and Indomethacin in Men With Localized Prostate Cancer Pre-Prostatectomy
Actual Study Start Date : March 9, 2017
Actual Primary Completion Date : December 10, 2018
Estimated Study Completion Date : December 10, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (neoadjuvant chemotherapy)
Patients receive androgen receptor antagonist ARN-509 and abiraterone acetate PO daily, prednisone PO BID and indomethacin PO TID. Patients also receive degarelix SC on day 1 and every 4 weeks for 3 doses. Treatment continues for up to 12 weeks in the absence of disease progression or unacceptable toxicity. Patients undergo prostatectomy on day 85.
Drug: Abiraterone Acetate
Given PO
Other Names:
  • CB7630
  • Zytiga

Drug: Apalutamide
Given PO
Other Names:
  • ARN 509
  • ARN-509
  • ARN509
  • JNJ 56021927
  • JNJ-56021927

Drug: Degarelix
Given SC
Other Names:
  • FE200486
  • Firmagon

Drug: Indomethacin
Given PO
Other Names:
  • Indocin
  • Indometacin

Other: Laboratory Biomarker Analysis
Correlative study

Drug: Prednisone
Given PO
Other Names:
  • .delta.1-Cortisone
  • 1, 2-Dehydrocortisone
  • Adasone
  • Cortancyl
  • Dacortin
  • DeCortin
  • Decortisyl
  • Decorton
  • Delta 1-Cortisone
  • Delta-Dome
  • Deltacortene
  • Deltacortisone
  • Deltadehydrocortisone
  • Deltasone
  • Deltison
  • Deltra
  • Econosone
  • Lisacort
  • Meprosona-F
  • Metacortandracin
  • Meticorten
  • Ofisolona
  • Orasone
  • Panafcort
  • Panasol-S
  • Paracort
  • PRED
  • Predicor
  • Predicorten
  • Prednicen-M
  • Prednicort
  • Prednidib
  • Prednilonga
  • Predniment
  • Prednisonum
  • Prednitone
  • Promifen
  • Servisone
  • SK-Prednisone




Primary Outcome Measures :
  1. Pathologic complete response rate as assessed from prostatectomy specimens following neoadjuvant treatment [ Time Frame: At 3 months ]
    A 1-sample chi-square test will be used to compare the proportion of subjects with a pathologic complete response to the null hypothesis value of 5%. The 95% confidence interval of the primary endpoint estimate will be computed.


Secondary Outcome Measures :
  1. Apoptotic index (i.e. percentage of tumor cells undergoing apoptosis) [ Time Frame: At 3 months ]
    Will be determined by cleaved caspase-3 immunohistochemistry.

  2. Incidence of adverse events [ Time Frame: Up to 2 years ]
    Will be assessed by National Cancer Institute Common Toxicity Criteria, version 4.0. Will characterize toxicity as percentage by type and grade.

  3. Negative margin rate [ Time Frame: At 3 months ]
    Will be assessed on prostatectomy specimens.

  4. Overall survival (OS) [ Time Frame: At 2 years ]
    Will be estimated using Kaplan-Meier methods and 95% CI will be estimated using Greenwood's formula.

  5. Rate of near pathologic complete response (i.e. =< 5 mm of residual tumor) [ Time Frame: At 3 months ]
    Will be assessed on prostatectomy specimens.

  6. Rate of negative nodal metastases [ Time Frame: At 3 months ]
    Will be assessed on surgical lymph node specimens.

  7. Rate of pathologic T3 disease [ Time Frame: At 3 months ]
    Will be determined by cleaved caspase-3 immunohistochemistry.

  8. The biochemical (i.e. prostate-specific antigen) progression-free survival (PFS) estimate [ Time Frame: At 2 years ]
    Prostate-specific antigen progression (i.e. biochemical failure) will be defined per the American Urological Association guidelines (i.e. confirmed prostate-specific antigen post-radical prostatectomy >= 0.2 ng/mL). Will be estimated using Kaplan-Meier methods and 95% CI will be estimated using Greenwood's formula.

  9. The proportion of men who receive adjuvant radiation therapy [ Time Frame: Up to 1 year post prostatectomy ]
    Will be computed along with their 95% confidence interval (CI).


Other Outcome Measures:
  1. Alteration in MYC/chromosome 8q24 via fluorescence in situ hybridization [ Time Frame: Baseline to 3 months ]
    Fluorescence in situ hybridization will be conducted to assess for genomic alterations (loss or amplification) of the MYC gene, which is located on chromosome 8q24. Will be correlated with the primary and secondary endpoints using chi-square tests and logistic regression or (for PFS and OS) using proportional hazards models, Kaplan-Meier methods, and log-rank tests.

  2. Phosphatase and tensin homolog fluorescence in situ hybridization [ Time Frame: Baseline to 3 months ]
    Fluorescence in situ hybridization will be conducted to assess for genomic loss of the phosphatase and tensin gene. Will be correlated with the primary and secondary endpoints using chi-square tests and logistic regression or (for PFS and OS) using proportional hazards models, Kaplan-Meier methods, and log-rank tests.

  3. Phosphatase and tensin immunohistochemistry [ Time Frame: Baseline to 3 months ]
    Immunohistochemistry will be conducted to assess for loss of phosphatase and tensin protein expression. Will be correlated with the primary and secondary endpoints using chi-square tests and logistic regression or (for PFS and OS) using proportional hazards models, Kaplan-Meier methods, and log-rank tests.

  4. Tumor messenger ribonucleic acid expression profiling/risk classification (e.g. Decipher or ribonucleic acid-sequencing) [ Time Frame: Baseline to 3 months ]
    Messenger ribonucleic acid expression profiling will be conducted using the Decipher assay and/or ribonucleic acid-sequencing. Will be correlated with the primary and secondary endpoints using chi-square tests and logistic regression or (for PFS and OS) using proportional hazards models, Kaplan-Meier methods, and log-rank tests.



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Willing and able to provide written informed consent
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Documented histologically confirmed adenocarcinoma of the prostate
  • Willing to undergo prostatectomy as primary treatment for localized prostate cancer
  • High risk prostate cancer (per National Comprehensive Cancer Network [NCCN] criteria): Gleason score 8-10 or T3a or PSA > 20 ng/mL or very-high risk prostate cancer (per NCCN criteria): T3b-T4
  • Serum testosterone >= 150 ng/dL
  • Able to swallow the study drugs whole
  • Willing to take abiraterone acetate on an empty stomach (no food should be consumed at least two hours before and for one hour after dosing)
  • 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
  • Medications known to lower the seizure threshold (see list under prohibited meds) must be discontinued or substituted at least 4 weeks prior to study entry

Exclusion Criteria:

  • Prior local therapy to treat prostate cancer (e.g. radical prostatectomy, radiation therapy, brachytherapy)
  • Prior use of apalutamide, abiraterone acetate or degarelix
  • Prior or ongoing systemic therapy for prostate cancer including, but not limited to:

    • Hormonal therapy (for example [e.g.] leuprolide, goserelin, triptorelin, degarelix)
    • Cytochrome P450 (CYP)-17 inhibitors (e.g. ketoconazole)
    • Antiandrogens (e.g. bicalutamide, nilutamide)
    • Second generation antiandrogens (e.g. enzalutamide, apalutamide)
    • Immunotherapy (e.g. sipuleucel-T, ipilimumab)
    • Chemotherapy (e.g. docetaxel, cabazitaxel)
  • Evidence of serious and/or unstable pre-existing medical, psychiatric or other condition (including laboratory abnormalities) that could interfere with patient safety or provision of informed consent to participate in this study
  • Any psychological, familial, sociological, or geographical condition that could potentially interfere with compliance with the study protocol and follow-up schedule
  • Absolute neutrophil count [ANC] < 1500/mm^3
  • Platelet count < 100,000/mm^3
  • Hemoglobin < 9 g/dL
  • Total bilirubin > 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >= 2.5 x ULN; Note: in subjects with Gilbert's syndrome, if total bilirubin is > 1.5 x ULN, measure direct and indirect bilirubin and if direct bilirubin is =< 1.5 x ULN, subject may be eligible
  • Abnormal kidney function (glomerular filtration rate GFR < 45 mL/min)
  • Serum albumin < 3 g/dL
  • Serum potassium < 3.5 mmol/L
  • Seizure or known condition that may pre-dispose to seizure (e.g. prior stroke within 1 year to randomization, brain arteriovenous malformation, schwannoma, meningioma, or other benign central nervous system [CNS] or meningeal disease which may require treatment with surgery or radiation therapy)
  • Severe or unstable angina, myocardial infarction, symptomatic congestive heart failure, arterial or venous thromboembolic events (eg, pulmonary embolism, cerebrovascular accident including transient ischemic attacks), or clinically significant ventricular arrhythmias within 6 months prior to randomization
  • History of stroke within the last 5-years
  • History of gastrointestinal (GI) bleed requiring transfusion
  • History of peptic ulcer disease requiring treatment within the last 5-years
  • History of asthma that is nonsteroidal anti-inflammatory drug (NSAID)-induced or with asthma that is classified as 'mild-persistent' or worse (based on symptoms occurring more than 2 days per week)
  • Uncontrolled hypertension
  • Gastrointestinal disorder affecting absorption
  • Active infection (eg, human immunodeficiency virus [HIV] or viral hepatitis)
  • Any chronic medical condition requiring a higher dose of corticosteroid than 10 mg prednisone/ prednisolone once daily
  • Any condition that in the opinion of the investigator, would preclude participation in this study
  • Child Pugh class B & C
  • Pre-existing viral hepatitis

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02849990


Locations
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United States, Washington
Fred Hutch/University of Washington Cancer Consortium
Seattle, Washington, United States, 98109
Sponsors and Collaborators
University of Washington
Janssen Scientific Affairs, LLC
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Michael Schweizer Fred Hutch/University of Washington Cancer Consortium

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Responsible Party: University of Washington
ClinicalTrials.gov Identifier: NCT02849990     History of Changes
Other Study ID Numbers: 9628
NCI-2016-01027 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
9628 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
P30CA015704 ( U.S. NIH Grant/Contract )
RG1716056 ( Other Identifier: Fred Hutch/University of Washington Cancer Consortium )
First Posted: July 29, 2016    Key Record Dates
Last Update Posted: February 22, 2019
Last Verified: February 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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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
Indomethacin
Cortisone
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
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics