Clinical trial NCT02799706: Trial Comparing Irradiation Plus Long Term Adjuvant Androgen Deprivation With GnRH Antagonist Versus GnRH Agonist Plus Flare Protection in Patients With Very High Risk Localized or Locally Advanced Prostate Cancer
Official title: Phase IIIb Randomized Trial Comparing Irradiation Plus Long Term Adjuvant Androgen Deprivation With GnRH Antagonist Versus GnRH Agonist Plus Flare Protection in Patients With Very High Risk Localized or Locally Advanced Prostate Cancer. A Joint Study of the EORTC ROG and GUCG
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Prostate Cancer
Keywords: Prostate cancer
GnRH antagonist
GnRH agonist
radiation therapy
very high risk localized prostate cancer
locally advanced prostate cancer
Lead sponsor: European Organisation for Research and Treatment of Cancer - EORTC
Sponsor class: NETWORK
First posted: 2016-06-15
Enrollment: 885
Sex: MALE
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of the trial is to assess if GnRH antagonists in combination with external beam radiation therapy improve progression free survival (progression that can be biological, clinical, or death) compared to GnRH agonists in combination with external beam radiation therapy.

Secondary objectives include:

* documentation of effect of GnRH antagonists on clinically significant cardiovascular events in the subgroup of patients at high risk of such events at baseline;
* documentation of side effects and quality of life, I-PSS and urinary tract infections;
* assessment of relative treatment effect on secondary efficacy endpoints (clinical progression, time to next line of systemic therapy, time on therapy, overall and cancer specific survival) and on PSA at 6 months after end of RT.

Detailed description: Phase IIIb randomized stratified open-label comparative 2-arm superiority study with a pre-set non-inferiority boundary.

Registered GnRH antagonists, degarelix, will be given at the dose of 240 mg given as two subcutaneous injections of 120 mg at a concentration of 40 mg/mL on day 1, followed by 80 mg given as one subcutaneous injection at a concentration of 20 mg/mL every 28 days (±2 days).

External beam radiotherapy (EBRT) to a total dose of 78-80 Gy, delivered as one daily fraction, five days a week, started between d1 and months 6 of the androgen deprivation therapy as per institution policy. The irradiation is the same as in the reference therapy arm.

The minimum duration of androgen deprivation with GnRH agonist or antagonist therapy is 18 months.

For each patient, the duration of therapy must be elected upfront by the treating physician among three possible options: 18, 24 or 36 months. The institution shall also declare upfront the duration of the neoadjuvant treatment they intend to deliver to each patient (between 0 and 6 months).

The primary endpoint is progression-free survival defined as the time in days from randomization to death, clinical or biochemical progression, whichever comes first.

Where

* PSA progression based on Phoenix definition, i.e. a rise by 2 ng/mL or more above the nadir PSA (Ref. 17) confirmed by a second value measured minimum 3 months later
* Clinical progression is defined as onset of obstructive symptoms requiring local treatment and demonstrated to be caused by cancer progression or evidence of metastases detected by clinical symptoms and confirmed by imaging
* Start of another line of systemic therapy in absence of progression
* Death due to any cause

Secondary endpoints:

* Clinical progression-free survival
* Time to next systemic anticancer therapy (including secondary hormonal manipulation)
* Proportion of patients switching from GnRH antagonists to GnRH agonists and total effective duration of treatment with the originally allocated drug.
* Overall survival
* Cancer specific survival
* PSA at six months after completion of RT Safety will be scored by the CTCAE version 4.0. The major safety endpoints in this study are
* the incidence of clinical cardiovascular events - CCE (i.e. arterial embolic or thrombotic events, hemorrhagic or ischemic cerebrovascular conditions, myocardial infarction, and other ischemic heart disease) in patients who had cardiovascular events before entering the trial and in those without such events.
* Incidence of urinary tract infection

Eligibility criteria: Inclusion Criteria:

* Histologically confirmed diagnosis of prostate adenocarcinoma
* PSA ≥ 10 ng/ml and two of the following 4 criteria:
* PSA ≥ 20 ng/ml,
* Gleason sum ≥ 8,
* cN1 (regional LN with a short axis length \>10mm by CT scan or MRI) or pathologically confirmed lymph nodes (pN1),
* cT3-T4 (by MRI or core biopsy) (i.e. If PSA≥ 20 ng/ml then only one of the other 3 risk factors is needed)
* M0 by standard imaging work-up (see chapter 6.1.1.1)
* Testosterone ≥ 200 ng/dl
* Adequate renal function: calculated creatinine clearance ≥ 50 mL/min (Appendix D) Magnesium and potassium within normal limits of the institution or corrected to within normal limits prior to the first dose of treatment.
* Patients with prolonged QT-intervals due to prescribed Class IA (quinidine, procainamide) or Class III (amiodarone, sotalol) antiarrhythmic medication must be carefully evaluated for GnRH-agonist or GnRH antagonist use, because these drugs may prolong the QT-interval.
* WHO Performance status 0-1
* Age ≥ 18 and ≤ 80 years
* Participants who have partners of childbearing potential must use adequate birth control measures, as defined by the investigator, during the study treatment period and for at least 3 months after last dose of study treatment. A highly effective method of birth control is defined as those which result in low failure rate (i.e. less than 1% per year) when used consistently and correctly
* Before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion Criteria:

* Previous use of androgen deprivation therapy (ADT), antiandrogens. 5-alpha reductase inhibitors are allowed if interrupted for more than 6 months prior to entering the study
* History of severe untreated asthma, anaphylactic reactions or severe urticaria and/or angioedema.
* Hypersensitivity towards the investigational drug
* The following biological parameters :AST, ALT, total bilirubin, prothrombin time, serum albumin above upper level of normal range No severe hepatic impairment (Child Pugh C)
* History of gastro-intestinal disorders (medical disorder or extensive surgery) that may interfere with the absorption of the protocol treatment.
* History of pituitary or adrenal dysfunction
* Uncontrolled diabetes mellitus
* History of ulcerative colitis, Crohn's Disease, ataxia, telangiectasia, systemic lupus erythematous, or Fanconi anemia.
* Clinically significant heart disease as evidence myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) class III or IV heart disease or cardiac ejection fraction measurement of \< 50 % at baseline
* Coronary revascularization (PCI or multivessel CABG), carotid artery or iliofemoral artery revascularization (percutaneous or surgical procedure) within the last 30 days prior to entering the trial
* Certain risk factors for abnormal heart rhythms/QT prolongation: torsade de pointes ventricular arrhythmias (e.g, heart failure, hypokalemia, or a family history of a long QT syndrome), a QT or corrected QT (QTc) interval \>450 ms at baseline, or intake of medications that prolong the QT/QTc interval
* Uncontrolled hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg); patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment.
* Prior history of malignancies other than prostate adenocarcinoma (except patients with basal cell, squamous cell carcinoma of the skin), or the patient has been free of malignancy for a period of 3 years prior to first dose of study drug(s). Prior history of bladder cancer excludes the patient.
* Prior radical prostatectomy (TURP or suprapubic adenomectomy for benign prostatic hyperplasia is allowed)
* Prior brachytherapy or other radiotherapy that would result in an overlap of radiotherapy fields
* Any contraindication to external beam radiotherapy
* Patients with significantly altered mental status prohibiting the understanding of the study or with psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule or any condition which, in the opinion of the investigator, would preclude participation in this trial

Primary outcomes:
measure: Progression free survival
timeFrame: through study completion, an average of 1 year
Secondary outcomes:
measure: Clinical progression-free survival
timeFrame: through study completion, an average of 1 year
measure: Time to next systemic anticancer therapy (including secondary hormonal manipulation)
timeFrame: through study completion, an average of 1 year
measure: ♦ Proportion of patients switching from GnRH antagonists to GnRH agonists
timeFrame: through study completion, an average of 1 year
measure: ♦ Overall survival
timeFrame: through study completion, an average of 1 year
measure: Incidence of clinical cardiovascular events
timeFrame: through study completion, an average of 1 year
measure: ♦ Incidence of urinary tract infection
timeFrame: through study completion, an average of 1 year
Other outcomes:
Locations:
city: Brussels
country: Belgium
facility: Hopitaux Universitaires Bordet-Erasme - Hopitaux Universitaires Bordet- Institut Jules Bordet
city: Brussels
country: Belgium
facility: Hopitaux Universitaires Bordet-Erasme - Hopital Universitaire Erasme
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Brussel
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Haine-Saint-Paul
country: Belgium
facility: Hopital De Jolimont
city: Kortrijk
country: Belgium
facility: AZ Groeninge Kortrijk - Campus Kennedylaan
city: Namur
country: Belgium
facility: CHU Ucl Namur - Site Sainte-Elisabeth
city: Wilrijk
country: Belgium
facility: Gasthuiszusters van Antwerpen - GasthuisZusters Antwerpen - Sint-Augustinus
city: Copenhagen
country: Denmark
facility: University Hospitals Copenhagen - Rigshospitalet
city: Amiens
country: France
facility: Clinique de l'Europe
city: Arras
country: France
facility: Centre de radiotherapie Marie Curie
city: Bayonne
country: France
facility: Centre D'Onco. & Radioth. De Haute Energie Du Pays Basque
city: Beuvry
country: France
facility: Groupe Radiopole Artois - Centre de Radiotherapie Pierre Curie
city: Grenoble
country: France
facility: CHU de Grenoble - La Tronche - Hôpital A. Michallon
city: Lyon
country: France
facility: Centre Leon Berard
city: Nantes
country: France
facility: Institut de Cancerologie de l'Ouest (ICO) - Centre Rene Gauducheau
city: Paris
country: France
facility: Assistance Publique - Hopitaux de Paris - La Pitie Salpetriere
city: Saint-Gregoire
country: France
facility: Centre Hospitalier Privé Saint-Grégoire
city: Toulouse
country: France
facility: Clinique Pasteur-Toulouse-Atrium
city: Berlin
country: Germany
facility: Charite - Universitaetsmedizin Berlin - Campus Benjamin Franklin
city: Freiburg
country: Germany
facility: Universitaetsklinikum Freiburg
city: Magdeburg
country: Germany
facility: Otto-Von-Guericke-Universitaet Magdeburg - Universitaetsklinik
city: Firenze
country: Italy
facility: Azienda Ospedaliero-Universitaria Careggi
city: Meldola
country: Italy
facility: AUSL Romagna - Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
city: Alcorcón
country: Spain
facility: Fundacion Hospital Alcorcon
city: Barcelona
country: Spain
facility: Institut Catala d'Oncologia - ICO Badalona - Hospital Germans Trias i Pujol (Institut Catala D'Oncologia)
city: Bilbao
country: Spain
facility: Clinica IMQ Zorrotzaurre
city: Cartagena
country: Spain
facility: Hospital General Universitario Santa Lucia
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofia
city: Las Palmas De Gran Canaria
country: Spain
facility: Hospital Universitario de Gran Canaria Doctor Negrin
city: Pamplona
country: Spain
facility: Complejo Hospitalario A
city: Sabadell
country: Spain
facility: Corporacio Sanitaria Parc Tauli
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Terrassa
country: Spain
facility: Hospital Consorci Sanitari De Terrassa
city: Vigo
country: Spain
facility: Complejo Hospitalario Universitario de Vigo -CHUVI - Hospital Alvaro Cunqueiro
city: Bellinzona
country: Switzerland
facility: Oncology Institute of Southern Switzerland (IOSI) - Oncology Institute of Southern Switzerland - Ospedale Regionale Bellinzona e Valli
city: Bern
country: Switzerland
facility: Inselspital
city: Geneve
country: Switzerland
facility: Hôpitaux universitaires de Genève - HUG - site de Cluse-Roseraie
city: Nottingham
country: United Kingdom
facility: Nottingham University Hospitals NHS Trust - City Hospital
Study officials:
affiliation: Charite - Universitaetsmedizin Berlin - Campus Benjamin Franklin
name: Dirk Boehmer, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: San Roque University Hospital
name: Pedro Lara, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpitaux universitaires de Genève - HUG - site de Cluse-Roseraie
name: Thomas Zilli, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Group Of Private Clinics Hirslanden - Hirslanden Klinik Zurich
name: Martin Spahn, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Zengerling F, Jakob JJ, Schmidt S, Meerpohl JJ, Blumle A, Schmucker C, Mayer B, Kunath F. Degarelix for treating advanced hormone-sensitive prostate cancer. Cochrane Database Syst Rev. 2021 Aug 5;8(8):CD012548. doi: 10.1002/14651858.CD012548.pub2.