Clinical trial NCT01957436: A Phase III Study for Patients With Metastatic Hormone-naïve Prostate Cancer
Official title: A Prospective Randomised Phase III Study Of Androgen Deprivation Therapy With Or Without Docetaxel With Or Without Local Radiotherapy With Or Without Abiraterone Acetate And Prednisone In Patients With Metastatic Hormone-Naïve Prostate Cancer
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Metastatic Prostate Cancer
Keywords: prostate
cancer
metastatic hormone-naive
radiotherapy
abiraterone acetate
docetaxel
Lead sponsor: UNICANCER
Sponsor class: OTHER
Collaborators: name: Janssen-Cilag Ltd.
name: European Organisation for Research and Treatment of Cancer - EORTC
name: Ipsen
name: Sanofi
First posted: 2013-10-08
Enrollment: 1173
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 multi-center phase III study to compare the clinical benefit of androgen deprivation therapy with or without docetaxel with or without local radiotherapy with or without abiraterone acetate and prednisone in patient with metastatic hormone-naïve prostate cancer.

Detailed description: Eligible patients can be randomize in the trial after his consent form has been signed, and after all inclusion and non-inclusion criteria have been checked.

The randomisation will result in the allocation of arm A (ADT +docetaxel), arm B (ADT +docetaxel +Abiraterone), arm C (ADT +docetaxel +radiotherapy) or arm D (ADT +docetaxel +Abiraterone +radiotherapy) in a 1:1:1:1 ratio.

The randomization will be stratified (by minimization) according to:

* enrolment center,
* performance status (0 vs. 1-2)
* disease extent: lymph nodes only vs. bone (with or without lymph nodes) vs. presence of visceral metastases.

CRPC is defined by cancer progression (either a confirmed PSA rise or a radiological progression) with serum testosterone being at castrated levels (\<0.50 ng/mL).

When the CRPC stage is reached, castration (either LHRH agonist or LHRH antagonist) will be maintained in all patients.

Investigators will be free to manage patients reaching CRPC at their discretion (using for example docetaxel, zoledronic acid, denosumab, sipuleucel-T, radium-223, cabazitaxel, etc) according to local uses and guidelines.

Abiraterone may be used in arm A and C if abiraterone has become the standard treatment for CRPC when this stage is reached.

Eligibility criteria: Inclusion criteria:

1. Histologically or cytologically confirmed adenocarcinoma of the prostate,
2. Metastatic disease documented by a positive bone scan (any technique) or CT scan or an MRI. For patients with nodal metastases only, only patients with extra-pelvic enlarged lymph nodes (lymph nodes located above the iliac bifurcation) can be included if they have either:

   o At least one extra-pelvic lymph node ≥ 2 cm or extra-pelvic lymph node (s) ≥ 1 cm if the patients also have at least one pelvic lymph node ≥ 2 cm
3. Patients with ECOG ≤ 1 (patient with PS 2 due to bone pain can be accrued in the trial),
4. Life expectancy of at least 6 months,
5. Male aged ≥ 18 years old and ≤ 80 years old ,
6. Hematology values:

   * Hemoglobin ≥ 10.0 g/dL,
   * Platelet count ≥ 100,000/mL,
   * Neutrophil ≥ 1500 cells/mm³
7. Biochemistry values:

   * Renal function: Serum creatinine \< 1.5 x ULN or a calculated creatinine clearance ≥ 60 mL/min,
   * Serum potassium ≥ 4 mmol/L,
   * Liver function:

     * Serum bilirubin ≤ 1.5 x ULN (except for patients with documented Gilbert's disease),
     * AST and ALT ≤ 1.5 x ULN (and ≤ 5 ULN in case of liver metastases),
   * ALK-P ≤ 2.5 x ULN (in case of bone metastasis, ALK-P\<1000U/L if bilirubin is normal)
8. Patients must have received ADT for a maximum of 3 months before randomization and there must be a minimum of 6 weeks between the start of ADT and the start of Docetaxel,
9. Patients willing and clinically fit to receive Docetaxel which is defined by the following :

   * Patients respecting all inclusion and exclusion criteria And
   * Patients with no contraindication to docetaxel according to the SmPC of the drug And
   * Patients presenting all medical requirements to receive docetaxel according to the investigator's opinion.
10. Patients might have received previous radiation therapy directed to bone lesions,
11. Patients able to take oral medication,
12. Patients who have received the information sheet and signed the informed consent form,
13. Male patients who will receive Docetaxel and/or Abiraterone acetate and have partners of childbearing potential and/or pregnant partners must use a method of birth control in addition to an adequate barrier protection (condoms) as determined to be acceptable by the study doctor during the treatment period and for 4 weeks after the last dose of abiraterone acetate and/or for 6 months after the last dose of Docetaxel
14. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures,
15. Patients with a public or a private health insurance coverage, according to local laws for participation in clinical trials.

Exclusion Criteria:

1. Patients with previous definitive local treatment directed to the prostate primary cancer (radiotherapy, brachytherapy, radical prostatectomy, ultrasound, cryotherapy, or other). A previous trans-urethral resection of the prostate (TURP) and previous local treatments of metastases are allowed,
2. Prior cytotoxic chemotherapy or biological therapy for the treatment of prostate cancer,
3. Any chronic medical condition requiring a higher dose of corticosteroid than 5 mg prednisone/prednisolone twice daily,
4. Active infection or other medical condition for which prednisone/prednisolone (corticosteroid) use would be contra-indicated,
5. Previously treated with ketoconazole for prostate cancer for more than 7 days,
6. Prior systemic treatment with an azole drug (e.g. fluconazole, itraconazole) within 4 weeks of randomization,
7. Hypertension not controlled by an anti-hypertensive treatment (systolic BP ≥ 160 mmHg or diastolic BP ≥ 95 mmHg; 3 consecutive measures taken 5 minutes apart),
8. Severe or moderate hepatic impairment (Child - Pugh class C or B)
9. Active or symptomatic viral hepatitis or chronic liver disease (except Gilbert's disease),
10. History of pituitary or adrenal dysfunction,
11. Clinically known significant heart disease in the past 6 months as evidenced by myocardial infarction, or arterial thrombotic events, severe or unstable angina, or New York Heart association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of \< 50% at baseline,
12. Atrial Fibrillation, or other cardiac arrhythmia requiring therapy,
13. Patient with unstable pulmonary disease (eg. Pulmonary embolism)
14. Pathological finding consistent with small cell carcinoma of the prostate,
15. History of malignancy, except non-melanoma skin cancer, with a ≥ 30% probability of recurrence within 24 months,
16. Known allergies, hypersensitivity or intolerance to the study drugs or excipients or docetaxel
17. Administration of an investigational therapeutic within 30 days of randomization,
18. Patients already included in another therapeutic trial involving an experimental drug (patient in a non-experimental trial with no modification of the patient's care can be included),
19. 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. Those conditions should be discussed with the patient before registration in the trial,
20. Individual deprived of liberty or placed under the authority of a tutor.
21. Patients with impaired vision should undergo a prompt and complete ophthalmologic examination.

    Patients with Cystoid Macular Oedema cannot be included due to a potential risk of deterioration associated with docetaxel.
22. Concomitant use of strong CYP3A4 inhibitors (clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin.)

Primary outcomes:
measure: Survival
timeFrame: 7.5 years after the first inclusion
measure: Survival
timeFrame: 9.5 years after the first inclusion
Secondary outcomes:
measure: Castration resistance-free survival (CRFS)
timeFrame: 9.5 years after the first inclusion
measure: Serious Genitourinary event-free survival (S-GU-EFS)
timeFrame: 9.5 years after the first inclusion
measure: Prostate cancer specific survival
timeFrame: 9.5 years after the first inclusion
measure: Time to next skeletal-related event
timeFrame: 9.5 years after the first inclusion
measure: PSA response rate
timeFrame: 9.5 years after the first inclusion
measure: Prospective correlative study of PSA response/progression at 8 months after initation of ADT
timeFrame: 9.5 years after the first inclusion
measure: Time to pain progression
timeFrame: 9.5 years after the first inclusion
measure: Time to chemotherapy for CRPC
timeFrame: 9.5 years after the first inclusion
measure: Quality of life questionnaire - Core 30 (QLQ-C30)
timeFrame: At baseline, 6 months, 18 months, and at the end of treatment (up to 9.5 years)
measure: Functional Assessment of Cancer Therapy - Prostate (FACT-P)
timeFrame: At baseline, 6 months, 12 months, 18 months, and at the end of treatment (up to 9.5 years)
measure: Toxicity (with a specific focus on the use of long-term low-dose steroids)
timeFrame: Throughout study completion, up to 9.5 years
measure: Changes in bone mineral density
timeFrame: At baseline, 6 months, 12 months, and 24 months
measure: Correlation of biomarkers with outcome
timeFrame: 9.5 years after the first inclusion
Other outcomes:
Locations:
city: Aalst
country: Belgium
facility: Onze Lieve Vrouw Ziekenhuis
city: Brussels
country: Belgium
facility: Hôpitaux Universitaires Bordet Erasme- Institut Jules Bordet
city: Haine Saint Paul
country: Belgium
facility: Hopital de Jolimont
city: Kortrijk
country: Belgium
facility: AZ Groeninge Kortrijk - Campus Vercruysselaan
city: Leuven
country: Belgium
facility: U.Z. Leuven - Campus Gasthuisberg
city: Louvain
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Albi
country: France
facility: Clinique Claude Bernard
city: ANGERS Cedex 9
country: France
facility: Institut de cancerologie de l'Ouest
city: Annecy
country: France
facility: Clinique Générale d'Annecy
city: Avignon Cedex 9
country: France
facility: Institut Sainte Catherine
city: Avranches
country: France
facility: Centre de la Baie
city: Bayonne
country: France
facility: Centre d'Oncologie et de Radiothérapie du Pays Basque
city: Besancon
country: France
facility: Chu Jean Minjoz
city: Beuvry
country: France
facility: Centre Pierre Curie
city: Bordeaux
country: France
facility: Institut Bergonie
city: Caen
country: France
facility: Centre François Baclesse
city: Contamine Sur Arve
country: France
facility: Centre Hospitalier Alpes Leman
city: Creteil
country: France
facility: Chu de Mondor
city: Dechy
country: France
facility: Centre Leonard de Vinci
city: Dijon
country: France
facility: Centre Georges-François LECLERC
city: Hyères
country: France
facility: Clinique Sainte Marguerite
city: La ROCHE sur YON
country: France
facility: CHD Vendée
city: Le Mans
country: France
facility: Clinique Victor Hugo
city: Limoges
country: France
facility: Chu de Limoges
city: Lyon cedex 08
country: France
facility: Centre Léon Bérard
city: Lyon
country: France
facility: CHU Lyon Sud
city: MARSEILLE Cedex 5
country: France
facility: Chu Timone
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Marseille
country: France
facility: Hôpital Nord
city: Mougins
country: France
facility: Centre Azuréen de Cancérologie
city: Nantes Cedex 2
country: France
facility: Centre Catherine de Sienne
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: NIMES Cedex 9
country: France
facility: CHU Carémeau
city: Orleans
country: France
facility: CHR Orléans la source
city: Paris
country: France
facility: Institut Curie
city: Paris
country: France
facility: Hôpital St Louis
city: Paris
country: France
facility: Hopital TENON
city: Quimper
country: France
facility: Chic Quimper
city: Reims
country: France
facility: Institut Jean Godinot
city: RENNES Cedex
country: France
facility: Centre Eugène Marquis
city: Saint Brieuc
country: France
facility: Clinique Armoricaine de radiologie
city: Saint Etienne
country: France
facility: CHU ST ETIENNE - Hôpital Nord
city: Saint Gregoire
country: France
facility: CHP Saint Grégoire
city: Saint-herblain
country: France
facility: Institut de Cancérologie del'Ouest - site René Gauducheau
city: Sarcelles
country: France
facility: CENTRE DE CANCEROLOGIE Paris Nord
city: St PRIEST EN JAREZ
country: France
facility: Institut de Cancérologie Lucien Neuwirth
city: Strasbourg
country: France
facility: Strasbourg Oncologie Libérale
city: Thonon-les-bains
country: France
facility: Hopitaux du Leman
city: Toulon
country: France
facility: Centre Hospitalier Intercommunal de Toulon - La Seyne sur Mer - Hôpital Sainte Musse
city: TOULOUSE Cedex 3
country: France
facility: Clinique Pasteur
city: TOULOUSE Cedex
country: France
facility: Institut Claudius Regaud
city: Tours
country: France
facility: CHU de TOURS Hôpital Bretonneau
city: Vandœuvre-lès-Nancy
country: France
facility: Institut de Cancérologie de Lorraine
city: Vannes
country: France
facility: Centre d'Oncologie Saint Yves
city: Villejuif
country: France
facility: INSTITUT GUSTAVE ROUSSY, Cancer Campus, Grand Paris
city: Cork
country: Ireland
facility: Cork University Hospital
city: Dublin
country: Ireland
facility: Adelaide and Meath incorporating National Children's hospital department
city: Dublin
country: Ireland
facility: Mater Misericordiae University Hospital
city: Dublin
country: Ireland
facility: Mater Private Hospital
city: Dublin
country: Ireland
facility: St Vincent's University Hospital
city: Galway
country: Ireland
facility: Galway University Hospital
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
city: Roma
country: Italy
facility: San Camillo Forlanini Hospitals
city: Cluj
country: Romania
facility: Sc Radiotherapy Center Cluj SRL
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital De la Santa Creu I Sant Pau
city: Barcelona
country: Spain
facility: Hospital del Mar
city: Barcelona
country: Spain
facility: Vall d'Hebron University Hospital
city: Girona
country: Spain
facility: ICO Girona - Hospital Josep Trueta
city: Madrid
country: Spain
facility: Hospital Universitario HM Sanchinarro
city: Manresa
country: Spain
facility: Althaia
city: Málaga
country: Spain
facility: 'Hospital Clinico Virgen de la Victoria
city: Sabadell
country: Spain
facility: 'Parc Tauli Sabadell Hospital Universitari
city: Salamanca
country: Spain
facility: Hospital Universitario de Salamanca
city: Valencia
country: Spain
facility: Institut Valenciano de Oncologia
city: Geneva
country: Switzerland
facility: Fondation Dr. Henri Dubois-Ferrière Dinu Lipatti
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
Study officials:
affiliation: Gustave Roussy, Cancer Campus Grand Paris - Paris
name: Karim FIZAZI, Professor
role: STUDY_CHAIR
affiliation: Gustave Roussy, Cancer Campus Grand Paris - Paris
name: Alberto BOSSI, Doctor
role: STUDY_CHAIR
References:
citation: Fizazi K, Foulon S, Carles J, Roubaud G, McDermott R, Flechon A, Tombal B, Supiot S, Berthold D, Ronchin P, Kacso G, Gravis G, Calabro F, Berdah JF, Hasbini A, Silva M, Thiery-Vuillemin A, Latorzeff I, Mourey L, Laguerre B, Abadie-Lacourtoisie S, Martin E, El Kouri C, Escande A, Rosello A, Magne N, Schlurmann F, Priou F, Chand-Fouche ME, Freixa SV, Jamaluddin M, Rieger I, Bossi A; PEACE-1 investigators. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 x 2 factorial design. Lancet. 2022 Apr 30;399(10336):1695-1707. doi: 10.1016/S0140-6736(22)00367-1. Epub 2022 Apr 8.