Clinical trial NCT05676203: A Trial Comparing Docetaxel 75 mg/m2 (3w) Versus Docetaxel 50 mg/m2 (2w) in Combination With Darolutamide + ADT in mHSPC Patients
Official title: A Randomised, Phase 3 Trial Comparing 3-weekly Docetaxel 75 mg/m2 (in a 3 Week Cycle) Versus 2-weekly Docetaxel 50 mg/m2 (in a 4 Week Cycle) in Combination With Darolutamide + ADT in Patients With mHSPC
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)
Keywords: prostate cancer
metastatic prostate cancer
metastatic hormone-sensitive prostate cancer
docetaxel
darolutamide
safety
Lead sponsor: Jena University Hospital
Sponsor class: OTHER
Collaborators: name: Bayer
First posted: 2023-01-09
Enrollment: 250
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: The purpose of this clinical phase 3 randomized trial is to compare two different dosing schedules of Docetaxel in combination with ADT and Darolutamide in subjects with mHSPC. The main question aims to compare grade 3-5 adverse events (AEs) in patients with mHSPC treated with 6 cycles of either Docetaxel 75 mg/m2 every 3 weeks in a 3 week cycle or 6 cycles of Docetaxel 50 mg/m2 every 2 weeks in a 4 week cycle in combination with Darolutamide + ADT. The primary endpoint are Grade 3-5 AEs, followed by neutropenia grade 3/4 + grade 5 AEs to be analysed 28 weeks after last patient first Docetaxel dose (LPFD).

Detailed description: This is a randomized, open, controlled, multicenter phase III clinical trial. Approximately 250 patients with mHSPC who are candidates for docetaxel, darolutamide and ADT will be randomized (1:1 ratio) to one of the following study arms:

* Arm 1: 6 x Docetaxel 75 mg/m2 every 3 weeks of a 3 week cycle
* Arm 2: 6 x Docetaxel 50 mg/ m2 every 2 weeks of a 4 week cycle Subjects will be stratified at randomization for the extent of disease and for Alkaline Phosphatase levels.

All subjects must receive ADT of Investigator's choice (LHRH agonist/antagonists or orchiectomy) and darolutamide as standard therapy. Six cycles of docetaxel are be administered after randomization according to either Arm 1 or Arm 2. After completion of study drug treatment, subjects will continue with the observation period. During the observation period all subjects will continue with Darolutamide+ADT until occurrence of metastatic castration-resistant prostate cancer (mCRPC).

Eligibility criteria: Inclusion Criteria:

* Written informed consent
* Males ≥18 years of age
* Histologically or cytologically confirmed adenocarcinoma of prostate
* Investigator assessed metastatic disease documented either by a positive bone scan, or for soft tissue or visceral metastases, either by contrast-enhanced abdominal/pelvic/chest computed tomography (CT) or magnetic resonance imaging (MRI) scan assessed. Metastatic disease is defined as either malignant lesions in bone scan or soft tissue/visceral lesions according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. Lymph nodes are measurable if the short axis diameter is ≥15 mm, soft tissue/visceral lesions are measurable if the long axis diameter is ≥10 mm.
* Subjects with lymph node metastases only (either below the aortic bifurcation (N1) or above the aortic bifurcation (M1a)) will not be eligible for the study.
* Subjects must be candidates for ADT, docetaxel and darolutamide therapy per Investigator's judgment
* Started ADT (LHRH agonist/antagonist or orchiectomy) with or without first generation anti-androgen, but no longer than 12 weeks before randomization. For subjects receiving LHRH agonists, treatment in combination with a first generation anti-androgen for at least 4 weeks, prior to randomization is recommended. First generation anti-androgen has to be stopped prior to randomization.
* An Eastern Cooperative Oncology Group performance status of 0 or 1
* Blood counts at Screening: hemoglobin ≥9.0 g/dL, absolute neutrophil count ≥1.5x109/L, platelet count ≥100x109/L (subject must not have received any growth factor within 4 weeks or a blood transfusion within 7 days of the hematology laboratory sample obtained at Screening)
* Screening values of serum alanine aminotransferase and/or aspartate transaminase ≤1.5x upper limit of normal (ULN), total bilirubin ≤ULN, creatinine ≤2.0x ULN

Sexually active male subjects must agree to use condoms as an effective barrier method and refrain from sperm donation, and/or their female partners of reproductive potential to use a method of effective birth control, during the treatment with darolutamide and for 3 months after the end of the treatment with darolutamide and 6 months after treatment with docetaxel.

Exclusion Criteria:

* Exclusion criteria
* Prior treatment with:
* LHRH agonist/antagonists started more than 12 weeks before randomization Second-generation androgen receptor (AR) inhibitors such as enzalutamide, apalutamide, darolutamide, other investigational AR inhibitors
* Cytochrome P 17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as antineoplastic treatment for prostate cancer
* Chemotherapy, immunotherapy, radium or other therapeutic radiopharmaceuticals for prostate cancer (e.g. Lutetium177-PSMA) prior to randomization
* Treatment with radiotherapy (external beam radiation therapy, brachytherapy) within 2 weeks before randomization
* Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
* Contraindication to both CT and MRI contrast agent
* Had any of the following within 6 months before randomization: stroke, myocardial infarction, severe/unstable angina pectoris,coronary/peripheral artery bypass graft, congestive heart failure (New York Heart Association Class III or IV)
* Uncontrolled hypertension as indicated by a resting systolic blood pressure (BP) ≥160 mmHg or diastolic BP ≥100 mmHg despite medical management
* Had a prior malignancy. Adequately treated basal cell or squamous cell carcinoma of skin or superficial bladder cancer that has not spread behind the connective tissue layer (i.e., pTis, pTa, and pT1) is allowed, as well as any other cancer for which treatment has been completed ≥5 years before randomization and from which the subject has been disease-free
* A gastrointestinal disorder or procedure which is expected to interfere significantly with absorption of study drug
* An active viral hepatitis, known human immunodeficiency virus infection with detectable viral load, or chronic liver disease with a need for treatment
* Previous (within 28 days before the start of study drug or 5 half-lives of the investigational treatment of the previous study, whichever is longer) or concomitant participation in another clinical study with investigational medicinal product(s)
* Any other serious or unstable illness, or medical, social, or psychological condition, that could jeopardize the safety of the subject and/or his/her compliance with study procedures, or may interfere with the subject's participation in the study or evaluation of the study results
* Inability to swallow oral medications
* Previous assignment to treatment in this study

Primary outcomes:
measure: Rate of grade 3-5 AEs
timeFrame: 28 weeks after last patient first Docetaxel dose (LPFD)
Secondary outcomes:
measure: PSA-response
timeFrame: 28 after LPFD
measure: Time to castration-resistant prostate cancer
timeFrame: approximately 42 months
measure: Overall survival
timeFrame: approximately 42 months
measure: Time to initiation of subsequent antineoplastic therapy
timeFrame: approximately 42 months
measure: Symptomatic skeletal event free survival (SSE)
timeFrame: approximately 42 months
measure: Time to first symptomatic skeletal event (SSE)
timeFrame: approximately 42 months
measure: Time to pain progression
timeFrame: approximately 42 months
measure: Time to worsening of physical symptoms of disease
timeFrame: approximately 42 months
measure: Treatment emergent adverse events
timeFrame: approximately 42 months
Other outcomes:
Locations:
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH, Elisabethinen
city: Wien
country: Austria
facility: Krankenhaus der Barmherzigen Brüder
city: Heidelberg
country: Germany
facility: Nationales Centrum für Tumorerkrankungen (NCT) Heidelberg
state: Baden-Württemberg
city: Wetzlar
country: Germany
facility: Klinikum Wetzlar
state: Hessen
city: Planegg
country: Germany
facility: Urologische Klinik München Planegg
state: München
city: Hannover
country: Germany
facility: Med. Hochschule Hannover
state: Niedersachsen
city: Duisburg
country: Germany
facility: Urologicum Duisburg
state: Nordrhein-Westfalen
city: Paderborn
country: Germany
facility: Brüderkrankenhaus St- Josef Paderborn
state: Nordrhein-Westfalen
city: Würselen
country: Germany
facility: Urologisches Zentrum Euregio
state: Nordrhein-Westfalen
city: Halle/Saale
country: Germany
facility: Krankenhaus Martha-Maria Halle Dölau gGmbH
state: Sachsen-Anhalt
city: Wilhelmshaven
country: Germany
facility: Praxisgemeinschaft f. Onkologie & Urologie
state: Schleswig Holstein
city: Jena
country: Germany
facility: University Hospital Jena, Department of Urology
state: Thuringia
city: Bergisch Gladbach
country: Germany
facility: Marien Krankenhaus
city: Berlin
country: Germany
facility: Vivantes Prostatazentrum im Klinikum am Urban
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Braunschweig
country: Germany
facility: Urologie Schlosscarree
city: Dessau
country: Germany
facility: Städtisches Klinikum Dessau
city: Düsseldorf
country: Germany
facility: Universitätsklinikum Düsseldorf
city: Erfurt
country: Germany
facility: Helios Klinikum Erfurt
city: Erlangen
country: Germany
facility: Uniklinikum Erlangen
city: Essen
country: Germany
facility: KEM | Evang. Kliniken Essen-Mitte
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Frankfurt am Main
country: Germany
facility: Krankenhaus Nordwest
city: Frankfurt am Main
country: Germany
facility: Universitäts Klinikum Frankfurt
city: Giessen
country: Germany
facility: Universitätsklinikum Giessen und Marburg GmbH, Standort Giessen
city: Hamburg
country: Germany
facility: Universitätsklinikum Hamburg-Eppendorf
city: Herne
country: Germany
facility: St. Anna Hospital Herne
city: Köln
country: Germany
facility: UROLOGIE BAYENTHAL Gemeinschaftspraxis
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein - Campus Lübeck
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim
city: Marburg
country: Germany
facility: Universitätsklinikum Gießen und Marburg - Standort Marburg
city: München
country: Germany
facility: LMU Klinikum
city: München
country: Germany
facility: TUM Klinikum
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Nürnberg
country: Germany
facility: Klinikum Nürnberg
city: Nürnberg
country: Germany
facility: St. Theresien Krankenhaus Nürnberg
city: Nürtingen
country: Germany
facility: Studienpraxis Urologie
city: Trier
country: Germany
facility: Brüderkrankenhaus
city: Tuebingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Ulm
country: Germany
facility: Universitätsklinikum Ulm
city: Wuppertal
country: Germany
facility: Helios Universitätsklinikum Wuppertal
city: Würzburg
country: Germany
facility: Uniklinikum Würzburg
Study officials:
References: