A randomised, phase 3 trial comparing 3-weekly docetaxel 75 mg/m2 versus 2-weekly Docetaxel 50 mg/m2 in combination with Darolutamide + ADT in patients with mHSPC (ARASAFE)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Friedrich-Schiller-Universitaet Jena

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Male Urogenital Diseases [C12]

Trial duration

16 May 2023 → ongoing

Decision date (initial)

2024-05-24

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Bayer Vital GmbH

External identifiers

EU CT number

2022-502634-52-00

WHO UTN

U1111-1287-2738

ClinicalTrials.gov

NCT05676203

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

The main objective is to compare grade 3-5 adverse event rate (AER) in patients with mHSPC treated with 6 cycles of either Docetaxel 75 mg/m2 every 3 weeks in a 3 week cycle or Docetaxel 50 mg/m2 every 2 weeks in a 4 week cycle in combination with Darolutamide + ADT, A secondary safety endpoint is “Occurence of neutropenia grade 3/4 AE or death regardless of reason”, which will be summarized as neutropenia AE rate (NAER)

Secondary objectives 1

1. to compare longterm outcome with regard to efficacy (e.g time to mCRPC, PSA response, OS)

Conditions and MedDRA coding

prostate cancer

Study design 2 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Written informed consent
2. Males ≥18 years of age
3. Histologically or cytologically confirmed adenocarcinoma of prostate
4. 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.
5. 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
6. Subjects must be candidates for ADT, docetaxel and darolutamide therapy per Investigator's judgment
7. 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
8. An Eastern Cooperative Oncology Group performance status of 0 or 1
9. 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)
10. Screening values of serum alanine aminotransferase and/or aspartate transaminase ≤1.5x upper limit of normal (ULN), total bilirubin ≤ULN, creatinine ≤2.0x ULN
11. 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 docetaxel and darolutamide, 6 months after end of the treatment with docetaxel and for 3 months after the end of the treatment with darolutamide

Exclusion criteria 13

1. Prior treatment with: LHRH agonist/antagonists started more than 12 weeks before randomization,o Second-generation androgen receptor (AR) inhibitors such as enzalutamide, apalutamide, darolutamide, other investigational AR inhibitors,o Cytochrome P 17 enzyme inhibitor such as abiraterone acetate or oral ketoconazole as antineoplastic treatment for prostate cancer,o Chemotherapy, immunotherapy, radium or other therapeutic radiopharmaceuticals for prostate cancer (e.g. Lutetium177-PSMA) prior to randomization
2. Treatment with radiotherapy (external beam radiation therapy, brachytherapy) within 2 weeks before randomization
3. Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation of the study drugs
4. Contraindication to both CT and MRI contrast agent
5. 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)
6. Uncontrolled hypertension as indicated by a resting systolic blood pressure (BP) ≥160 mmHg or diastolic BP ≥100 mmHg despite medical management
7. 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
8. A gastrointestinal disorder or procedure which is expected to interfere significantly with absorption of study drug
9. An active viral hepatitis, known human immunodeficiency virus infection with detectable viral load, or chronic liver disease with a need for treatment
10. 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)
11. 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
12. Inability to swallow oral medications
13. Previous assignment to treatment in this study

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. “Occurrence of a high grade (3 to 5) adverse event” (yes/no), which will be analyzed 26 weeks after last patient first docetaxel dose (LPFD), will be summarized as adverse event (AE) rate (AER). A secondary safety endpoint is “Occurence of neutropenia grade 3/4 AE or death regardless of reason”, which will be summarized as neutropenia AE rate (NAER)

Secondary endpoints 12

1. PSA-response (PSA ≤0.2, >0.2-4.0 und >4.0 ng/ml) determined at week 26 after LPFD
2. Time to castration-resistant prostate cancer
3. Overall survival
4. Time to initiation of subsequent antineoplastic therapy
5. Time to first symptomatic skeletal event (SSE)
6. Time to pain progression
7. Time to worsening of physical symptoms of disease based on functional assessment of cancer therapy / National Comprehensive Cancer Network prostate cancer symptom index 17 item questionnaire (NCCN-FACT FPSI-17)
8. Treatment emergent adverse events according to NCI-CTCAE version 5.0
9. Long-term overall safety and tolerability
10. Quality of life
11. Prostate-specific antigen (PSA) assessments
12. Docetaxel-exposure-response analysis

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Friedrich-Schiller-Universitaet Jena

Sponsor organisation

Friedrich-Schiller-Universitaet Jena

Address

Am Klinikum 1, Lobeda Lobeda

City

Jena

Postcode

07747

Country

Germany

Scientific contact point

Organisation

Friedrich-Schiller-Universitaet Jena

Contact name

Sponsor representative and medical expert

Public contact point

Organisation

Friedrich-Schiller-Universitaet Jena

Contact name

Sponsor representative and medical expert

Locations

2 EU/EEA countries · 41 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 33 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications