A randomized phase II trial on the addition of dutasteride to combined androgen blockade therapy versus combined androgen blockade therapy alone in patients with advanced or metastatic salivary duct carcinoma - the DUCT study protocol.
Humans
Dutasteride
/ therapeutic use
Male
Salivary Gland Neoplasms
/ drug therapy
Antineoplastic Combined Chemotherapy Protocols
/ therapeutic use
Tosyl Compounds
/ therapeutic use
Androgen Antagonists
/ therapeutic use
Anilides
/ administration & dosage
Nitriles
/ therapeutic use
Female
Prospective Studies
Middle Aged
Aged
Adult
Salivary Ducts
/ pathology
5-alpha Reductase Inhibitors
/ therapeutic use
Androgen Deprivation Therapy
Androgen Receptor
Anti-hormonal therapy
Combined Androgen Blockade
Dutasteride
Rare Cancer
Salivary Duct Carcinoma
Salivary gland cancer
Steroid 5α-reductase
Systemic therapy
Journal
BMC cancer
ISSN: 1471-2407
Titre abrégé: BMC Cancer
Pays: England
ID NLM: 100967800
Informations de publication
Date de publication:
20 Sep 2024
20 Sep 2024
Historique:
received:
25
07
2024
accepted:
02
09
2024
medline:
21
9
2024
pubmed:
21
9
2024
entrez:
20
9
2024
Statut:
epublish
Résumé
Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer, frequently associated with incurable recurrences and distant metastases (R/M). Proliferation of SDC relies on androgen receptor (AR) signalling, prompting the use of combined androgen blockade (CAB, i.e., luteinizing hormone-releasing hormone agonist and/or AR antagonists) to R/M SDC patients. However, only a subset of patients benefits from such treatments. We have shown that response to CAB is associated with steroid 5α-reductase 1 (SRD5A1) mRNA expression. SRD5A1 catalyses the intracellular conversion of testosterone into the more potent AR-agonist dihydrotestosterone. This conversion can be inhibited by dutasteride, a potent SRD5A1-inhibitor, which is currently prescribed for benign prostatic hyperplasia. We hypothesize that repurposing dutasteride to target AR signalling in SDC could enhance therapeutic response and clinical outcome in SDC patients. This prospective, open-label, randomized controlled phase II clinical trial, is designed to investigate whether dutasteride as an adjunct drug to CAB improves response rate and clinical outcome in patients with AR-positive R/M SDC. Patients are divided in two cohorts based on their prior systemic treatments. In cohort A, CAB-naïve patients (n = 74) will be randomly assigned to either a control arm (Arm 1) receiving CAB (goserelin 10.8 mg/3m and bicalutamide 50 mg/OD) or an experimental arm (Arm 2) where dutasteride (0.5 mg/OD) is added to the CAB regimen. In cohort B, patients with disease progression after adjuvant or first-line palliative CAB therapy (max. n = 24) will receive goserelin, bicalutamide, and dutasteride to assess whether the addition of dutasteride can overcome therapy resistance. The primary endpoints are the objective response rate and duration of response. Secondary endpoints are progression-free survival, overall survival, clinical benefit rate, quality of life, and safety. Translational research will be performed to explore molecular target expression differences and their correlation with clinical outcome. The DUCT study addresses an unmet medical need by investigating the repurposing of dutasteride to enhance treatment response and improve clinical outcome for patients with R/M SDC, especially those with limited alternative treatment options, such as HER2-negative cases. By repurposing a registered low-cost drug, this trial's findings could be readily applied into clinical practice. Clinicaltrials.gov Identifier: NCT05513365. Date of registration: August 24, 2022. Current protocol version 4.0, February 21, 2024.
Sections du résumé
BACKGROUND
BACKGROUND
Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer, frequently associated with incurable recurrences and distant metastases (R/M). Proliferation of SDC relies on androgen receptor (AR) signalling, prompting the use of combined androgen blockade (CAB, i.e., luteinizing hormone-releasing hormone agonist and/or AR antagonists) to R/M SDC patients. However, only a subset of patients benefits from such treatments. We have shown that response to CAB is associated with steroid 5α-reductase 1 (SRD5A1) mRNA expression. SRD5A1 catalyses the intracellular conversion of testosterone into the more potent AR-agonist dihydrotestosterone. This conversion can be inhibited by dutasteride, a potent SRD5A1-inhibitor, which is currently prescribed for benign prostatic hyperplasia. We hypothesize that repurposing dutasteride to target AR signalling in SDC could enhance therapeutic response and clinical outcome in SDC patients.
METHODS
METHODS
This prospective, open-label, randomized controlled phase II clinical trial, is designed to investigate whether dutasteride as an adjunct drug to CAB improves response rate and clinical outcome in patients with AR-positive R/M SDC. Patients are divided in two cohorts based on their prior systemic treatments. In cohort A, CAB-naïve patients (n = 74) will be randomly assigned to either a control arm (Arm 1) receiving CAB (goserelin 10.8 mg/3m and bicalutamide 50 mg/OD) or an experimental arm (Arm 2) where dutasteride (0.5 mg/OD) is added to the CAB regimen. In cohort B, patients with disease progression after adjuvant or first-line palliative CAB therapy (max. n = 24) will receive goserelin, bicalutamide, and dutasteride to assess whether the addition of dutasteride can overcome therapy resistance. The primary endpoints are the objective response rate and duration of response. Secondary endpoints are progression-free survival, overall survival, clinical benefit rate, quality of life, and safety. Translational research will be performed to explore molecular target expression differences and their correlation with clinical outcome.
DISCUSSION
CONCLUSIONS
The DUCT study addresses an unmet medical need by investigating the repurposing of dutasteride to enhance treatment response and improve clinical outcome for patients with R/M SDC, especially those with limited alternative treatment options, such as HER2-negative cases. By repurposing a registered low-cost drug, this trial's findings could be readily applied into clinical practice.
TRIAL REGISTRATION
BACKGROUND
Clinicaltrials.gov Identifier: NCT05513365. Date of registration: August 24, 2022.
PROTOCOL VERSION
METHODS
Current protocol version 4.0, February 21, 2024.
Identifiants
pubmed: 39304797
doi: 10.1186/s12885-024-12889-0
pii: 10.1186/s12885-024-12889-0
doi:
Substances chimiques
Dutasteride
O0J6XJN02I
Tosyl Compounds
0
Androgen Antagonists
0
Anilides
0
Nitriles
0
bicalutamide
A0Z3NAU9DP
5-alpha Reductase Inhibitors
0
Banques de données
ClinicalTrials.gov
['NCT05513365']
Types de publication
Journal Article
Clinical Trial, Phase II
Randomized Controlled Trial
Clinical Trial Protocol
Langues
eng
Sous-ensembles de citation
IM
Pagination
1174Subventions
Organisme : ZonMw
ID : 10140022110057
Pays : Netherlands
Organisme : ZonMw
ID : 10140022110057
Pays : Netherlands
Organisme : ZonMw
ID : 10140022110057
Pays : Netherlands
Organisme : ZonMw
ID : 10140022110057
Pays : Netherlands
Organisme : ZonMw
ID : 10140022110057
Pays : Netherlands
Organisme : ZonMw
ID : 10140022110057
Pays : Netherlands
Organisme : ZonMw
ID : 10140022110057
Pays : Netherlands
Organisme : ZonMw
ID : 10140022110057
Pays : Netherlands
Organisme : ZonMw
ID : 10140022110057
Pays : Netherlands
Informations de copyright
© 2024. The Author(s).
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