Phase II Dutasteride in Combination With CAB vs CAB in SDC

Study Overview
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Brief Summary
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Phase 2 clinical trial on the addition of dutasteride to combined androgen blockade (CAB) therapy in recurrent and/or metastatic (R/M) salivary duct carcinoma (SDC) patients. The study will include two cohorts of patients: Cohort A, which comprises ADT-naïve patients, and Cohort B, which comprises ADT-resistant patients.

Detailed Description
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A prospective, randomized controlled, single-institution, phase II clinical trial to assess the objective response rate (ORR), duration of response (DoR), progression free survival (PFS), overall survival (OS), toxicity, quality of life (QoL), and expression of molecular targets of patients with R/M SDC treated with either combined androgen blockade (CAB; goserelin + bicalutamide) or CAB + dutasteride, Participants in Cohort A will be randomized 1:1 at the study entry to receive CAB (goserelin 10.8 mg/3months + bicalutamide 50 mg/once daily) or CAB + dutasteride (0.5 mg/once daily). Participants will receive treatment until until progressive disease, intolerable toxicity, or investigator and/or patient decision to withdraw.

Official Title
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A Randomized Phase II Trial on the Addition of Dutasteride to Combined Androgen Blockade Therapy Versus Combined Androgen Blockade Therapy Alone in Patients With Recurrent and/or Metastatic Salivary Duct Carcinoma - DUCT Study

Conditions
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Salivary Duct Carcinoma

Intervention / Treatment
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* Drug: Goserelin 10.8 mg
* Drug: Bicalutamide 50 mg
* Drug: Dutasteride 0.5 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically/histologically proven diagnosis of (incurable) AR+ R/M salivary duct carcinoma AR positive diseases (strong expression in at least 1% of nuclei of neoplastic cells based on central IHC review) Measurable disease per RECIST version 1.1 at baseline. Appendix II. Age ≥ 18 years Written informed consent must be given according to national/local regulation Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Appendix III). Adequate bone marrow function: WBC ≥ 3.5/10^9 /L Absolute neutrophil count (ANC) ≥ 1.5x10^9/L Hemoglobin ≥ 6.20 mmol/L Platelet count ≥ 100x10^9/L Adequate liver function: Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times upper limit of normal (ULN) OR ≤ 5.0 times ULN for patients with liver metastases Bilirubin ≤ 1.5 times ULN. For patients known with Gilbert's Syndrome ≤ 3.0 times ULN is permitted. Adequate renal function: Serum creatinine level ≤ 1.5 times ULN or calculated creatinine clearance ≥ 30 mL/min based on CKD-EPI-GFR Adequate cardiac function Exclusion Criteria: Patients with history of allergic reactions attributed to compounds of similar chemical or biological composition to goserelin, bicalutamide or dutasteride Patients with peanut or soy allergy (dutasteride capsules contain lecithin which may contain soy oil) Patients who do not have adequate swallowing capacity Patients familiar with Long QT-syndrome (LQTS) Patients (M/F) with reproductive potential not implementing adequate contraceptive measures Patients that are pregnant or lactating Patients with uncontrolled illness including: Cardiovascular disorders, including symptomatic congestive heart failure, unstable angina pectoris, or serious cardiac arrhythmias Uncontrolled hypertension Stroke (including TIA), myocardial infarction, or other ischemic event within 6 months before inclusion Serious active infections Patients undergoing concomitant treatments including: Concomitant (or within 4 weeks before inclusion) administration of any other experimental drug under investigation Concomitant (or within 6 months before inclusion) administration of any 5-alpha reductase inhibitor, i.e. dutasteride or finasteride Concurrent treatment with any other anti-cancer therapy within the last 4 weeks before inclusion Curative radiation therapy within the last 4 weeks before inclusion or palliative radiation therapy 1 week before start of study Any condition which, in the opinion of the investigator, would preclude participation in this clinical study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients will be included into two cohorts based on their previous treatments, either ADT-naïve (cohort A) or ADT-resistant patients (cohort B). In cohort A, the randomization will result in the allocation of the control arm (goserelin and bicalutamide) and experimental arm (goserelin, bicalutamide, and dutasteride) in a 1:1 ratio. In cohort B, patients ADT-resistant will be enrolled receiving similar therapy to the experimental arm, i.e. goserelin, bicalutamide, and dutasteride.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Combined androgen blockade (CAB)<br>Patients from cohort A (ADT-naïve) may be randomized in this arm to receive CAB. | Drug: Goserelin 10.8 mg<br>* Goserelin injection (10.8 mg) once per 3 months until progressive disease, intolerable toxicity, or investigator and/or patient decision to withdraw.<br>* Other names: Zoladex;Drug: Bicalutamide 50 mg<br>* Bicalutamide tablets (50 mg) once daily until progressive disease, intolerable toxicity, or investigator and/or patient decision to withdraw.<br>* Other names: Casodex;|
| Experimental: Combined androgen blockade (CAB) + dutasteride<br>Patients from cohort A (ADT-naïve) may be randomized in this arm to receive CAB+dutasteride, and patients from cohort B (ADT-resistant) will receive CAB+dutasteride without having been randomized. | Drug: Goserelin 10.8 mg<br>* Goserelin injection (10.8 mg) once per 3 months until progressive disease, intolerable toxicity, or investigator and/or patient decision to withdraw.<br>* Other names: Zoladex;Drug: Bicalutamide 50 mg<br>* Bicalutamide tablets (50 mg) once daily until progressive disease, intolerable toxicity, or investigator and/or patient decision to withdraw.<br>* Other names: Casodex;Drug: Dutasteride 0.5 mg<br>* Dutasteride capsules (0.5 mg) once daily until progressive disease, intolerable toxicity, or investigator and/or patient decision to withdraw.<br>* Other names: Avodart;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Response will be measured according to RECIST version 1.1, the ORR is defined as the sum of the complete remissions plus partial responses. The best response will be used in each patient. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| Duration of Response (DoR) | Response will be measured according to RECIST version 1.1, the DoR is defined as the time from first tumor assessment at which the overall response was recorded as partial response (PR) or complete response (CR) that is subsequently confirmed until documented progressive disease (PD) or death form any cause, whichever occurs first. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Response will be measured according to RECIST version 1.1, the PFS is defined as the time from study enrolment until date of first documented disease progression or death due to any cause, whichever occurs first.Every 12 weeks a CT/MRI scan will be made to asses the progression free survival until PD. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| Clinical benefit rate (CBR) | Response will be measured according to RECIST version 1.1, the CBR is defined as the confirmed CR or PR at any time or stable disease (SD) of at least 6 months. Every 12 weeks a CT/MRI scan will be made to asses the clinical benefit rate until PD. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| Overall survival (OS) | The OS is defined as the time from study enrolment to the date of death to any cause. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 3 years | 
| Quality of Life (QoL) based on the EORTC QLQ-C30 questionnaire | Quality of Life (QoL) based on the EORTC QLQ-C30 questionnaire. Participants are asked to fill in the questionnaires in week 0 (before start of treatment, baseline), every 12 weeks, and at PD. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| Quality of Life (QoL) based on the EORTC QLQ-H&N43 questionnaire | Quality of Life (QoL) based on the EORTC QLQ-H&N43 questionnaire. Participants are asked to fill in the questionnaires in week 0 (before start of treatment, baseline), every 12 weeks, and at PD. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| Quality of Life (QoL) based on the EORTC QLQ-SHQ22 questionnaire | Quality of Life (QoL) based on the EORTC QLQ-SHQ22 questionnaire. Participants are asked to fill in the questionnaires in week 0 (before start of treatment, baseline), every 12 weeks, and at PD. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| Pain level assessed by the VAS (visual analog scale) questionnaire | Scale range 0-10, in which a higher score represents more pain. Participants are asked to fill in the questionnaires in week 0 (before start of treatment, baseline), every 12 weeks, and at PD. | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| Adverse Events according to CTCAE v5.0 | Adverse events will be recorded using International Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, the investigator will assess whether those events are drug related. Every OPD visit (every 3 months until PD) | From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| Circulating tumor DNA (ctDNA) levels | ctDNA levels will be assessed to evaluate whether treatment response and disease progression can be predicted. Baseline, 3 months, 6 months, and at PD. | through study completion, estimated after 3 years | 
| mRNA expression levels of AR and AR splice variants | mRNA expression of AR and AR splice variants on baseline and post-treatment tumor tissue samples to evaluate whether treatment response and disease progression can be predicted. Pre-treatment and post-treatment (i.e. PD) | through study completion, estimated after 3 years | 
| mRNA expression levels of SRD5A1/SRD5A2 | mRNA expression of SRD5A1/SRD5A2 on baseline and post-treatment tumor tissue samples to evaluate whether treatment response and disease progression can be predicted. Pre-treatment and post-treatment (i.e. PD) | through study completion, estimated after 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Goserelin, Salivary duct carcinoma, Androgen deprivation therapy, Combined androgen blockade, Dutasteride, Bicalutamide, anti-androgens