Neoplasms

All Conditions

Symptoms and General Pathology

Carcinoma

Recurrence

Carcinoma, Ductal

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

All Drugs and Chemicals

Antineoplastic Agents

Androgens

Goserelin

Androgen Antagonists

Bicalutamide

Dutasteride

Antineoplastic Agents, Hormonal

Hormones

Hormone Antagonists

5-alpha Reductase Inhibitors

Enzyme Inhibitors

Patients from cohort B (ADT-resistant) will receive CAB+dutasteride.

Goserelin injection (10.8 mg) once per 3 months until progressive disease, intolerable toxicity, or investigator and/or patient decision to withdraw.

Goserelin 10.8 mg

Bicalutamide tablets (50 mg) once daily until progressive disease, intolerable toxicity, or investigator and/or patient decision to withdraw.

Bicalutamide 50 mg

Dutasteride capsules (0.5 mg) once daily until progressive disease, intolerable toxicity, or investigator and/or patient decision to withdraw.

Dutasteride 0.5 mg

Jetty AM Weijers, MSc

Carla ML van Herpen, MD, PhD

Jack A Schalken, PhD

Gerald W Verhaegh, PhD

Carla van Herpen, MD, PhD

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 included two cohorts of patients: Cohort A, which comprises ADT-naïve patients, and Cohort B, which comprises ADT-resistant patients.

Cohort A is closed for inclusion as of April 18, 2024.

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.

Cohort A is closed for inclusion as of April 18, 2024.

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.

Cohort A is closed for inclusion as of April 18, 2024.

Phase II Dutasteride in Combination With CAB vs CAB in SDC

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

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.

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.

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.

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.

The OS is defined as the time from study enrolment to the date of death to any cause.

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.

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.

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.

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.

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)

ctDNA levels will be assessed to evaluate whether treatment response and disease progression can be predicted. Baseline, 3 months, 6 months, and at PD.

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)

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)

ZonMw: The Netherlands Organisation for Health Research and Development

Radboud University Medical Center

Nutritional and Metabolic Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Diseases and Abnormalities at or Before Birth

Rare Diseases

Syndrome

Metabolic Diseases

Polycystic Ovary Syndrome

Hyperandrogenism

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Gonadal Disorders

Endocrine System Diseases

Disorders of Sex Development

46, XX Disorders of Sex Development

Congenital Abnormalities

Urogenital Abnormalities

Adrenal Hyperplasia, Congenital

Adrenogenital Syndrome

Male Urogenital Diseases

Congenital Adrenal Hyperplasia

21-hydroxylase Deficiency

Adult females with polycystic ovary syndrome (PCOS) and evidence of clinical or biochemical androgen excess will be recruited.

Bicalutamide at a dose of 50mg once daily for 28 days.

Polycystic ovary syndrome (PCOS) affects 10% of all women, and it usually co-exists with high levels of sex hormones called androgens, such as testosterone. Women with PCOS are at increased risk of metabolic complications such as diabetes, non-alcoholic fatty liver disease, high blood pressure and heart disease. However, very little is understood about how androgen excess may drive the metabolic complications observed in women with PCOS.

Skeletal muscle is an important site of energy metabolism; increasingly, it is suspected that skeletal muscle energy balance is adversely impacted by androgens, thereby driving metabolic complications. To take this theory forward, we want to investigate the effects of androgens on muscle energy metabolism. We will perform detailed metabolic testing (including blood tests and muscle biopsies) in women with PCOS before and after taking tablets that block the action of testosterone for 28 days. In addition, we will be using a gold standard technique to see how women with PCOS metabolise fat and other nutrients by measuring markers in blood and breath samples after a breakfast test meal. This clinical research will increase our understanding of the complex relationships between hormonal abnormalities and metabolic disease in women with PCOS.

Background:

Polycystic ovary syndrome (PCOS) is a lifelong metabolic disorder affecting 10-13% of all women and is associated with major healthcare and economic burden, estimated at $8 billion annually the US in 2020. Traditionally considered a reproductive disorder only, it is now increasingly clear that PCOS is associated with severe metabolic health consequences across the entire life course of women. There is a two-fold increased risk of type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease, and emerging evidence of increased cardiovascular disease (CVD) incidence. There are no disease-specific therapies to mitigate or treat metabolic risk in women with PCOS. This is consistently highlighted as the priority concern amongst PCOS patient advocacy groups.

Androgen excess is a cardinal feature of PCOS, and circulating androgen burden is closely correlated with metabolic complications. In women with PCOS, the risk of developing metabolic dysfunction is above that conferred by simple obesity, suggesting that androgen excess is a key player; however, a distinct mechanistic role for androgens in this process remains to be elucidated. Androgen excess is associated with metabolically deleterious visceral fat accumulation and circulating testosterone levels correlate directly with the risk of T2DM and NAFLD. Muscle is a critical metabolic target tissue that plays a central role in energy metabolism through processes such as glucose uptake and oxidation, as well as oxidation of fatty acids to generate ATP in the mitochondria. Recent mechanistic data have shown that androgen excess is associated with changes in the transcriptional profile of skeletal muscle genes linked with metabolism and energy balance. Therefore, skeletal muscle is likely to represent an important site of crosstalk between androgen excess, disturbances in energy metabolism and risk of metabolic disease in PCOS.

Defective skeletal muscle glucose uptake is a key early step in the pathogenesis of insulin resistance in PCOS, and an early predictor of progression to overt type 2 diabetes mellitus. Impaired mitochondrial oxidation of free fatty acids in skeletal muscle and other disturbances in skeletal muscle mitochondrial function, such as oxidative phosphorylation, are increasingly implicated in the pathogenesis of metabolic disease such as T2DM. Abnormalities in skeletal muscle mitochondrial function have also been identified in small-scale studies in women with PCOS, and were associated with impaired fatty acid oxidation, weight gain and an increased risk of diabetes.

We hypothesise that androgen-mediated disturbances in skeletal muscle energy balance play a major role in the pathogenesis of metabolic disease in women with PCOS.

Study description:

We propose to test our hypothesis utilising state-of-the-art metabolic phenotyping tools in two study visits. We will examine systemic fatty acid oxidation, muscle proteomics and targeted and non-targeted metabolomics in women with PCOS before and after pharmacological androgen receptor blocade. In addition, a subset of ex vivo muscle biopsies will undergo in vitro experiments to measure skeletal muscle mitochondrial morphology and function.

After study visit 1, all recruited participants will receive 50mg of an oral androgen receptor antagonist (bicalutamide), resulting in pharmacological AR blockade, before undertaking an identical study visit for repeat assessment.

Women with a confirmed diagnosis of polycystic ovary syndrome with androgen excess on clinical or biochemical grounds

The RolE oF Androgen Excess in MUscle Energy MetaboLism in Women With PolyCystic Ovary Syndrome (REFUEL PCOS) Study 2

Change in whole body fatty acid oxidation on stable isotope breath after 28 days of androgen receptor (AR) blockade compared to baseline

Changes in metabolomic pathways relating to energy balance and mitochondrial function in serum and muscle after AR blockade

Changes in mitochondrial morphology ex vivo post AR blockade

Differences in mitochondrial oxygen consumption and oxidative phosphorylation using Seahorse technology pre and post AR blockade

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase II Dutasteride in Combination With CAB vs CAB in SDC	NCT05513365	Salivary Duct C...	Goserelin 10.8 ... Bicalutamide 50... Dutasteride 0.5...	18 Years -	Radboud University Medical Center
Phase II Dutasteride in Combination With CAB vs CAB in SDC	NCT05513365	Salivary Duct C...	Goserelin 10.8 ... Bicalutamide 50... Dutasteride 0.5...	18 Years -	Radboud University Medical Center
The RolE oF Androgen Excess in MUscle Energy MetaboLism in Women With PolyCystic Ovary Syndrome (REFUEL PCOS) Study 2	NCT05647356	Polycystic Ovar... Androgen Excess Metabolic Disea...	Bicalutamide 50...	18 Years - 40 Years	Royal College of Surgeons, Ireland

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