DiEtary Mimicry by Glucocorticoid Modulation Evaluation in ER+ Metastatic Breast Cancer Treatment: Efficacy and Response (DEMETER Trial)

DiEtary Mimicry by Glucocorticoid Modulation Evaluation in ER+ Metastatic Breast Cancer Treatment: Efficacy and Response - DEMETER Trial A Phase II Clinical Study to Investigate the Efficacy of Dexamethasone as an Adjunct to Endocrine Therapy in ER+, HER2- Metastatic Breast Cancer.

This is a single centre, open label, phase II clinical study consisting of two parts, each consisting of a different dose of the same intervention to investigate the efficacy of dexamethasone as an adjunct to endocrine therapy in the treatment of ER+ HER2- metastatic breast cancer after progression on the same endocrine therapy.

Inclusion Criteria:

1. Have provided written informed consent and are willing to comply to study procedures and treatment plan.

2. Documentation of histologically confirmed diagnosis of oestrogen receptor (ER) expression >10% breast cancer based on local laboratory results. Tumour must be HER2 negative as defined by American Society of Clinical Oncology - College of American Pathologists (ASCOCAP) guidelines. If HER2 status is unavailable, then testing must be performed/repeated.

3. Have relapsed/refractory to treatment with aromatase inhibitors or Fulvestrant as monotherapy or in combination with CDK4/6 inhibitors in the 1st or 2nd line in metastatic setting. Prior treatment discontinuation must not be > 8 weeks ago.

4. Participants must meet one of the following criteria:

   1. Pre-menopausal women are required to have ovarian function suppression by means of bilateral oophorectomy or continued LHRH/GnRH agonists treatment.
   2. Are over the age of 60 years or are of postmenopausal status as defined by no menses for 12 months without an alternative medical cause. A high FSH level (>35 mIU/mL) in the postmenopausal range may be used to confirm a postmenopausal state.

5. Have metastatic disease.

6. At least 1 measurable lesion that would qualify as target lesion by RECIST v1.1, (assessed by the investigator) that can be accurately measured at baseline with CT or MRI and that is suitable for accurate repeated measurements. Lesions previously irradiated or subjected to other locoregional therapy will only be deemed measurable if disease progression at the treated site after completion of therapy is clearly documented.

7. ECOG performance status 0-2.

8. Have adequate organ function defined as follows:

   1. Hb: >5.7 mmol/L.
   2. ANC: >1.0 mmol/L
   3. Platelets: ≥ 75 x109/L
   4. Transaminases: ASAT and ALAT ≤3 x ULN (≤5.0 x ULN if liver metastases present);
   5. T. Bilirubin: ≤1.5 x ULN (≤3.0 x ULN if Gilbert's disease);
   6. eGFR: >30 ml/min/1,73 m2 (CKD-EPI)

9. Has negative HIV (Ag+Ab), Hepatitis B surface antigen (HBsAg), or Hepatitis C antibody (anti-HCV) test.

10. For participants opting to provide an on-treatment and/or EOT biopsy:

    1. Lesion to be biopsied for this study is deemed accessible and clinically feasible according to the (sub) investigator.

Exclusion Criteria:

1. Primary endocrine resistance: Progressed on endocrine therapy within 6 months of initiating treatment in the 1st line for advanced or mBC, or relapsed within first 2 years of endocrine therapy in the adjuvant setting.

2. Metastases such as massive uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and >50% liver involvement which have risk of life-threatening complications in the short term.

3. Known Central Nervous System (CNS) metastases.

4. Current use of corticosteroids including local administration such as intranasal, intraocular, intra-articular, inhaled or topical application, and/or having ongoing conditions requiring long-term use of corticosteroids.

5. History of hypersensitivity and/or other adverse effects to corticosteroids.

6. Known Diabetes mellitus (type 1 or type 2) or Random Blood Sugar (RBS) of ≥11.1 mmol/L.

7. Clinically significant osteoporosis unless treated with denosumab or bisphosphonates.

8. Have (history of) clinically significant ocular conditions such as glaucoma, papilledema and retinopathy.

9. Presence of clinically significant or uncontrolled cardiovascular disease such as:

   1. Congestive Heart Failure: > New York Heart Association (NYHA) class II.
   2. Coronary Artery Disease: Participants must not have unstable angina or angina de novo within the last 3 months and myocardial infarction in the last 6 months.
   3. Clinically significant cardiac arrhythmias.
   4. Therapy resistant hypertension in the opinion of investigator.
   5. For participants receiving Ribociclib: QTcF > 480 ms.

10. Diagnosis of any other malignancy prior to C1D1, except those that are not believed to influence the participant's prognosis and do not require any further treatment. This includes but is not limited to adequately treated basal cell or squamous cell skin cancer and carcinoma in situ of the cervix.

11. Known history of psychosis or suicidal ideation.

12. Are taking a prohibited medication (as defined in section 9.1.2) that cannot be discontinued for the duration of the study.

13. Any other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the clinician or investigator, would make the participant inappropriate for entry into this study.

14. Participation in any other interventional study or receiving any other anti-cancer therapy other than endocrine therapy.