Discontinuation of CDK4/6 Inhibitors in Patients With Metastatic HR Positive, HER2 Negative Breast Cancer

This is a low-intervention, randomized, non-comparative, open-label, multicenter, prospective, phase II trial investigating discontinuation of CDK4/6 inhibitors in patients with metastatic HR positive, HER2 negative breast cancer with durable disease control.

The primary objective is to evaluate long-term disease stabilization of CDK4/6 inhibitors discontinuation after a prolonged treatment period with continued endocrine therapy in breast cancer patients exhibiting at least stable disease after at least 12 months of combination treatment.

Eligibility Criteria:
Inclusion Criteria:

1. Female patient has given written informed consent
2. Patient is ≥ 18 years of age at time of signing the written informed consent
3. Patient has been diagnosed with histologically confirmed metastatic adenocarcinoma of the breast
4. Patient has documented histological or cytological confirmation of estrogen receptor positive (ER+) and HER2 negative (HER2-) disease
5. Patient has no curative treatment option by surgery or radiotherapy
6. Patient was treated with CDK4/6 inhibitor plus endocrine therapy for at least 12 months with disease control (complete remission, partial remission or stable disease) as judged by the treating physician before planned study treatment initiation
7. Patient has a preserved performance status (ECOG ≤ 2)
8. Patient has adequate bone marrow, renal and hepatic function:

   1. Hemoglobin \> 9.0 g/dL
   2. Absolute neutrophil count judged as appropriate for study therapy by the investigator
   3. Platelets ≥ 100 x 109/L
   4. Calculated creatinine clearance judged as appropriate for study therapy by the investigator
   5. AST (SGOT) / ALT (SGPT) and alkaline phosphatase ≤ 2.5x ULN
   6. Serum albumin \> 30 g/L
9. Patients considered postmenopausal according to one of the following definition:

   1. Women \<50 years of age who are amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and whose levels of luteinizing hormone and follicle-stimulating hormone are in the post-menopausal institutional range
   2. Women ≥50 years of age who are amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago or had chemotherapy-induced menopause with last menses \>1 year ago
   3. Artificially induced postmenopausal women (by Gonadotropin-releasing hormone \[GnRH\] analogs)
10. WOCBP must have a negative serum pregnancy test within 7 days prior to start of trial

Exclusion Criteria:

1. Patient has active (or history of) brain or leptomeningeal metastases
2. Patient is pre- or perimenopausal. Patient is pregnant or breast feeding or planning to become pregnant within five times the half-life of the IMPs after the end of treatment.
3. Patient has significant cardiovascular disease, such as cardiac disease (New York Heart Association Class II or greater), myocardial infarction or cerebrovascular accident within 6 months prior to initiation of study treatment, unstable arrhythmias, or unstable angina
4. Patient has other concomitant or previous malignancy, except adequately treated in-situ carcinoma of the uterine cervix, basal or squamous cell carcinoma of the skin, cancer in complete remission for \> 5 years
5. Patient has contraindication or shows hypersensitivity to the existing treatment with CDK4/6 inhibitor plus endocrine therapy
6. Patient shows evidence of any other disease, neurologic or metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of any of the study medications, puts the patient at higher risk for treatment-related complications or may affect the interpretation of study results
7. Patient participated in another clinical study with an investigational medicinal product during the last 28 days before treatment initiation or 7 half-lives of previously used trial medication, whichever is longer or participate in such a study at the same time as this trial.

   Note: Participation in non-interventional clinical studies or registries is allowed.
8. Any co-existing medical condition that in the investigator's judgement will substantially increase the risk associated with the patient's participation in the study.
9. Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities.
10. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts.