Study in Women With Advanced Breast Cancer Receiving Palbociclib With AI or Fulvestrant

This is a prospective, open-label, multi-center, single arm, non-comparative phase II study in women with HR+/HER2- advanced breast cancer receiving palbociclib in addition to an aromatase inhibitor or fulvestrant. The study will take place in Germany (85 study centers).

In total, 360 patients will be enrolled in this study. 6 treatment groups are planned. The study seeks to recruit 60 (58-62) patients per recruitment group. For first-line treatment with palbociclib - and letrozole (Enrollment Group 1), anastrozole (Enrollment Group 2), exemestane (Enrollment Group 3) or fulvestrant (Enrollment Group 4) and 60 (58-62) patients for second- or later-line treatment with palbociclib -and letrozole (Enrollment Group 5) or fulvestrant (Enrollment Group 6). Recruitment will be centrally monitored to allow closure of a respective group as soon as 60 (58-62) patients have been enrolled.

Treatment will be continued until disease progression, intolerable toxicity, death or any other reason. In case a combination partner is discontinued, palbociclib has to be discontinued. In case treatment with palbociclib is stopped, combination partner can be continued according to investigator's discretion. Irrespectively of the combination partner, the discontinuation of palbociclib is defined as end of treatment (EOT) in this study. After EOT the patient enters the follow-up period.

Primary end point is clinical benefit rate 24 weeks after the first study treatment of the patient.

A study independent, decentral, "virtual" biobank will be established. All patients will be asked to give consent for their tumor samples to be used for future investigational research. Study sites will inform the local pathologists about the patient's consent and ask for the tissue sample to be reserved for future analyses. The site is requested to collect contact details of the pathologist storing the tumor sample, the sample's identification number(s), and to document these in the eCRF.

The decision to perform subsequent investigational research studies on collected samples will be based on outcome data from this study or from new scientific findings related to the drug class or disease, as well as reagent and assay availability.

Inclusion criteria

• Personally signed written informed consent prior to beginning protocol specific procedures, including expected cooperation of the patient for the treatment and follow-up, must be obtained and documented according to the local regulatory requirements
• Women with proven diagnosis of advanced, defined as locally advanced inoperable or metastatic, adenocarcinoma of the breast
• Hormone-receptor-positive (HR+) disease, defined as estrogen-receptor-positive (ER+) and/or progesterone-receptor-positive (PgR+)
• Human epidermal growth factor receptor 2-negative (HER2-) disease (HER2 neg/+ or HER2++ with CISH/FISH neg.)
• Pre-/perimenopausal women receiving concomitant therapy with an luteinizing hormone-releasing hormone (LHRH) agonist / ovarian ablation or postmenopausal status
• Age ≥18 years
• Measurable disease as per Response Evaluation Criteria in Solid Tumors [RECIST] or bone-only disease
• Patients scheduled for palliative treatment with an combination partner for first- or later-line
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2
• Adequate organ and marrow function
• Resolution of all acute toxic effects of prior therapy, including radiotherapy Grade <1 (except toxicities not considered a safety risk for the patient) and recovery from surgical procedures
• Fluent in spoken and written German

Exclusion criteria

• Prior treatment with any CDK4/6 inhibitor
• Prior adjuvant therapy with the respective endocrine combination partner if last intake <12 months prior to entering the study
• Prior palliative therapy with the respective endocrine combination partner
• More than one prior palliative chemotherapy
• 5. Known hypersensitivity to letrozole, anastrozole, exemestane, fulvestrant or any of their excipients
• Current use of food or drugs known to be potent inhibitors or inducers of CYP3A4 (refer to Appendix 15.4)
• Current use of preparations containing St. John's Wort
• Participation in other studies involving investigational drug(s) (Phases I-IV) within 2 weeks before the current study treatment begins
• QTc > 480 msec on the screening ECG (using the QTcF formula and/or the QTcB (Bazett) formula); history of QT syndrome, Brugada syndrome or known history of QTc prolongation, or Torsade de Pointes
• High cardiovascular risk, including, but not limited to recent myocardial infarction, severe/unstable angina and severe cardiac dysrhythmias in the past 6 months prior to enrollment
• Patients with advanced symptomatic, visceral spread, that were at risk of life-threatening complications in the short term (including patients with massive uncontrolled effusions [pleural, pericardial, peritoneal], pulmonary lymphangitis, and over 50% liver involvement)
• Diagnosis of any second malignancy within the last 3 years prior to enrollment, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix
• Known, not-irradiated CNS metastases