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

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and quality of life in women with advanced breast cancer (locally advance inoperable or metastatic adenocarcinoma of the breast), HR+ / HER2-, who are treated with an aromatase inhibitor or fulvestrant as baseline therapy in combination with palbociclib (Ibrance)

Detailed Description
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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.

Official Title
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Open-label, Multi-center, sINGlE Arm Clinical Study to Evaluate Efficacy/QoL in Women With HR+, HER2-, Regionally Recurrent or Metastatic Breast Cancer Receiving Palbociclib With an AI or Fulvestrant After Prior Endocrine Therapy

Conditions
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Breast Cancer, Hormone Receptor Positive Tumor, Human Epidermal Growth Factor 2 Negative Carcinoma of Breast

Intervention / Treatment
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* Drug: Palbociclib
* Drug: Letrozole
* Drug: Anastrozole
* Drug: Exemestane
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palbociclib+AI or Fulvestrant<br>Letrozole as first-line or later line, Anastrozole as first-line, Exemestane as first-line, Fulvestrant as first-line or later line after prior endocrine therapy. | Drug: Palbociclib<br>* Capsules (commercially available, obtained from local pharmacies), 125mg daily, 21 days, 7 days off, cycles of 28 days. Dose reductions: 100mg, 75mg (no change in administration schedule) Number of cycles: until disease progression, intolerable toxicity, death or any other reasons<br>* Other names: Ibrance;Drug: Letrozole<br>* Letrozole will be administered as basic therapy (commercially available tablets, obtained from local pharmacies) as followed: 2.5mg/daily, oral intake<br>* Other names: Femara;Drug: Anastrozole<br>* Anastrozole will be administered as basic therapy (commercially available tablets, obtained from local pharmacies) as followed: 1mg/daily, oral intake<br>* Other names: Arimidex;Drug: Exemestane<br>* Exemestane will be administered as basic therapy (commercially available tablets, obtained from local pharmacies) as followed: 25mg/daily, oral intake<br>* Other names: Aromasin;Drug: Fulvestrant<br>* Fulvestrant will be administered as basic therapy (commercially available injection, obtained from local pharmacies) as followed: 500mg/once monthly, intramuscular injection<br>* Other names: Faslodex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Benefit Rate (CBR) | CBR is defined as complete response (CR), partial response (PR), or stable disease (SD) according to RECIST 1.1. | 24 weeks after first administration of Palbociclib in combination with AI / fulvestrant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with Adverse Events as assessed by CTCAE V4.0 | Adverse Events as characterized by type, frequency, severity (as graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.03), and seriousness | From Date of Signed informed consent until PD, assessed up to 60 months. | 
| Clinical Benefit Rate (CBR) | CBR is defined as complete response (CR), partial response (PR), or stable disease (SD) according to RECIST 1.1. | 48 weeks after first administration of Palbociclib in combination with AI / fulvestrant | 
| Progression-free Survival rate | Follow up 4 years after LPI | At 48 weeks (all patients) and 2 years (first-line patients only) after first administration of Palbociclib in combination with AI / fulvestrant | 
| Overall Survival rate | Follow up 4 years after LPI | At 48 weeks after first administration of Palbociclib in combination with AI / fulvestrant and yearly until EOS, assessed up to 60 months. | 
| Time on treatment | Study treatment will be continued until disease progression, intolerable toxicity, death or any other reason. | From day of first treatment until permanent discontinuation (EOT), assessed up to 60 months. | 
| Dosage | starting dose (mg) adjusted doses (mg) | From day of first treatment until EOT, assessed up to 60 months. | 
| Adminstration schedule | - dates of administration | From day of first treatment until EOT, assessed up to 60 months. | 
| Health-related quality of life (QoL) | Health-related QoL will be assessed with the FACT-B (Functional Assessment of Cancer Therapy-Breast) questionnaire | From date of signed informed consent until disease progression or start of next anti-cancer therapy: every 12 weeks, assessed up to 60 months. | 
| Health-related fatigue | Fatigue will be assessed with the BFI (Brief Fatigue Inventory) questionnaire | From date of signed informed consent until disease progression or start of next anti-cancer therapy: every 12 weeks, assessed up to 60 months. | 
| Health-related anxiety and depression | Depression and anxiety will be assessed with the HADS-D (Hospital Anxiety and Depression Scale) questionnaire | From date of signed informed consent until disease progression or start of next anti-cancer therapy: every 12 weeks, assessed up to 60 months. | 
| Physician's assessment of patient's overall health status and change in health status compared to previous visit | Assessed by 2 items at each cycle/at scheduled patient visit | From Screening until disease progression or start of next anti-cancer therapy, assessed up to 60 months. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HR+, HER2-, Locally advanced (inoperable or metastatic) Breast Cancer, Palbociclib, Aromatase inhibitor or fulvestrant, Pre-/perimenopausal receiving LHRH agonist / ovarian ablation, Postmenopausal