Patient Preference for Everolimus in Combination With Exemestane or Capecitabine in Combination With Bevacizumab

Study Overview
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Brief Summary
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This is a clinical trial with a crossover design to determine patients' preference for capecitabine in combination with bevacizumab or everolimus in combination with exemestane for advanced breast cancer patients and to evaluate, if any combination is associated with a better quality of life. To identify patients' preference for either therapy in this trial, patients without disease progression or other reasons for early discontinuation will be asked for their treatment preference and their treatment satisfaction. To correlate patients' preference with other patient reported outcomes (PROs), quality of life (QoL) will be assessed at baseline and throughout the study, using dedicated questionnaires. With similarly active treatment options, it is of utmost importance to identify the treatment that has the least negative impact on the patients' quality of life.

Official Title
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An Open Label, randomIzed Controlled Prospective Multicenter Two Arm Phase IV Trial to Determine Patient Preference for Everolimus in Combination With Exemestane or Capecitabine in Combination With Bevacizumab for Advanced (Inoperable or Metastatic) HER2-negative Hormone Receptor Positive Breast Cancer

Conditions
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Breast Cancer Recurrent, HER2/Neu-negative Carcinoma of Breast, Hormone Receptor Positive Malignant Neoplasm of Breast

Intervention / Treatment
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* Drug: Bevacizumab
* Drug: Capecitabine
* Drug: Everolimus
* Drug: Exemestane
* Other: Patient questionaires


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent must be obtained prior to any study specific procedure. Adult women (≥ 18 years of age) . Postmenopausal status The investigator must confirm postmenopausal status. Postmenopausal status is defined either by: Age ≥ 55 years and one year or more of amenorrhea Age < 55 years and one year or more of amenorrhea and postmenopausal levels of follicle stimulating hormone (FSH) and Luteinizing hormone (LH) per local institutional standards Prior hysterectomy and has postmenopausal levels of FSH and LH per local institutional standards Surgical menopause with bilateral oophorectomy For women with therapy-induced amenorrhea, oophorectomy or serial measurements of FSH and / or estradiol are needed to ensure postmenopausal status. Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone (LH-RH) agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of ovarian suppression. Pathologically confirmed HER2/neu-negative, ER/PR positive inoperable or metastatic adenocarcinoma of the breast Indication for systemic palliative targeted therapy / first line chemotherapy after failure of at least one non-steroidal aromatase inhibitor therapy at any time during the disease course (no restriction regarding the number of previous endocrine lines) No indication for other chemotherapeutic treatment including Taxanes or Anthracyclines Measurable or non-measurable disease as per RECIST 1.1 Adequate bone marrow, liver and renal function (according to current SmPCs of both treatment regimens) ECOG performance status 0-2 Fluent German (spoken and written) language Exclusion Criteria: Prior palliative cytotoxic chemotherapies Prior exposure to mTOR-Inhibitors (prior treatment with exemestane is allowed) Concomitant antihormonal therapies, other than study medication Symptomatic visceral metastases (as deemed by the investigator) Uncontrolled CNS metastases Unstable skeletal metastases Medically uncontrolled cardiovascular diseases (e.g. uncontrolled hypertension) Medically uncontrolled diabetes mellitus Severe hepatic impairment (Child-Pugh C) Inadequate organ function as specified below: Hemoglobin < 9.0 g/dl Absolute neutrophil count (ANC) <1,5 x109/L Platelets <100 x109/L Creatinine clearance < 30ml/min [Cockcroft and Gault] Known HIV infection or chronic hepatitis B or C or history of hepatitis B or C Known dihydropyrimidine dehydrogenase (DPD) deficiency Any other contraindications to the study drugs used or their excipients according to current SmPCs Concomitant use of immunosuppressive agents or chronic use of systemic corticosteroids Use of any other concomitant medication known to interfere with the study drugs Use of concomitant medication known to interfere with the study results (e.g. hormonal therapy) during the whole study duration Premenopausal patients Pregnant or breast feeding patients Participation in additional parallel interventional drug or device studies within four weeks before start of study.

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: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Bevacizumab plus Capecitabine (1st treatment phase) followed by Everolimus plus Exemestane (2nd treatment phase) Dosing (treatment cycle: 21days): Capecitabine: 1000 mg/m2 orally applied twice daily as combined 150 mg and 500 mg tablets on days 1 to 14 of each 21-day cycle, followed by a seven day rest period (i.e. off-treatment) --- Bevacizumab: 15 mg/kg intravenously applied once every three weeks (i.e. 5 mg/kg/wk dose equivalent) Everolimus: 10 mg/day orally applied tablet --- Exemestane: 25 mg/day orally applied tablet Patient questionaires to assess patient reported outcome and patients' preference will be completed at four specific time points during study treatment (two timepoints in each treatment phase) | Drug: Bevacizumab<br>* administered as combined therapy with Capecitabine<br>* Other names: Avastin®;Drug: Capecitabine<br>* administered as combined therapy with Bevacizumab<br>Drug: Everolimus<br>* administered as combined therapy with Exemestane<br>* Other names: Afinitor®;Drug: Exemestane<br>* administered as combined therapy with Everolimus<br>Other: Patient questionaires<br>* Patients will fill out questionaires at four specific time points during study treatment to assess patient reported outcome and patients' preference<br>* Other names: Patients' preference;|
| Experimental: Arm B<br>Everolimus plus Exemestane (1st treatment phase) followed by Bevacizumab plus Capecitabine (2nd treatment phase) Dosing (treatment cycle: 21days): Everolimus: 10 mg/day orally applied tablet --- Exemestane: 25 mg/day orally applied tablet Capecitabine: 1000 mg/m2 orally applied twice daily as combined 150 mg and 500 mg tablets on days 1 to 14 of each 21-day cycle, followed by a seven day rest period (i.e. off-treatment) --- Bevacizumab: 15 mg/kg intravenously applied once every three weeks (i.e. 5 mg/kg/wk dose equivalent) Patient questionaires to assess patient reported outcome and patients' preference will be completed at four specific time points during study treatment (two timepoints in each treatment phase) | Drug: Bevacizumab<br>* administered as combined therapy with Capecitabine<br>* Other names: Avastin®;Drug: Capecitabine<br>* administered as combined therapy with Bevacizumab<br>Drug: Everolimus<br>* administered as combined therapy with Exemestane<br>* Other names: Afinitor®;Drug: Exemestane<br>* administered as combined therapy with Everolimus<br>Other: Patient questionaires<br>* Patients will fill out questionaires at four specific time points during study treatment to assess patient reported outcome and patients' preference<br>* Other names: Patients' preference;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients' preference | Patients' preference of the two treatment combinations capecitabine plus bevacizumab or everolimus in combination with exemestane after failure of standard antihormonal therapy in patients with advanced (inoperable or metastatic) HER2/neu-negative hormone receptor positive breast cancer. The preference will be ascertained using the patient preference questionnaire. | After 12 weeks of second treatment phase or two weeks after early (< 12 weeks) treatment discontinuation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reasons for patients' preference | To evaluate reasons for preference as assessed by the patient preference questionnaire | After 12 weeks of second treatment phase or two weeks after early (< 12 weeks) treatment discontinuation | 
| Patient reported treatment satisfaction | To compare patient reported treatment satisfaction as assessed by the treatment satisfaction questionnaire in first- and second treatment phase | After 12 weeks of first and second treatment phase or two weeks after early (< 12 weeks) treatment discontinuation of each treatment phase | 
| Quality of life | To investigate differences in quality of life by the European Organization for Research and Treatment of Cancer quality of life questionnaire 30 (EORTC QLQ-C30) and EORTC QLQ-FA13 questionnaire | At baseline and after 12 weeks of first and second treatment phase or two weeks after early (< 12 weeks) treatment discontinuation of each treatment phase | 
| Progression free survival rate | To assess progression free survival rates after 12 weeks of therapy in first- (PFS rate 1) and second treatment phase (PFS rate 2) | After 12 weeks of first and second treatment phase | 
| Objective response rates and disease control rates based on tumor assessment (RECIST 1.1) | To assess clinical benefit by determining objective response rates and disease control rates based on tumor assessment as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria | Participants will be followed for the whole duration of first phase therapy, with an expected average of 12 months, plus 3 months of second phase therapy (15 months in total) | 
| Safety and tolerability as measured by number of treatment-emergent adverse events (AEs) and clinical laboratory abnormalities | To evaluate safety and tolerability throughout the study according to Common Toxicity Criteria for Adverse Effects (CTCAE) 4.03 criteria, including clinical laboratory (grades 3 or 4 - separately for hematology and biochemistry) and number of treatment-emergent AEs (safety data for pre- and post-treatment periods will be listed separately) | From date of informed consent to +30 days from last application of study medication | 
| Physicians' treatment preference | To determine physicians' treatment preference as assessed by the physician preference questionnaire | After 12 weeks of second treatment phase or two weeks after early (< 12 weeks) treatment discontinuation | 
| Progression free survival for first and second treatment phase | To explore progression free survival separately for each treatment phase | Participants will be followed until progressive disease in boths treatment phases (expected 21 months in total) | 
| Overall survival | To explore overall survival for each treatment arm beginning from start of respective treatment phase until end of follow-up phase | Participants will be followed until death (expected median of 24 months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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female, breast cancer, advanced, inoperable, metastatic, HER2/neu-negative, hormone receptor positive, HR+, postmenopausal