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

Phase 4

Completed

• Conditions: Breast Cancer Recurrent; Hormone Receptor Positive Malignant Neoplasm of Breast; HER2/Neu-negative Carcinoma of Breast
• Interventions: Drug: Bevacizumab; Drug: Capecitabine; Drug: Everolimus; Drug: Exemestane; Other: Patient questionaires

• Registration Number: NCT02248571
• Lead Sponsor: iOMEDICO AG

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2014-08
• Study First Submitted: 2014-08-28
• Study First Submitted QC: 2014-09-22
• Study First Posted: 2014-09-25
• Primary Completion: 2017-08-31
• Study Completion: 2017-09-30
• Status Verified: 2017-11
• Last Update Submitted: 2017-11-08
• Last Update Posted: 2017-11-13

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 85

Inclusion Criteria

Written informed consent must be obtained prior to any study specific procedure.

1. Adult women (≥ 18 years of age)

2. . 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.

3. Pathologically confirmed HER2/neu-negative, ER/PR positive inoperable or metastatic adenocarcinoma of the breast

4. 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)

5. No indication for other chemotherapeutic treatment including Taxanes or Anthracyclines

6. Measurable or non-measurable disease as per RECIST 1.1

7. Adequate bone marrow, liver and renal function (according to current SmPCs of both treatment regimens)

8. ECOG performance status 0-2

9. Fluent German (spoken and written) language

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Exclusion Criteria

1. Prior palliative cytotoxic chemotherapies

2. Prior exposure to mTOR-Inhibitors (prior treatment with exemestane is allowed)

3. Concomitant antihormonal therapies, other than study medication

4. Symptomatic visceral metastases (as deemed by the investigator)

5. Uncontrolled CNS metastases

6. Unstable skeletal metastases

7. Medically uncontrolled cardiovascular diseases (e.g. uncontrolled hypertension)

8. Medically uncontrolled diabetes mellitus

9. Severe hepatic impairment (Child-Pugh C)

10. 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]

11. Known HIV infection or chronic hepatitis B or C or history of hepatitis B or C

12. Known dihydropyrimidine dehydrogenase (DPD) deficiency

13. Any other contraindications to the study drugs used or their excipients according to current SmPCs

14. Concomitant use of immunosuppressive agents or chronic use of systemic corticosteroids

15. Use of any other concomitant medication known to interfere with the study drugs

16. Use of concomitant medication known to interfere with the study results (e.g. hormonal therapy) during the whole study duration

17. Premenopausal patients

18. Pregnant or breast feeding patients

19. Participation in additional parallel interventional drug or device studies within four weeks before start of study.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Arm A	Patient questionaires	Bevacizumab plus Capecitabine (1st treatment phase) followed by Everolimus plus Exemestane (2nd treatment phase) Dosing (treatment cycle: 21days): 1. 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) 2. 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)
Arm B	Patient questionaires	Everolimus plus Exemestane (1st treatment phase) followed by Bevacizumab plus Capecitabine (2nd treatment phase) Dosing (treatment cycle: 21days): 1. Everolimus: 10 mg/day orally applied tablet --- Exemestane: 25 mg/day orally applied tablet 2. 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)
Arm A	Everolimus	Bevacizumab plus Capecitabine (1st treatment phase) followed by Everolimus plus Exemestane (2nd treatment phase) Dosing (treatment cycle: 21days): 1. 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) 2. 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)
Arm A	Bevacizumab	Bevacizumab plus Capecitabine (1st treatment phase) followed by Everolimus plus Exemestane (2nd treatment phase) Dosing (treatment cycle: 21days): 1. 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) 2. 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)
Arm A	Capecitabine	Bevacizumab plus Capecitabine (1st treatment phase) followed by Everolimus plus Exemestane (2nd treatment phase) Dosing (treatment cycle: 21days): 1. 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) 2. 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)
Arm A	Exemestane	Bevacizumab plus Capecitabine (1st treatment phase) followed by Everolimus plus Exemestane (2nd treatment phase) Dosing (treatment cycle: 21days): 1. 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) 2. 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)
Arm B	Bevacizumab	Everolimus plus Exemestane (1st treatment phase) followed by Bevacizumab plus Capecitabine (2nd treatment phase) Dosing (treatment cycle: 21days): 1. Everolimus: 10 mg/day orally applied tablet --- Exemestane: 25 mg/day orally applied tablet 2. 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)
Arm B	Capecitabine	Everolimus plus Exemestane (1st treatment phase) followed by Bevacizumab plus Capecitabine (2nd treatment phase) Dosing (treatment cycle: 21days): 1. Everolimus: 10 mg/day orally applied tablet --- Exemestane: 25 mg/day orally applied tablet 2. 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)
Arm B	Exemestane	Everolimus plus Exemestane (1st treatment phase) followed by Bevacizumab plus Capecitabine (2nd treatment phase) Dosing (treatment cycle: 21days): 1. Everolimus: 10 mg/day orally applied tablet --- Exemestane: 25 mg/day orally applied tablet 2. 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)
Arm B	Everolimus	Everolimus plus Exemestane (1st treatment phase) followed by Bevacizumab plus Capecitabine (2nd treatment phase) Dosing (treatment cycle: 21days): 1. Everolimus: 10 mg/day orally applied tablet --- Exemestane: 25 mg/day orally applied tablet 2. 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)

Primary Outcome Measures

Name	Time	Method
Patients' preference	After 12 weeks of second treatment phase or two weeks after early (< 12 weeks) treatment discontinuation	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.

Secondary Outcome Measures

Name	Time	Method
Patient reported treatment satisfaction	After 12 weeks of first and second treatment phase or two weeks after early (< 12 weeks) treatment discontinuation of each treatment phase	To compare patient reported treatment satisfaction as assessed by the treatment satisfaction questionnaire in first- and second treatment phase
Safety and tolerability as measured by number of treatment-emergent adverse events (AEs) and clinical laboratory abnormalities	From date of informed consent to +30 days from last application of study medication	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)
Progression free survival for first and second treatment phase	Participants will be followed until progressive disease in boths treatment phases (expected 21 months in total)	To explore progression free survival separately for each treatment phase
Overall survival	Participants will be followed until death (expected median of 24 months)	To explore overall survival for each treatment arm beginning from start of respective treatment phase until end of follow-up phase
Objective response rates and disease control rates based on tumor assessment (RECIST 1.1)	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)	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
Progression free survival rate	After 12 weeks of first and second treatment phase	To assess progression free survival rates after 12 weeks of therapy in first- (PFS rate 1) and second treatment phase (PFS rate 2)
Quality of life	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	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
Reasons for patients' preference	After 12 weeks of second treatment phase or two weeks after early (< 12 weeks) treatment discontinuation	To evaluate reasons for preference as assessed by the patient preference questionnaire
Physicians' treatment preference	After 12 weeks of second treatment phase or two weeks after early (< 12 weeks) treatment discontinuation	To determine physicians' treatment preference as assessed by the physician preference questionnaire

Trial Locations

Locations (1)

iOMEDICO AG; 🇩🇪 Freiburg, Baden-Wuerttemberg, Germany