Maintenance Aromatase Inhibitors (AIs)+ Everolimus vs AIs in Hormone Receptor Positive Metastatic Breast Cancer Patients

Phase 3

Completed

• Conditions: Breast Cancer Metastatic
• Interventions: Drug: Everolimus; Drug: Aromatase Inhibitors

• Registration Number: NCT02511639
• Lead Sponsor: Istituto Oncologico Veneto IRCCS

Brief Summary

The purpose of this study is to compare maintenance Aromatase Inhibitors (AIs) + everolimus with Aromatase Inhibitors alone after 1st line chemotherapy in patients with HR+ metastatic breast cancer.

Detailed Description

The purpose of this study is:

* to compare the progression free survival (PFS) of AIs/everolimus to AIs administered as maintenance therapy in HR+ advanced breast cancer patients with disease control (Complete Response (CR), Partial Response (PR) or Stable Disease (SD))after 1st line chemotherapy.

* To evaluate the overall survival

* To assess the safety profile

* To evaluate the response rate

Study Timeline

• Study Start: 2014-07-30
• Study First Submitted: 2015-07-16
• Study First Submitted QC: 2015-07-28
• Study First Posted: 2015-07-30
• Primary Completion: 2020-02-28
• Study Completion: 2020-07-31
• Status Verified: 2020-12
• Last Update Submitted: 2020-12-02
• Last Update Posted: 2020-12-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 110

Inclusion Criteria

1. >18 years old women with metastatic breast cancer
2. Histological confirmation of hormone-receptor positive (defined as at least 10% of estrogen receptor (ER) and/or progesterone receptor (PgR) positivity) and human epidermal growth factor receptor 2 (HER2) negative (score 0-1+ in immunohistochemistry or FISH negativity) breast cancer
3. Postmenopausal status
4. One line of chemotherapy for metastatic disease; patients must have received a minimum of 6 cycles of chemotherapy in order to be eligible, and must have obtained disease control (CR or PR od SD)
5. Eastern Cooperative Oncology Group (ECOG) Performance status < 2
6. Adequate bone marrow and coagulation function
7. Adequate liver function
8. Adequate renal function
9. Fasting serum cholesterol ≤ 300 mg/dl or 7.75 mmol/L and fasting triglycerides ≤ 2.5 × upper limit of normal (ULN). In case one or both of these thresholds are exceeded, the patient can only be included after initiation of statin therapy or other lipid lowering drugs (eg fibrates), and when the above mentioned values have been achieved
10. Fasting glucose < 1.5 × ULN
11. Written informed consent obtained before any screening procedure and according to local guidelines.

Exclusion Criteria

1. HER2-overexpressing patients by local laboratory testing (immunohistochemistry 3+ staining or in situ hybridization positive)

2. Previous treatment with mammalian target of rapamycin (mTOR) inhibitors

3. Known hypersensitivity to mTOR inhibitors, e.g. sirolimus (rapamycin)

4. More than one chemotherapy line for metastatic disease

5. Treatment with angiogenetic compounds as maintenance therapy (eg. bevacizumab)

6. Radiotherapy within four weeks prior to enrollment except in case of localized radiotherapy for analgesic purpose or for lytic lesions at risk of fracture which can then be completed within two weeks prior to enrollment. Patients must have recovered from radiotherapy toxicities prior to enrollment

7. Symptomatic central nervous system metastases

8. Patients with a known history of HIV positivity

9. Active, bleeding diathesis, or on oral anti-vitamin K medication (except low dose warfarin and acetylsalicylic acid or equivalent, as long as the international normalized ratio (INR) is ≤ 2.0)

10. Any severe and / or uncontrolled medical conditions such as:

    • Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to enrollment, serious uncontrolled cardiac arrhythmia
    • Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN
    • Acute and chronic, active infectious disorders and nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the complications of this study therapy
    • Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drugs (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome)
    • Significant symptomatic deterioration of lung function. If clinically indicated, pulmonary function tests including measures of predicted lung volumes, diffusion capacity of lung for carbon monoxide (DLco) and O2 saturation at rest on room air should be considered to exclude restrictive pulmonary disease, pneumonitis or pulmonary infiltrates.

11. Patients who test positive for hepatitis B or C (patients who test negative for hepatitis B virus (HBV)-DNA, HBsAg, and HBcAb but positive for HBsAb with prior history of vaccination against Hepatitis B will be eligible)

12. Patients being treated with drugs recognized as being strong inhibitors or inducers of the isoenzyme Cytochrome P3A (Rifabutin, Rifampicin, Clarithromycin, Ketoconazole, Itraconazole, Voriconazole, Ritonavir, Telithromycin) within the last 5 days prior to enrollment

13. History of non-compliance to medical regimens

14. Patients unwilling to or unable to comply with the protocol

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm A: Everolimus & Aromatase inhibitors	Everolimus	Everolimus 10 mg po daily + Aromatase inhibitors (Exemestane 25 mg po daily or Letrozole 2.5 mg po daily or Anastrozole 1 mg po daily)
Arm A: Everolimus & Aromatase inhibitors	Aromatase Inhibitors	Everolimus 10 mg po daily + Aromatase inhibitors (Exemestane 25 mg po daily or Letrozole 2.5 mg po daily or Anastrozole 1 mg po daily)
Arm B: Aromatase inhibitors	Aromatase Inhibitors	Aromatase inhibitors (Exemestane 25 mg po daily or Letrozole 2.5 mg po daily or Anastrozole 1 mg po daily)

Primary Outcome Measures

Name	Time	Method
Progression free survival	Up to 2 years after randomisation	PFS is defined as the time from randomization to the first documentation of objective disease progression or death from any cause

Secondary Outcome Measures

Name	Time	Method
Overall survival	Up to 2 years after randomisation	Overall survival is defined as the interval between the date of randomization and the date of patient death due to any cause, or the last date the patient was known to be alive
Response rate	Every 12 weeks during treatment, up to 2 years after randomisation	Responses will be assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria only for patients with measurable disease at the time of study entry.
Safety profile	Baseline and every 4 weeks during treatment, up to 2 years after randomisation	Toxicity will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI -CTCAE), version 4.

Trial Locations

Locations (16)

Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona; 🇮🇹 Ancona, AN, Italy

ASL Brindisi "Antonio Perrini"; 🇮🇹 Brindisi, BR, Italy

Ospedale Papa Giovanni XXIII; 🇮🇹 Bergamo, Bg, Italy

Azienda Spedali Civili di Brescia; 🇮🇹 Brescia, BS, Italy

Istituto Nazionale dei Tumori IRCCS; 🇮🇹 Milano, MI, Italy

Azienda Ospedaliera Universitaria di Parma; 🇮🇹 Parma, PR, Italy

Azienda Ospedaliero-Universitaria "Santa Maria della Misericordia"; 🇮🇹 Udine, UD, Italy

Ospedale Sacro Cuore - Don Calabria; 🇮🇹 Negrar, VR, Italy

Policlinico Sant'Orsola Malpighi; 🇮🇹 Bologna, BO, Italy

A.S.O. S.Croce e Carle di Cuneo; 🇮🇹 Cuneo, CN, Italy

Azienda Ospedaliero - Universitaria "Policlinico - Vittorio Emanuele"; 🇮🇹 Catania, CT, Italy

Azienda Ospedaliero-Universitaria di Ferrara - Arcispedale Sant'Anna; 🇮🇹 Cona, FE, Italy

Ospedale Misericordia di Grosseto; 🇮🇹 Grosseto, GR, Italy

IRCCS - Azienda Ospedaliera S.M. Nuova; 🇮🇹 Reggio Emilia, RE, Italy

Ospedale Civile Santa Chiara; 🇮🇹 Trento, TN, Italy

Ospedale dell'Angelo; 🇮🇹 Mestre, Italy