4EVER - Efficacy, Safety, Health Economics, Translational Research of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer

Metastatic Breast Cancer Clinical Trial

— MACS2096  

Official title:

A Phase IIIB, Multi-Center, Open Label Study For Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer Treated With Everolimus (RAD001) in Combination With Exemestane: 4EVER - Efficacy, Safety, Health Economics, Translational Research

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01626222
• Other study ID #: CRAD001JDE49
• Status: Completed
• Phase: Phase 3
• First received: June 20, 2012
• Last updated: February 21, 2017
• Start date: June 2012
• Est. completion date: November 2013

Study information

• Verified date: February 2017
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The present multi-center, open-label, single-arm study aims to evaluate the efficacy and safety, quality of life and health resources utilization in postmenopausal women with hormone receptor positive breast cancer progressing following prior therapy with non-steroidal aromatase inhibitors (NSAI) treated with the combination of Everolimus and Exemestane.

Description:

In light of the need for new treatment options for postmenopausal, hormone receptor positive, HER2 negative women after failure of prior non-steroidal aromatase inhibitor (NSAI) therapy, the BOLERO-2 trial was performed and demonstrated significant efficacy of the combinatorial treatment of Everolimus and Exemestane compared to an Exemestane monotherapy in this setting.

In this randomized, double blind, placebo-controlled trial a statistically significant improvement in progression-free survival (PFS) by adding Everolimus to exemestane versus Exemestane alone was reported. Adding Everolimus determined a 2.4-fold prolongation in PFS from 3.2 up to 7.4 months and so lowered the risk of cancer progression by 56% for these women. These findings were confirmed by an independent assessment (4.1 vs. 11.0 months, risk reduction: 64%). The quality of life data shows positive trend in the Everolimus plus Exemestane treatment arm. (Baselga 2011, Hortobagyi 2011). Thus, the benefit of the combinatorial treatment versus Exemestane monotherapy was shown in a defined patient population under controlled conditions.

The primary objective of this trial to assess the Overall Response Rate (ORR) in postmenopausal women with hormone receptor positive breast cancer progressing following prior therapy with NSAIs treated with the combination of Everolimus and Exemestane. The secondary objectives include, Progression free survival (PFS), Overall survival (OS), Safety, Change in Quality of life scores over time, Health resource utilization. The exploratory objectives reflect scientific interest within the treatment of metastatic breast cancer and are to be modified, if applicable, according to the current scientific state of the art at the time of actual analysis. These include: the influence of age, performance status, cancer activity and inflammation on anxiety and depression; changes in serum bone-turnover biomarkers; Pharmacogenetics of Everolimus in patients with advanced breast cancer; presence and molecular characteristics of Circulating Tumor Cells; correlation of response to Exemestane/Everolimus with Proteomic analysis.

The present national, multi-center, open-label, single-arm study aims to evaluate the efficacy and safety, quality of life and health resources utilization of the combination of Everolimus and Exemestane in a broader patient population compared to BOLERO-2, i.e. without limitations as to the number of previous chemotherapy lines, the time point of progression after NSAI therapy, and the previous endocrine therapy as patients under Exemestane monotherapy may be enrolled. Since the combination was shown to significantly improve PFS in the previous BOLERO-2 trial, for ethical reasons no endocrine comparator drugs will be investigated in the present study, due to the low efficacy of Exemestane monotherapy (PFS 3.2 months).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 301
• Est. completion date: November 2013
• Est. primary completion date: November 2013
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Main Inclusion criteria:

Metastatic or locally advanced breast cancer not amenable to curative treatment by surgery or radiotherapy or any other non-systemic treatment.

Histological or cytological confirmation of estrogen receptor positive (ER+) and/or progesterone receptor positive (PgR+), human epidermal growth factor receptor 2 (HER2) negative breast cancer Postmenopausal women. Disease progression following prior therapy with non steroidal aromatase inhibitors (NSAI), defined as: Recurrence while on, or following completion of an adjuvant treatment with Letrozole or Anastrozole, or Progression while on or following completion of Letrozole or Anastrozole treatment for ABC/MBC.

Radiological evidence of recurrence or progression on last systemic therapy prior to enrollment.

Patients must have at least one lesion that can be accurately measured or bone lesions:

lytic or mixed (lytic + sclerotic) in the absence of measurable disease.

Written informed consent obtained before any screening procedure and according to local guidelines.

Other protocol defined inclusion criteria apply.

Main Exclusion criteria:

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

Patients with only non-measurable lesions other than bone metastasis (e.g. pleural effusion, ascites etc.).

Previous treatment with mTOR inhibitors or known hypersensitivity to mTOR inhibitors.

Symptomatic brain or other CNS metastases. Previously treated brain metastases are allowed provided the patient is free of symptoms, prior radiotherapy for brain metastasis was more than four weeks before enrollment and the dose of corticosteroids is low (i.e. = 10 mg/d Prednisolone equivalent) and stable for at least two weeks prior to enrollment.

Patients with Hepatitis B or C or with a history of Hepatitis B or C. Patients unwilling to or unable to comply with the protocol. Other protocol defined exclusion criteria apply.

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

Drug:
• Exemestane
Exemestane is supplied by Novartis until Everolimus is commercially available for the study setting. Afterwards the investigator will prescribe Exemestane according to the individual label. Commercially available Exemestane will be supplied as tablets of 25 mg strength for oral administration. Complete guidelines for management and administration of Exemestane can be found in the package insert. Exemestane will be dosed starting on treatment Day 1. Patients will be instructed to take 1 tablet of 25 mg Exemestane orally. Package insert instructions should be followed. On the first day of each cycle, patients will receive an adequate drug supply (before commercial availability) or a prescription (after commercial availability) for self-administration at home. The investigator must emphasize compliance and will instruct the patient to take Exemestane exactly as prescribed.
• Everolimus (RAD001)
Everolimus (RAD001) is supplied by Novartis until Everolimus is commercially available for the study setting. Afterwards the investigator will prescribe Everolimus according to the individual label. Everolimus is formulated as tablets of 10 and 5 mg strength for oral administration. All study medication will be packaged into blister packs. The blisters should be opened only at the time of administration, as the drugs are both hygroscopic and light sensitive. Everolimus will be dosed starting on treatment Day 1. Patients will be instructed to take 1 tablet × 10 mg Everolimus orally with a large glass of water once daily at the same time each day with or without food. On the first day of each cycle, patients will receive an adequate drug supply (before commercial availability) or a prescription (after commercial availability) for self-administration at home. The investigator must emphasize compliance and will instruct the patient to take Everolimus exactly as prescribed.

Locations

Country	Name	City	State
Germany	Novartis Investigative Site	Aachen
Germany	Novartis Investigative Site	Amberg
Germany	Novartis Investigative Site	Augsburg
Germany	Novartis Investigative Site	Augsburg
Germany	Novartis Investigative Site	Bergisch Gladbach
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Böblingen
Germany	Novartis Investigative Site	Bochum
Germany	Novartis Investigative Site	Bonn
Germany	Novartis Investigative Site	Bonn
Germany	Novartis Investigative Site	Bottrop
Germany	Novartis Investigative Site	Braunschweig
Germany	Novartis Investigative Site	Bremen
Germany	Novartis Investigative Site	Chemnitz
Germany	Novartis Investigative Site	Donauwoerth
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Duesseldorf
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Esslingen
Germany	Novartis Investigative Site	Eutin
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Freiburg
Germany	Novartis Investigative Site	Fuerstenwalde
Germany	Novartis Investigative Site	Fuerth
Germany	Novartis Investigative Site	Fulda
Germany	Novartis Investigative Site	Gera
Germany	Novartis Investigative Site	Gerlingen
Germany	Novartis Investigative Site	Goslar
Germany	Novartis Investigative Site	Gütersloh
Germany	Novartis Investigative Site	Halle
Germany	Novartis Investigative Site	Halle/'Saale
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Jena
Germany	Novartis Investigative Site	Kassel
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Kiel
Germany	Novartis Investigative Site	Koeln
Germany	Novartis Investigative Site	Köln
Germany	Novartis Investigative Site	Langen
Germany	Novartis Investigative Site	Lemgo
Germany	Novartis Investigative Site	Lüneburg
Germany	Novartis Investigative Site	Magdeburg
Germany	Novartis Investigative Site	Mainz
Germany	Novartis Investigative Site	Mannheim
Germany	Novartis Investigative Site	Marburg
Germany	Novartis Investigative Site	Memmingen
Germany	Novartis Investigative Site	Mönchengladbach
Germany	Novartis Investigative Site	Muelheim
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Muenchen
Germany	Novartis Investigative Site	Muenster
Germany	Novartis Investigative Site	Mühlhausen
Germany	Novartis Investigative Site	München
Germany	Novartis Investigative Site	Nuernberg
Germany	Novartis Investigative Site	Oldenburg
Germany	Novartis Investigative Site	Plauen-Kauschwitz
Germany	Novartis Investigative Site	Ravensburg
Germany	Novartis Investigative Site	Recklinghausen
Germany	Novartis Investigative Site	Rosenheim
Germany	Novartis Investigative Site	Rostock
Germany	Novartis Investigative Site	Singen
Germany	Novartis Investigative Site	Soest
Germany	Novartis Investigative Site	Speyer
Germany	Novartis Investigative Site	Stralsund
Germany	Novartis Investigative Site	Stuttgart
Germany	Novartis Investigative Site	Trier
Germany	Novartis Investigative Site	Troisdorf
Germany	Novartis Investigative Site	Tuebingen
Germany	Novartis Investigative Site	Velbert
Germany	Novartis Investigative Site	Villingen-Schwenningen
Germany	Novartis Investigative Site	Weißenfels
Germany	Novartis Investigative Site	Wuppertal

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response Rate (ORR) after 24 weeks of treatment	The Overall response rate (ORR) is the proportion of patients with a best overall response of confirmed complete (CR) or partial (PR) response by Week 24. The best overall response is determined from the sequence of investigator overall lesion responses according to RECIST 1.1. To be assigned a best overall response of CR at least two determinations of CR at least 4 weeks apart before progression are required. To be assigned a best overall response of PR at least two determinations of PR or better at least 4 weeks apart before progression (and not qualifying for a CR) are required.	24 weeks
Secondary	Progression free survival (PFS) after 48 weeks of treatment	Progression-free survival (PFS) is the time from date of start of treatment to the date of event defined as the first documented progression or death due to any cause. If a patient has not had an event, progression-free survival is censored at the date of last adequate tumor assessment.	48 weeks
Secondary	Overall Response Rate (ORR) after 48 weeks of treatment	The ORR by Week 48 will be derived from the sequence of overall lesion responses as described for the primary efficacy variable. The ORR by Week 48 will be summarized using frequency tables presenting absolute and relative frequencies together with appropriate confidence intervals	48 weeks
Secondary	Overall survival (OS) after 48 weeks of treatment	Overall survival (OS) is defined as the time from date of start of treatment to date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of last contact. OS will be summarized using the Kaplan-Meier method.	48 weeks
Secondary	Safety within 48 weeks of treatment	The assessment of safety will be based mainly on the frequency of adverse events and on the number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g. vital signs, and special tests) will be considered as appropriate. For all safety analyses, the safety set will be used.	48 weeks
Secondary	Resource utilization	Data relating to Resource Utilization will be used for the purpose of economic evaluation, which will be carried out and reported as a separate activity.; The study population receiving RAD001 plus Exemestane will be compared to alternative cohorts (e.g., purely endocrine treatment with Fulvestrant monotherapy, Exemestane monotherapy or chemotherapy, e.g. Capecitabine) using a Markov model. For each alternative therapy option, median PFS, OS and health-related quality of life will be determined by a systematic review of literature or databases.	48 weeks
Secondary	Health-related quality of life	Health-related quality of life (HRQoL) will be assessed using the EORTC QLQ-C30 and BR23 questionnaires and the EuroQoL EQ-5D questionnaire. The HADS D questionnaire will be used to assess anxiety and depression. Scoring will follow the instructions of the respective manuals.	48 weeks

External Links

•   Abstract (Embase Number 71097997)
•   Results for CRAD001JDE49 from the Novartis Cliniccal Trials website