MACS2096: 4EVER - Efficacy, Safety, Health Economics, Translational Research of Postmenopausal Women With Estrogen Receptor Positive Locally Advanced or Metastatic Breast Cancer

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Completed

CT.gov ID

NCT01626222

Collaborator

(none)

301

Enrollment

Locations

Arm

Duration (Months)

3.6

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Breast Cancer	Drug: Exemestane Drug: Everolimus (RAD001)	Phase 3

Detailed 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).

Study Design

Study Type:

Interventional

Actual Enrollment :

301 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Study Start Date :

Jun 1, 2012

Actual Primary Completion Date :

Nov 1, 2013

Actual Study Completion Date :

Nov 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Everolimus & Exemestane This study will be performed in 300 postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer progressing following prior therapy with non-steroidal aromatase inhibitors (NSAI) as defined by: 1. Recurrence while on or after completion of an adjuvant treatment including Letrozole or Anastrozole, or 2. Progression while on or following the completion of Letrozole or Anastrozole treatment for locally advanced or metastatic breast cancer. Except for prior use of mTOR inhibitors, there are no restrictions as to the last anticancer treatment prior to enrollment. Patients must have documented evidence of recurrence or progression on last therapy prior to enrollment. Written informed consent must be obtained prior to any screening procedures. The investigator or designee must ensure that only patients who meet all the following inclusion and none of the exclusion criteria are offered enrollment in the study.	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. Drug: 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.

Arm

Intervention/Treatment

Experimental: Everolimus & Exemestane

This study will be performed in 300 postmenopausal women with hormone receptor positive locally advanced or metastatic breast cancer progressing following prior therapy with non-steroidal aromatase inhibitors (NSAI) as defined by: 1. Recurrence while on or after completion of an adjuvant treatment including Letrozole or Anastrozole, or 2. Progression while on or following the completion of Letrozole or Anastrozole treatment for locally advanced or metastatic breast cancer. Except for prior use of mTOR inhibitors, there are no restrictions as to the last anticancer treatment prior to enrollment. Patients must have documented evidence of recurrence or progression on last therapy prior to enrollment. Written informed consent must be obtained prior to any screening procedures. The investigator or designee must ensure that only patients who meet all the following inclusion and none of the exclusion criteria are offered enrollment in the study.

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.

Drug: 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.

Outcome Measures

Primary Outcome Measures

Overall Response Rate (ORR) after 24 weeks of treatment [24 weeks]
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.

Secondary Outcome Measures

Progression free survival (PFS) after 48 weeks of treatment [48 weeks]
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.
Overall Response Rate (ORR) after 48 weeks of treatment [48 weeks]
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
Overall survival (OS) after 48 weeks of treatment [48 weeks]
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.
Safety within 48 weeks of treatment [48 weeks]
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.
Resource utilization [48 weeks]
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.
Health-related quality of life [48 weeks]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Novartis Investigative Site	Aachen	Germany	52074
2	Novartis Investigative Site	Amberg	Germany	92224
3	Novartis Investigative Site	Augsburg	Germany	86150
4	Novartis Investigative Site	Augsburg	Germany	86156
5	Novartis Investigative Site	Bergisch Gladbach	Germany	51465
6	Novartis Investigative Site	Berlin	Germany	10367
7	Novartis Investigative Site	Berlin	Germany	10707
8	Novartis Investigative Site	Berlin	Germany	12203
9	Novartis Investigative Site	Berlin	Germany	12552
10	Novartis Investigative Site	Berlin	Germany	12683
11	Novartis Investigative Site	Berlin	Germany	14169
12	Novartis Investigative Site	Berlin	Germany	14195
13	Novartis Investigative Site	Bochum	Germany	44787
14	Novartis Investigative Site	Bonn	Germany	53105
15	Novartis Investigative Site	Bonn	Germany	53111
16	Novartis Investigative Site	Bottrop	Germany	46236
17	Novartis Investigative Site	Braunschweig	Germany	38100
18	Novartis Investigative Site	Bremen	Germany	28209
19	Novartis Investigative Site	Böblingen	Germany	71032
20	Novartis Investigative Site	Chemnitz	Germany	09113
21	Novartis Investigative Site	Donauwoerth	Germany	86609
22	Novartis Investigative Site	Dresden	Germany	01127
23	Novartis Investigative Site	Duesseldorf	Germany	40225
24	Novartis Investigative Site	Erlangen	Germany	91054
25	Novartis Investigative Site	Essen	Germany	45136
26	Novartis Investigative Site	Essen	Germany	45147
27	Novartis Investigative Site	Esslingen	Germany	73730
28	Novartis Investigative Site	Eutin	Germany	23701
29	Novartis Investigative Site	Frankfurt	Germany	60389
30	Novartis Investigative Site	Frankfurt	Germany	60590
31	Novartis Investigative Site	Freiburg	Germany	79106
32	Novartis Investigative Site	Fuerstenwalde	Germany	15517
33	Novartis Investigative Site	Fuerth	Germany	90766
34	Novartis Investigative Site	Fulda	Germany	36043
35	Novartis Investigative Site	Gera	Germany	07548
36	Novartis Investigative Site	Gerlingen	Germany	70839
37	Novartis Investigative Site	Goslar	Germany	38642
38	Novartis Investigative Site	Gütersloh	Germany	33332
39	Novartis Investigative Site	Halle/'Saale	Germany	06120
40	Novartis Investigative Site	Halle	Germany	06110
41	Novartis Investigative Site	Hamburg	Germany	20249
42	Novartis Investigative Site	Hannover	Germany	30177
43	Novartis Investigative Site	Heidelberg	Germany	69120
44	Novartis Investigative Site	Jena	Germany	07740
45	Novartis Investigative Site	Kassel	Germany	34125
46	Novartis Investigative Site	Kiel	Germany	24103
47	Novartis Investigative Site	Kiel	Germany	24105
48	Novartis Investigative Site	Koeln	Germany	50935
49	Novartis Investigative Site	Köln	Germany	50937
50	Novartis Investigative Site	Langen	Germany	63225
51	Novartis Investigative Site	Lemgo	Germany	32657
52	Novartis Investigative Site	Lüneburg	Germany	21339
53	Novartis Investigative Site	Magdeburg	Germany	39120
54	Novartis Investigative Site	Mainz	Germany	55131
55	Novartis Investigative Site	Mannheim	Germany	68165
56	Novartis Investigative Site	Marburg	Germany	35039
57	Novartis Investigative Site	Memmingen	Germany	87700
58	Novartis Investigative Site	Muelheim	Germany	45468
59	Novartis Investigative Site	Muenchen	Germany	80637
60	Novartis Investigative Site	Muenchen	Germany	81241
61	Novartis Investigative Site	Muenchen	Germany	81377
62	Novartis Investigative Site	Muenster	Germany	48149
63	Novartis Investigative Site	Mönchengladbach	Germany	41061
64	Novartis Investigative Site	Mühlhausen	Germany	99974
65	Novartis Investigative Site	München	Germany	80638
66	Novartis Investigative Site	Nuernberg	Germany	90403
67	Novartis Investigative Site	Oldenburg	Germany	26121
68	Novartis Investigative Site	Plauen-Kauschwitz	Germany	08525
69	Novartis Investigative Site	Ravensburg	Germany	88214
70	Novartis Investigative Site	Recklinghausen	Germany	45657
71	Novartis Investigative Site	Rosenheim	Germany	83022
72	Novartis Investigative Site	Rostock	Germany	18057
73	Novartis Investigative Site	Singen	Germany	78224
74	Novartis Investigative Site	Soest	Germany	59494
75	Novartis Investigative Site	Speyer	Germany	67346
76	Novartis Investigative Site	Stralsund	Germany	18435
77	Novartis Investigative Site	Stuttgart	Germany	70178
78	Novartis Investigative Site	Trier	Germany	54290
79	Novartis Investigative Site	Troisdorf	Germany	53840
80	Novartis Investigative Site	Tuebingen	Germany	72076
81	Novartis Investigative Site	Velbert	Germany	42551
82	Novartis Investigative Site	Villingen-Schwenningen	Germany	78052
83	Novartis Investigative Site	Weißenfels	Germany	06667
84	Novartis Investigative Site	Wuppertal	Germany	42105