Bevacizumab + Endocrine Treatment vs Endocrine Treatment as First Line in Postmenopausal Women

NCT ID: NCT00545077

Last Updated: 2023-03-31

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 380 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-11-06
• Study Completion Date: 2014-07-24

Brief Summary

Locally advanced or metastatic breast cancer in postmenopausal women with negative Human Epidermal Growth Factor Receptor 2 (HER2), who are candidates for hormone treatment and who have not received previous chemotherapy or hormonotherapy for the metastatic disease.

Detailed Description

The main endpoint of the study is progression-free survival (PFS). It has been calculated that 378 patients will need to be included, according to the following assumptions:

• Recruitment period of 21 months.
• Minimum follow-up period of 9 months.
• PFS of 9 months in the control arm (letrozole in monotherapy). Using a two-sided log-rank test, for a 5% α level, 344 patients (172 in each treatment arm) will be required for 270 events to occur, which will provide an 80% power for detecting a hazard ratio of 0.69 (corresponding to a PFS median of 13 months in the bevacizumab arm). This sample size has been adjusted for an intermediate analysis when 2/3 of the total of required events have occurred. This intermediate analysis can be avoided if, at the time in which it must be carried out, it is estimated that the final analysis will be carried out in 4 months.

Taking into account a 10% percentage of losses, 378 patients are expected to be included in the study.

An intermediate safety evaluation will be carried out when 63 patients have finished their treatment in each treatment arm.

A multicenter, randomized phase III clinical trial. After verifying the selection criteria, the patients will be randomized to receive letrozole alone or in combination with bevacizumab. Before randomization, the patients will be stratified according to the following prognosis factors:

• Estrogen Receptor (ER)+ / Progesterone Receptor (PgR)+ vs the other options (ER+/PgR- vs ER-/PgR+)
• Previous adjuvant hormonotherapy (yes/no)
• Status: locally advanced vs metastatic.
• Measurable vs non measurable disease
• Visceral disease (yes/no)
• PFS.

Conditions

Breast Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm A: Endocrine Therapy (ET)

Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent.

Group Type: ACTIVE_COMPARATOR

Letrozole

Intervention Type: DRUG

Fulvestrant

Intervention Type: DRUG

Arm B: ET with Bevacizumab (ET-B)

Endocrine treatment consisting of either letrozole or fulvestrant. Patients will be randomized to receive bevacizumab 15mg/kg i.v. on day 1 every 3 weeks plus endocrine treatment or endocrine treatment as a single agent. The patients will receive the assigned treatment until the progression of the disease, unacceptable toxicity or withdrawal of the consent.

Group Type: EXPERIMENTAL

Letrozole

Intervention Type: DRUG

Bevacizumab

Intervention Type: DRUG

Fulvestrant

Intervention Type: DRUG

Interventions

Letrozole

Intervention Type: DRUG

Bevacizumab

Intervention Type: DRUG

Fulvestrant

Intervention Type: DRUG

Other Intervention Names

Femara; Avastin; Faslodex

Eligibility Criteria

Inclusion Criteria

1. Before starting the specific protocol procedures, the written informed consent must be obtained and documented.

2. Women ≥ 18 years.

3. Capacity to comply with all the protocol requirements.

4. Functional Eastern Cooperative Oncology Group (ECOG) status of 0 or 1.

5. Life expectancy ≥ 24 weeks.

6. Histologically confirmed breast adenocarcinoma, with measurable or non-measurable, locally advanced or metastatic (stage IV) disease. In the event that the patient only has locally advanced disease, she will not be able to undergo curative local treatment. Patients with metastasis confined to the bone can be chosen, but the disease must be confirmed by radiology, CT scan or Nuclear magnetic resonance (NMR) if there is any doubt after a single bone scan.

7. Patients with HER2-negative disease evaluated by Immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH)/Chromogenic in situ hybridisation (CISH) (IHC 0 or 1+, or 2+ and negative FISH). Patients with 3+ by IHC cannot be chosen regardless of the FISH/CISH status and those with positive FISH/CISH (> 2 amplifications) cannot be chosen either, regardless of the IHC findings.

8. Positive hormone receptors (estrogen receptor [ER] and/or progesterone receptor [PgR]) evaluated by a local or central laboratory, according to the criteria of the participating institution.

9. Patients who are candidates for receiving first-line treatment with letrozole.

10. Patients may have received (neo)adjuvant chemotherapy, provided that the last dose of the latter was received at least 12 months before randomization. Patients must be recovered from toxicity.

11. The patients are allowed to have received adjuvant radiotherapy, provided that it was completed at least 6 weeks before randomization and the patient has recovered from the reversible acute effects of the radiation. The previous administration of radiotherapy to palliate the pain of bone metastases is authorized, provided that:

• Not more than 30% of bone marrow has been irradiated.
• The patient has recovered from the reversible acute effects of the radiation.
• The patient has at least one metastatic location which has not been irradiated and which may be evaluated for progression, or a clear progression of the bone disease has been objectified after the end of the palliative radiotherapy.

12. The patients may have received any kind of previous (neo)adjuvant hormone therapy provided that they are considered to be candidates for first-line hormonotherapy with either letrozole or fulvestrant.

13. The treatment with bisphosphonates is allowed and recommended for patients with bone metastases. Whenever it is possible, the treatment should be started before or within the 4 weeks of starting the study therapy. The patients starting treatment with bisphosphonates must be carefully evaluated so that they do not mask the progression of the disease.

14. In the patients with heart failure risk (e.g. previously treated with > 360mg/m2 of doxorubicin or equivalent doses of other anthracyclines), the Left Ventricular Ejection Fraction (LVEF) must be determined by means of an echocardiogram or radionuclide ventriculography (MUGA), and it must t be > the lower limit of normal.

Exclusion Criteria

1. Evolutionary disease requiring an immediate treatment with cytotoxic chemotherapy according to the investigator's judgment.

2. Patients with locally advanced breast cancer who are expected to undergo surgery or curative radiotherapy.

3. Previous chemotherapy or hormonotherapy for the metastatic disease. Patients may have received neoadjuvant chemotherapy or neoadjuvant hormonotherapy with curative intention as a part or as an alternative to an adjuvant treatment. For the previous neoadjuvant hormonotherapy the same premises than for the adjuvant hormonotherapy are valid.

4. Previous therapy with anti-vascular endothelial growth factor (VEGF) or VEGF Receptor (VEGFR) tyrosine-kinase inhibitors.

5. History of another pathology that may affect the development of the protocol or the interpretation of results. It is considered that patients who have suffered from a skin carcinoma that is not melanoma, cervical carcinoma in situ or another neoplasia treated with a curative intention and with a disease-free interval exceeding 5 years can be chosen.

6. Evidence of central nervous system (CNS) metastasis. A CT scan or brain NMR must be done within the 4 weeks before the randomization in case of suspecting brain metastasis.

7. History or evidence in the physical or neurological examination of CNS pathology unrelated to cancer unless it is suitable treated with standard therapy (e.g. uncontrolled convulsions).

8. History of peripheral neuropathy National Cancer Institute (NCI) CTCAE grade >2 at the time of randomization.

9. Patients subjected to major surgical procedures, open biopsies or those having significant trauma injuries within the 28 days prior to randomization, or patients who are expected to undergo a major surgical procedure that must necessarily be performed within the course of the study.

10. Minor surgical procedures in the 7 days prior to randomization.

11. Unsuitable bone marrow supply: absolute neutrophil count (ANC) < 1.5 x 109/L, platelets < 100 x 109/L or Hb < 10 g/dL.

12. Impaired liver function: total bilirubin total > 1.5 x upper limit of normal (ULN), aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) > 2.5 x ULN (> 5 x ULN in patients with liver metastases).

13. Impaired kidney function:

1. Serum creatinine > 2.0 mg/dL or 177 µmol/L.

2. Proteinuria determined by reactive strip > 2+. A 24h determination of proteins in urine will be requested for the patients with > 2+ in the baseline analysis and must have a protein figure < 1 g/24 h.

14. Chronic treatment with oral corticoids (dose > 10 mg/day of methylprednisolone or equivalent): the use of inhaled corticoids is allowed.

15. Chronic treatment with acetylsalicylic acid (> 325 mg/day) or clopidogrel (> 75 mg/day).

16. Uncontrolled arterial hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) or clinically significant cardiovascular disease: for example cerebrovascular accident (CVA) (in the 6 months prior to randomization), coronaropathy or history of acute mycardial infarction (AMI) in the last 6 months, unstable angina, congestive heart failure of grade > II of the New York Heart Association (NYHA) or severe heart arrhythmias which are not controlled with medication or which can potentially interfere with the study treatment.

17. History or evidence of hemorrhagic diathesis or coagulopathy with bleeding risk.

18. History of abdominal fistula, gastrointestinal perforation or intra-abdominal abcess in the 6 months prior to randomization.

19. Active infection requiring i.v. antibiotics at the time of randomization.

20. Unhealed wounds, active peptic ulcer, esophageal varices.

21. Any other disease, psychological or metabolic alteration, found in the physical or laboratory examination, providing reasonable indications for suspecting a disease or complaint for which the use of any of the study drugs are contraindicated, or which may affect the patient's compliance with the routine procedures of the study or which places the patient at a high risk of experiencing complications related to the treatment.

22. Current or recent (within 30 days prior to that start of the study treatment) treatment with another drug under investigation or participation in another investigation study.

23. Known hypersensitivity to any of the study drugs or their components.

24. Hypersensitivity to the products of Chinese hamster ovary cells or to other human or humanized recombinant antibodies.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: collaborator

GBG Forschungs GmbH

OTHER

Sponsor Role: collaborator

Spanish Breast Cancer Research Group

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director

Role: STUDY_DIRECTOR

GBG Forschungs GmbH

Study Director

Role: STUDY_DIRECTOR

Hospital San Carlos, Madrid

Study Director

Role: STUDY_DIRECTOR

Hospital Provincial de Córdoba

Locations

Klinikum Bayreuth

Bayreuth, , Germany

Universitätsklinikum Charité

Berlin, , Germany

Praxisklinik

Berlin, , Germany

Praxis Dr. med. W. Schoenegg

Berlin, , Germany

Johanniter Krankenhaus

Bonn, , Germany

Klinikum Sindelfingen-Böblingen / Kliniken Böblingen

Böblingen, , Germany

Onkologische Schwerpunktpraxis

Bremen, , Germany

St. Elisabeth-KKH

Cologne, , Germany

Berufsausübungsgemeinschaft

Dresden, , Germany

Kliniken Essen-Mitte Evang. Huyssens-Stiftung/Knappschaft

Essen, , Germany

Universitätsklinikum Essen

Essen, , Germany

Kliniken Esslingen

Esslingen am Neckar, , Germany

Klinikum Fulda

Fulda, , Germany

Albertinen-Krankenhaus

Hamburg, , Germany

Kreiskrankenhaus Hameln

Hamelin, , Germany

Gynäkologisch-onkologische Praxis

Hanover, , Germany

Medizinische Hochschule Hannover

Hanover, , Germany

Praxisklinik - Dialysezentrum - Herne

Herne, , Germany

St. Vincentius Kliniken Karlsruhe

Karlsruhe, , Germany

Onkologische Schwerpunktpraxis

Kronach, , Germany

Caritas Krankenhaus Lebach

Lebach, , Germany

St. Vincenz Krankenhaus

Limburg, , Germany

St. Vincenz und Elisabeth-Hospital

Mainz, , Germany

Universitätsklinikum

Mainz, , Germany

Ev. Krankenhaus Bethesda

Mönchengladbach, , Germany

Universitätsklinikum

Münster, , Germany

Frauenklinik Rheinfelden

Rheinfelden, , Germany

Klinikum Rosenheim

Rosenheim, , Germany

Onkolog. Schwerpunktpraxis

Rosenheim, , Germany

Gemeinschaftspraxis für Gynäkologie und Geburtshilfe

Salzgitter, , Germany

Krankenhaus Weinheim

Weinheim, , Germany

Praxis Dres. Reichert und Janssen

Westerstede, , Germany

St. Josefs-Hospital

Wiesbaden, , Germany

Dr.-Horst-Schmidt-Kliniken GmbH

Wiesbaden, , Germany

Marienhospital Witten

Witten, , Germany

Onkologische Gemeinschaftspraxis

Würselen, , Germany

Hospital General de Elche

Elche, Alicante, Spain

Hospital Germans Trias i Pujol

Badalona, Badalona/Barcelona, Spain

Hospital Son Dureta

Palma de Mallorca, Balearic Islands, Spain

Instituto catalán de Oncología de Barcelona

L'Hospitalet de Llobregat, Barcelona, Spain

Xarxa Asistencial de Manresa

Manresa, Barcelona, Spain

Corporación Sanitaria Parc Taulí

Sabadell, Barcelona, Spain

Consorci Sanitari de Terrasa

Terrassa, Barcelona, Spain

Hospital Mutua de Terrasa

Terrassa, Barcelona, Spain

Hospital de Barbastro

Barbastro, Huesca, Spain

Fundación Hospital de Alcorcón

Alcorcón, Madrid, Spain

Hospital Universitario de Canarias

San Cristóbal de La Laguna, Santa Cruz De Tenerife, Spain

Complejo Hospitalario Universitario A Coruña

A Coruña, , Spain

Centro Oncológico de Galicia

A Coruña, , Spain

Hospital General de Alicante

Alicante, , Spain

Hospital Infanta Cristina de Badajoz

Badajoz, , Spain

Hospital del Mar

Barcelona, , Spain

Hospital Clinic i Provincial

Barcelona, , Spain

Hospital Provincial de Córdoba

Córdoba, , Spain

Instituto Catalan de Oncologia de Girona

Girona, , Spain

Complejo Hospitalario de Jaén

Jaén, , Spain

Hospital Arnau de Vilanova de Lérida

Lleida, , Spain

Hospital Gregorio Marañon

Madrid, , Spain

Hospital Ramón y Cajal

Madrid, , Spain

Hospital Clínico San Carlos

Madrid, , Spain

CIOCC Clara Campal

Madrid, , Spain

Hospital Universitario Virgen de la Victoria

Málaga, , Spain

Hospital Virgen de La Macarena

Seville, , Spain

Hospital Universitario Virgen del Rocío

Seville, , Spain

Hospital Virgen de la Salud

Toledo, , Spain

Hospital Universitario La Fe

Valencia, , Spain

Instituto Valenciano de Oncología

Valencia, , Spain

Hospital Clinico de Valencia

Valencia, , Spain

Hospital Clinico Universitario Valencia

Valencia, , Spain

Hospital Miguel Servet

Zaragoza, , Spain

Countries

Germany; Spain

References

Martin M, Loibl S, von Minckwitz G, Morales S, Martinez N, Guerrero A, Anton A, Aktas B, Schoenegg W, Munoz M, Garcia-Saenz JA, Gil M, Ramos M, Margeli M, Carrasco E, Liedtke C, Wachsmann G, Mehta K, De la Haba-Rodriguez JR. Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: the letrozole/fulvestrant and avastin (LEA) study. J Clin Oncol. 2015 Mar 20;33(9):1045-52. doi: 10.1200/JCO.2014.57.2388. Epub 2015 Feb 17.

Reference Type: RESULT

PMID: 25691671 (View on PubMed)

Martin M, Loibl S, Hyslop T, De la Haba-Rodriguez J, Aktas B, Cirrincione CT, Mehta K, Barry WT, Morales S, Carey LA, Garcia-Saenz JA, Partridge A, Martinez-Janez N, Hahn O, Winer E, Guerrero-Zotano A, Hudis C, Casas M, Rodriguez-Martin C, Furlanetto J, Carrasco E, Dickler MN; GEICAM Spanish Breast Cancer Group; GBG (German Breast Group); Alliance for Clinical Trials in Oncology (Alliance). Evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for hormone receptor-positive metastatic breast cancer: a pooled analysis from the LEA (GEICAM/2006-11_GBG51) and CALGB 40503 (Alliance) trials. Eur J Cancer. 2019 Aug;117:91-98. doi: 10.1016/j.ejca.2019.06.002. Epub 2019 Jul 2.

Reference Type: RESULT

PMID: 31276981 (View on PubMed)

Polley MC, Dickler MN, Sinnwell J, Tenner K, de la Haba J, Loibl S, Goetz MP, Bergh J, Roberston J, Couch F, Ellis MJ, Martin M. A clinical calculator to predict disease outcomes in women with hormone receptor-positive advanced breast cancer treated with first-line endocrine therapy. Breast Cancer Res Treat. 2021 Aug;189(1):15-23. doi: 10.1007/s10549-021-06319-z. Epub 2021 Jul 3.

Reference Type: RESULT

PMID: 34218359 (View on PubMed)

Related Links

http://www.geicam.org/

Spanish Breast Cancer Research Group (GEICAM) is a Spanish Breast Cancer Research Group

Other Identifiers

2007-002841-19

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

GEICAM/2006-11/GBG 51

Identifier Type: -

Identifier Source: org_study_id