Postoperative Use of Zoledronic Acid in Breast Cancer Patients After Neoadjuvant Chemotherapy

Breast Cancer Clinical Trial

— NATAN  

Official title:

A Randomized, Multicenter, Open Phase III Study Comparing the Postoperative Use of Zoledronic Acid Versus no Treatment in Patients With Histological Tumor Residuals After Preoperative Anthracycline and Taxane Containing Chemotherapy for Primary Breast Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00512993
• Other study ID #: GBG 36
• Secondary ID: NATANABCSG 29
• Status: Completed
• Phase: Phase 3
• First received: August 3, 2007
• Last updated: March 4, 2015
• Start date: December 2004
• Est. completion date: November 2013

Study information

• Verified date: March 2015
• Source: German Breast Group
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine the event-free survival (EFS) after zoledronic acid for 5 years versus no postoperative treatment in patients with "chemo-insensitive" breast cancer (ypT1-4 and/or ypN1-3) after preoperative anthracycline/taxane containing chemotherapy

Description:

The study is restricted to patients having had primary systemic chemotherapy for stage II and III breast cancer. Participation in a preoperative chemotherapy trial investigating anthracycline and taxane based regimen is allowed, but not mandatory for all patients. Patients must have significant remaining tumor tissue in the breast and/or axillary lymph node. This implies resistance to further chemotherapy and a clinically relevant risk for relapse. Bisphosphonates have a distinct mechanism of action and have demonstrated efficacy in the treatment of breast cancer with metastasis to the bone as well as adjuvant treatment after surgery of primary breast cancer. The 3rd generation bisphosphonate zoledronic acid has a favorable toxicity profile and can be conveniently given to patients over a long term period.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 654
• Est. completion date: November 2013
• Est. primary completion date: November 2013
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Written informed consent must be obtained and documented according to the local regulatory requirements prior to beginning specific protocol procedures;

• Complete baseline documentation sent to GBG;

• Prior preoperative chemotherapy for at least 4 cycles, of which at least two must contain a taxane and an anthracycline;

• Completely resected unilateral or bilateral primary carcinoma of the breast with histologically detectable tumor residuals (ypT1-4) and/or histology confirmed involvement of axillary nodes (ypN1-3). Sentinel node biopsy is allowed, but complete axillary clearance is mandatory in node positive cases;

• A maximum interval of 3 years from date of axillary surgery to entering this trial;

• Age 18 years or older;

• Karnofsky index >= 70%;

• Life expectancy of at least 10 years, disregarding the diagnosis of cancer;

• No clinical evidence of local recurrence or distant metastases. Complete staging work-up: All patients must have breast ultrasound, chest X-ray, ultrasound or CT scan of the liver within 3 months prior to registration, as well as (bilateral) mammography or breast MRI and bone scan within 8 months prior to registration. In case of a positive bone scan, bone X-ray is mandatory. Other tests may be performed as clinically indicated;

• Adequate renal and hepatic function (serum creatinine, bilirubin, and transaminases within 1.5 × upper normal range);

• Patients must be available and compliant for treatment and follow-up. Patients registered on this trial must be treated and followed up at the participating center.

Exclusion Criteria:

• Known hypersensitivity reaction to the investigational compound;

• Prior postoperative chemotherapy;

• Prior treatment with bisphosphonates since breast cancer surgery;

• Pregnant or lactating patients. Patients of childbearing potential must have a negative pregnancy test (urine or serum) within 14 days prior to registration and must implement adequate non-hormonal contraceptive measures (barrier methods, intra uterine contraceptive devices, sterilization) during study treatment;

• History of diseases with influence on bone metabolism, such as Paget's disease of bone and primary hyperparathyroidism or osteoporosis requiring treatment at the time of study entry or considered likely to become necessary within the six months

• Other serious illness or medical condition that may interfere with the understanding and giving of informed consent and the conduct of the study

• Prior or concomitant secondary malignancy (except non-melanomatous skin cancer or carcinoma in situ of the uterine cervix)

• Concurrent treatment with other experimental drugs or any other anti-cancer therapy;

• Abnormal renal function as evidenced by a calculated creatinine clearance < 30 ml/minute;

• Serum calcium concentration < 8.0 mg/dl (2.00 mmol/L) or > 12.0 mg/dl (3.00 mmol/L)

• Concurrent treatment with sex hormones. Prior treatment must be stopped before study entry;

• Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw, of exposed bone in the mouth, or of slow healing after dental procedures.

• Recent (within 6 weeks) or planned dental or jaw surgery (e.g.. extraction, implants)

• Male patients.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• Zoledronic acid
Infusion of zoledronic acid (4 mg) every 4 weeks for six doses, followed by every 3 months for 8 doses, followed by every 6 months for 5 doses

Locations

Country	Name	City	State
Austria	LKH-Univ. Klinikum Graz, Onkologie	Graz	Styria
Austria	Universitäts Klinikum Innsbruck	Innsbruck	Tirol
Austria	Allgemeines Krankenhaus der Stadt Linz, Innere Medizin 3/Zentrum f. Häm. u. Med. Onkologie	Linz	Upper Austria
Austria	Landeskrankenhaus Feldkirch	Rankweil	Vorarlberg
Austria	LKH Salzburg, Uni.klinik f. Innere Med. III/Onkol. Amb.	Salzburg
Austria	A. ö. Krankenhaus der Barmherzigen Brüder, Interne Abteilung	St. Veit a. d. Glan	Carinthia
Austria	Landeskrankenhaus Steyr, 2. Med. Abt. Onkologie	Steyr	Upper Austria
Austria	Klinikum Wels-Grieskirchen GmbH, Abt. f. Innere Medizin IV	Wels	Upper Austria
Austria	Medizinische Universität Wien	Wien	Lower Austria
Austria	Landeskrankenhaus Wolfsberg, Chirurgische Abteilung	Wolfsberg	Carinthia
Germany	Ostalb-Klinikum, ABC Brustzentrum, Frauenklinik	Aalen	Baden-Württemberg
Germany	DRK Kliniken Köpenick, Frauenklinik	Berlin
Germany	Praxisklinik, Krebsheilkunde für Frauen / Brustzentrum	Berlin
Germany	Schwerpunktpraxis Gynäkologie, Onkologie, Naturheilverfahren	Berlin-Tempelhof	Berlin
Germany	Praxis Dr. Gottschalk, Fachärztin für Frauenheilkunde und Geburtshilfe	Bernau	Brandenburg
Germany	Onkologische Schwerpunktpraxis, Dres. Schäfer / Just / Görner	Bielefeld	Nordrhein-Westfalen
Germany	Klinikum Sindelfingen-Böblingen / Kliniken Böblingen, Frauenklinik	Böblingen	Baden-Württemberg
Germany	Praxis für Innere Medizin, Hämatologie, internistische Onkologie	Bochum	Nordrhein-Westfalen
Germany	Evangelisches Diakonie-Krankenhaus, Frauenklinik	Bremen
Germany	Onkologische Schwerpunktpraxis	Bremen
Germany	Allgm. Krankenhaus Celle, Frauenklinik	Celle	Niedersachsen
Germany	Klinikum Chemnitz gGmbH, Frauenklinik	Chemnitz	Sachsen
Germany	Onkologische Schwerpunktpraxis Dr. Glados, Hämatologie / Internistische Onkologie	Coesfeld	Nordrhein-Westfalen
Germany	Krankenhaus Cuxhaven, Frauenklinik	Cuxhaven	Niedersachsen
Germany	Gemeinschaftspraxis, Fachärzte für Innere Medizin, Hämatologie und Internistische Onkologie	Dresden	Sachsen
Germany	Technische Universität Dresden	Dresden	Sachsen
Germany	Luisenkrankenhaus, Senologie, Brustzentrum	Düsseldorf	Nordrhein-Westfalen
Germany	Kreiskrankenhaus Ebersberg, Gynäkologisch-onkologische Abteilung	Ebersberg	Bayern
Germany	Hermann-Josef Krankenhaus, Frauenklinik	Erkelenz	Nordrhein-Westfalen
Germany	Universitätsklinikum Erlangen, Frauenklinik mit Poliklinik	Erlangen	Bayern
Germany	St. Antonius Hospital, Klinik für Hämatologie u. Onkologie	Eschweiler	Nordrhein-Westfalen
Germany	Alfried-Krupp-Krankenhaus, Frauenklinik	Essen	Nordrhein-Westfalen
Germany	Gynäkologische Praxis Dr. Deertz	Essen	Nordrhein-Westfalen
Germany	Marienhospital Altenessen	Essen	Nordrhein-Westfalen
Germany	Universitätsklinikum Essen, Klinik für Frauenheilkunde und Geburtshilfe	Essen	Nordrhein-Westfalen
Germany	Onkologie Bethanien, Onkologie / Tagesklinik	Frankfurt	Hessen
Germany	St. Markus Krankenhaus, Frauenklinik	Frankfurt	Hessen
Germany	Städt. Kliniken Frankfurt-Höchst, Frauenklinik	Frankfurt/Höchst	Hessen
Germany	Intern. Gemeinschaftspraxis	Friedrichshafen
Germany	Schwerpunktpraxis der Gynäkologie und Onkologie	Fuerstenwalde	Brandenburg
Germany	SRH Wald-Klinikum Gera gGmbH, Brustzentrum Ostthüringen	Gera	Thüringen
Germany	Kreiskrankenhaus Gifhorn, Interdisziplinäres Brustzentrum	Gifhorn	Niedersachsen
Germany	Onkologische Schwerpunktpraxis Dr. Tessen	Goslar	Niedersachsen
Germany	Universität Greifswald, Klinik für Frauenheilkunde und Geburtshilfe	Greifswald	Mecklenburg-Vorpommern
Germany	Krankenhaus St. Elisabeth und St. Barbara Halle, Klinik für Gynäkologie und Geburtshilfe	Halle / Saale	Sachsen-Anhalt
Germany	Facharzt für Frauenheilkunde und Geburtshilfe	Hamburg
Germany	Kreiskrankenhaus Hameln, Brustzentrum	Hameln	Niedersachsen
Germany	Klinikum Stadt Hanau	Hanau	Hessen
Germany	Henriettenstiftung	Hannover	Niedersachsen
Germany	Vinzenzkrankenhaus, Gynäkologie	Hannover	Niedersachsen
Germany	Marienhospital Herne, Onkologische / Hämatologische Ambulanz	Herne	Nordrhein-Westfalen
Germany	Gemeinschaftspraxis Gynäkologie	Hildesheim	Niedersachsen
Germany	Elisabeth-Hospital, Frauenklinik	Ibbenbüren	Nordrhein-Westfalen
Germany	Facharzt für Frauenheilkunde und Geburtshilfe	Ilsede	Niedersachsen
Germany	Universitätsklinikum, Klinik für Frauenheilkunde und Geburtshilfe	Jena	Thüringen
Germany	St. Vincentius Kliniken Karlsruhe	Karlsruhe	Baden-Württemberg
Germany	Klinikum Kassel GmbH, Gynäkologische Ambulanz	Kassel	Hessen
Germany	Universitätsklinikum Schleswig-Holstein Campus Kiel	Kiel	Schleswig-Holstein
Germany	Klinikum der Universität zu Köln	Köln	Nordrhein-Westfalen
Germany	Klinikum der Universität zu Köln, Klinik und Poliklinik für Gyn. und Geburtshilfe	Köln	Nordrhein-Westfalen
Germany	St. Elisabeth-KKH, Brustzentrum Koeln-Hohenlind	Köln	Nordrhein-Westfalen
Germany	Asklepios Klinik, Frauenklinik	Langen	Hessen
Germany	Asklepios-Klinik Lich, Frauenklinik	Lich	Hessen
Germany	St. Vincenz Krankenhaus, Frauenklinik	Limburg	Hessen
Germany	Onkol. Schwerpunktpraxis Dr. Knoblich	Lörrach	Baden-Württemberg
Germany	Universitätsklinikum Schleswig-Holstein	Lübeck	Schleswig-Holstein
Germany	Schwerpunktpraxis, Internistisch-gynäkolog.-onkolog.	Lüneburg	Niedersachsen.
Germany	Klinikum der Otto-v.-Guericke-Universität, Frauenklinik	Magdeburg	Sachsen-Anhalt
Germany	St. Vincenz und Elisabeth-Hospital	Mainz	Rheinland-Pfalz
Germany	Uniklinikum, Klinik für Geburtshilfe und Gynäkologie	Mainz	Rheinland-Pfalz
Germany	Universitätsklinikum Mannheim, Frauenklinik	Mannheim	Baden-Württemberg
Germany	Universitätsklinikum, Frauenklinik / Mutter-Kind-Zentrum	Marburg	Hessen
Germany	GBG Forschungs GmbH	Neu-Isenburg	Hessen
Germany	Dietrich-Bonhoeffer Klinikum, Frauenklinik	Neubrandenburg	Mecklenburg-Vorpommern
Germany	Krankenhaus Neunkirchen gGmbH, Frauenklinik	Neunkirchen	Saarland
Germany	Ruppiner Kliniken, Frauenklinik	Neuruppin	Brandenburg
Germany	Ostholstein Kliniken GmbH Klinik Oldenburg, Zentrum für Gynäkologie und Geburtshilfe Sana Kliniken Ostholstein	Oldenburg	Schleswig-Holstein
Germany	Krankenhaus Siloah, Gynäkologie und Geburtshilfe	Pforzheim	Baden-Württemberg
Germany	Klinikum Quedlinburg, Frauenklinik	Quedlinburg	Sachsen-Anhalt
Germany	Caritas-Krankenhaus St. Josef, Klinik für Frauenheilkunde und Geburtshilfe	Regensburg	Bayern
Germany	Klinikum am Steinenberg	Reutlingen	Baden-Württemberg
Germany	Frauenklinik Rheinfelden	Rheinfelden	Baden-Württemberg
Germany	Klinikum Rosenheim, Abt. Gynäkologie u. Geburtshilfe	Rosenheim	Bayern
Germany	Klinikum Südstadt, Universitätsfrauenklinik	Rostock	Mecklenburg-Vorpommern
Germany	Krankenhaus Salzwedel	Salzwedel
Germany	Klinikum Schaumburg, Kreiskrankenhaus Stadthagen, Gynäkologie und Geburtshilfe	Stadhagen	Niedersachsen
Germany	Johanniter-Krankenhaus Genthin-Stendal GmbH, Frauenheilkunde und Geburtshilfe	Stendal	Sachsen-Anhalt
Germany	Krankenhaus Bad Cannstatt, Frauenklinik	Stuttgart	Baden-Württemberg
Germany	Universitätsklinikum Tübingen, Frauenklinik	Tübingen	Baden-Württemberg
Germany	Asklepios Paulinen Klinik, Frauenklinik	Wiesbaden	Hessen
Germany	Dr.-Horst-Schmidt-Kliniken GmbH, Klinik f. Gyn. und gyn. Onkologie	Wiesbaden	Hessen
Germany	St. Josefs-Hospital, Gynäkologie und Geburtshilfe	Wiesbaden	Hessen
Germany	Marienhospital Witten, Brustzentrum	Witten	Nordrhein-Westfalen

Sponsors (3)

Lead Sponsor	Collaborator
German Breast Group	Austrian Breast & Colorectal Cancer Study Group, Novartis Pharmaceuticals

Countries where clinical trial is conducted

Austria,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The event-free survival (EFS) after zoledronic acid for 5 years versus no postoperative treatment in patients with "chemo-insensitive" breast cancer (ypT1-4 and/or ypN1-3) after preoperative anthracycline/taxane containing chemotherapy.		5 years	No
Secondary	The overall survival in both treatment arms.		5 years	No
Secondary	The EFS with respect to the interval between surgery and randomization.		5 years	No
Secondary	The bone-metastasis free-survival in both arms.		5 years	No
Secondary	The toxicity of and compliance to zoledronic acid.		5 years	Yes
Secondary	The predictive value of primary breast tumor response on the effect of postoperative treatment.		5 years	No
Secondary	The prognostic impact of chemotherapy induced amenorrhea in premenopausal patients.		5 years	No

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