2-arm Trial of Paclitaxel Plus Bevacizumab vs. Capecitabine Plus Bevacizumab

NCT ID: NCT00600340

Last Updated: 2019-12-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 564 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-04-30
• Study Completion Date: 2014-12-31

Brief Summary

First-line treatment of patients with locally recurrent or metastatic, HER2-negative breast cancer who have not received prior chemotherapy for locally recurrent or metastatic disease.

Detailed Description

Arm A:

Bevacizumab 10 mg/kg intravenous (i.v.), days 1 and 15, every 4 weeks

Paclitaxel 90 mg/m2, days 1, 8 and 15, every 4 weeks

Arm B:

Bevacizumab 15 mg/kg i.v., day 1, every 3 weeks

Capecitabine 1000 mg/m² twice-daily, days 1-14, every 3 weeks

In both arms treatment will be given until first disease progression (PD), unacceptable toxicity or withdrawal of patient consent.

For patients who stop chemotherapy for any reason before PD (e.g. toxicity) the other treatment should be given as monotherapy until PD.

Conditions

Metastatic Breast Cancer

Study Design

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

Study Groups

A Bev+Pac

Bevacizumab plus Paclitaxel

Group Type: ACTIVE_COMPARATOR

Bevacizumab and Paclitaxel

Intervention Type: BIOLOGICAL

A: Bevacizumab 10 mg/kg i.v., days 1 and 15, every 4 weeks Paclitaxel 90 mg/m2, days 1, 8 and 15, every 4 weeks

B Bev+Cap

Bevacizumab plus Capecitabine

Group Type: ACTIVE_COMPARATOR

Bevacizumab and Capecitabine

Intervention Type: BIOLOGICAL

B:Bevacizumab 15 mg/kg i.v., day 1, every 3 weeks Capecitabine twice-daily 1000 mg/m², day 1 to 14, every 3 weeks

Interventions

Bevacizumab and Paclitaxel

A: Bevacizumab 10 mg/kg i.v., days 1 and 15, every 4 weeks Paclitaxel 90 mg/m2, days 1, 8 and 15, every 4 weeks

Intervention Type: BIOLOGICAL

Bevacizumab and Capecitabine

B:Bevacizumab 15 mg/kg i.v., day 1, every 3 weeks Capecitabine twice-daily 1000 mg/m², day 1 to 14, every 3 weeks

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

1. Written informed consent obtained prior to any study-specific procedure.

2. Age ≥18 years.

3. Able to comply with the protocol.

4. Histologically or cytologically confirmed, HER2-negative, adenocarcinoma of the breast with measurable or non-measurable locally recurrent or metastatic disease, who are candidates for chemotherapy. Locally recurrent disease must not be amenable to radiotherapy or resection with curative intent.

5. Eastern Cooperative Oncology Group (ECOG) performance Status (PS) of 0-2.

6. Life expectancy more than 12 weeks.

7. Prior (neo)adjuvant chemotherapy is allowed provided that the last dose of chemotherapy was more than 6 months prior to randomization. However, if (neo)adjuvant chemotherapy was:

• Taxane-based, patients are eligible only if they received their last taxane more than 12 months prior to randomization.
• Anthracycline-based, the maximum cumulative dose of prior anthracycline therapy must not exceed 360 mg/m2 for doxorubicin and 720 mg/m2 for epirubicin.

8. Prior adjuvant radiotherapy is allowed as part of the treatment of early breast cancer provided that last fraction of radiotherapy occurred at least 6 months prior to randomization. Radiotherapy administered solely for the relief of metastatic bone pain is allowed prior to study entry, providing that:

• no more than 30% of marrow-bearing bone was irradiated
• the last fraction of radiotherapy was administered ≥ 3 weeks prior to randomization.

9. Adequate left ventricular ejection function (LVEF) at baseline, defined as LVEF ≥ 50% by either echocardiogram or multigated acquisition scan (MUGA).

10. Adequate hematological function

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
• Platelet count ≥ 100 x 109/L
• Hemoglobin ≥ 9 g/dL (may be transfused to maintain or exceed this level).

11. Adequate liver function

• Total bilirubin ≤ 1.25 x upper normal limit (ULN)
• Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT) < 2.5 x ULN in patients without liver metastases; < 5.0 x ULN in patients with liver metastases.

12. Adequate renal function

• Serum creatinine ≤ 1.25 x ULN or calculated creatinine clearance ≥ 50 mL/min.
• Urine dipstick for proteinuria < +2. Patients discovered to have ≥ +2 proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate ≤ 1g of protein in 24 hours

13. The use of full-dose oral or parenteral anticoagulants is permitted as long as the patient has been on a stable level of anticoagulation for at least two weeks at the time of randomization

• Patients on heparin treatment should have a baseline activated partial thromboplastin time (aPTT) between 1.5 - 2.5 times ULN or patients value before starting heparin treatment
• Patients on low molecular weight heparins (LMWH) should receive daily dose of 1.5 - 2 mg/kg (of enoxaparin) or appropriate doses of the correspondent anticoagulant, according to package insert
• Patients on coumarin derivatives should have an international normalized ratio (INR) between 2.0 and 3.0 assessed at baseline in two consecutive measurements 1-4 days apart
• Patients not receiving anticoagulant medication must have an INR ≤ 1.5 and aPTT ≤ 1.5 times ULN within 7 days prior to randomization

Exclusion Criteria

1. Previous chemotherapy for metastatic or locally recurrent breast cancer.

2. Concomitant hormonal therapy for locally recurrent or metastatic disease. Note: previous hormonal therapy is allowed for adjuvant, locally recurrent or metastatic breast cancer, but must have been discontinued at least 3 weeks prior to randomization.

3. Previous radiotherapy for the treatment of metastatic disease (unless given for the relief of metastatic bone pain and with the precautions mentioned above).

4. Other primary tumors within the last 5 years, except for adequately controlled limited basal cell carcinoma of the skin, or carcinoma in situ of the cervix.

5. Pre-existing peripheral neuropathy NCI CTCAE grade > 2 at randomization.

6. Evidence of spinal cord compression or current evidence of central nervous system (CNS) metastases (even if previously treated). If suspected, the patient should be scanned by CT or magnetic resonance imaging (MRI) within 28 days prior to randomization to rule out spinal / CNS metastases.

7. History or evidence upon physical/neurological examination of CNS disease unrelated to cancer, unless adequately treated with standard medical therapy (e.g. uncontrolled seizures).

8. Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to randomization, or anticipation of the need for major surgery during the course of the study treatment.

9. Minor surgical procedures, including insertion of an indwelling catheter, within 24 hours prior to randomization.

10. Current or recent (within 10 days of first dose of bevacizumab) use of aspirin (> 325 mg/day) or clopidogrel (> 75 mg/day).

11. Chronic daily treatment with corticosteroids (dose of > 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).

12. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding.

13. Uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg).

14. Clinically significant (i.e. active) cardiovascular disease, requiring medication during the study and might interfere with regularity of the study treatment, or not controlled by medication.

15. Non-healing wound, active peptic ulcer or bone fracture.

16. History of abdominal fistula, or any grade 4 non-gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of randomization.

17. Active infection requiring i.v. antibiotics at randomization.

18. Pregnant or lactating females. Serum pregnancy test to be assessed within 7 days prior to study treatment start, or within 14 days with a confirmatory urine pregnancy test within 7 days prior to study treatment start.

19. Women of childbearing potential (< 2 years after the last menstruation) not using effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) during the study and for a period of 6 months following the last administration of study drug.

20. Men who do not agree to use effective contraception during the study and for a period of 6 months following the last administration of study drug.

21. Current or recent (within 28 days of randomization) treatment with another investigational drug or participation in another investigational study

22. Clinically significant malabsorption syndrome or inability to take oral medication.

23. Psychiatric disability judged by the Investigator to be interfering with compliance for oral drug intake.

24. Requirement for concurrent use of the antiviral agent sorivudine or chemically related analogues, such as brivudine.

25. Evidence of any other disease, metabolic or psychological dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug, or that may affect patient compliance with study routines, or places the patient at high risk from treatment related complications.

26. Known Dihydropyrimidine Dehydrogenase (DPD) deficiency or prior unanticipated severe reaction to fluoropyrimidine therapy (with or without documented DPD deficiency)

27. Known hypersensitivity to any of the study drugs (including 5-FU) or excipients. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies. History of hypersensitivity reactions with drugs formulated in Cremophor® EL (polyoxyethylated castor oil), or previous therapy with bevacizumab.

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

Sponsors

Central European Cooperative Oncology Group

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Christoph C Zielinski, MD

Role: PRINCIPAL_INVESTIGATOR

Dep. of Internal Medicin I, Oncology, Medical University of Vienna

Locations

LKH Leoben

Leoben, , Austria

Hospital Barmherzige Schwestern

Linz, , Austria

AKH Linz, Dep. of Oncology

Linz, , Austria

Hospital Elisabethinen Linz

Linz, , Austria

Univ. Klinik, Medicine III

Salzburg, , Austria

2. Med. Abteilung - LKH-Steyr

Steyr, , Austria

General Hospital, Medical University of Vienna

Vienna, , Austria

Hospital Hietzing

Vienna, , Austria

Institute of Oncology Sarajevo

Sarajevo, , Bosnia and Herzegovina

Cancer Center Plovdiv

Plovdiv, , Bulgaria

University Hospital "Queen Joanna"

Sofia, , Bulgaria

Interdistrict Oncology Dispensary

Varna, , Bulgaria

Department for Oncology, GH Osijek

Osijek, , Croatia

General Hospital Pula

Pula, , Croatia

University Hospital Centre Rijeka

Rijeka, , Croatia

University Hospital for Tumors

Zagreb, , Croatia

University Hospital Rebro

Zagreb, , Croatia

Krajska nemocnice Liberec

Liberec, , Czechia

Institut onkologie a rehablilitace na Plesi

Nová Ves pod Pleší, , Czechia

Fakultni nemocnice Olomouc

Olomouc, , Czechia

Charles University Prague, Dep of Oncology

Prague, , Czechia

Semmelweis Univ. Radiology Clinic

Budapest, , Hungary

National Institute of Oncology

Budapest, , Hungary

Onkotherápiás Klinika,

Szeged, , Hungary

Markusovszky Teaching Hospital

Szombathely, , Hungary

Meir Medical Center

Kfar Saba, , Israel

Rabin Medical Center

Petah Tikva, , Israel

Assuta Medical Center

Tel Aviv, , Israel

Tel Aviv Sourasky Medical Center, Div of Oncology

Tel Aviv, , Israel

Sheba Medical Center

Tel Litwinsky, , Israel

P. Stradins University Hospital

Riga, , Latvia

Riga Eastern Hospital - the latvian Center of Oncology

Riga, , Latvia

Wojewodzkie Centrum Onkologii

Gdansk, , Poland

Medical University of Gdansk

Gdansk, , Poland

Klinika Onkologii CMuJ

Krakow, , Poland

Lodz Oncology Center

Lodz, , Poland

Centrum Medyczne Poradnia Onkologiczna

Rzeszów, , Poland

Wojewodzki Szpital Specialistyczny

Siedlce, , Poland

Szpital Wojewodzki im Sw. Lukasza

Tarnów, , Poland

Memorial Cancer Center and Institute

Warsaw, , Poland

Dolnoslaskie Centrum Onkologii

Wroclaw, , Poland

Emergency University Bucharest Hospital

Bucharest, , Romania

Institutul Oncologic Bucuresti

Bucharest, , Romania

Cancer Institute "I. Chiricuta"

Cluj-Napoca, , Romania

University Hospital St. Spiridon Iasi

Iași, , Romania

Clinical County Hospital Sibiu

Sibiu, , Romania

Oncomed-Oncology Practice

Timișoara, , Romania

Institute for Oncology and Radiology

Belgrade, , Serbia

Clinical Hospital Center " Bezanijska Kosa"

Belgrade, , Serbia

Institute of Oncology

Kamenitz, , Serbia

Clinic of Oncology

Niš, , Serbia

Nomocnica Sv. Alzbety, Narodny Onkologicky Ustav

Bratislava, , Slovakia

National Cancer Institute

Bratislava, , Slovakia

Oncology Institute, Department of Radiotherapy and Onclogy

Košice, , Slovakia

POKO Porad, s.r.o

Poprad, , Slovakia

Countries

Austria; Bosnia and Herzegovina; Bulgaria; Croatia; Czechia; Hungary; Israel; Latvia; Poland; Romania; Serbia; Slovakia

References

Hoon SN, Lau PK, White AM, Bulsara MK, Banks PD, Redfern AD. Capecitabine for hormone receptor-positive versus hormone receptor-negative breast cancer. Cochrane Database Syst Rev. 2021 May 26;5(5):CD011220. doi: 10.1002/14651858.CD011220.pub2.

Reference Type: DERIVED

PMID: 34037241 (View on PubMed)

Zielinski C, Lang I, Inbar M, Kahan Z, Greil R, Beslija S, Stemmer SM, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Petruzelka L, Eniu A, Nisenbaum B, Dank M, Anghel R, Messinger D, Brodowicz T; TURANDOT investigators. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1230-9. doi: 10.1016/S1470-2045(16)30154-1. Epub 2016 Aug 5.

Reference Type: DERIVED

PMID: 27501767 (View on PubMed)

Brodowicz T, Lang I, Kahan Z, Greil R, Beslija S, Stemmer SM, Kaufman B, Petruzelka L, Eniu A, Anghel R, Koynov K, Vrbanec D, Pienkowski T, Melichar B, Spanik S, Ahlers S, Messinger D, Inbar MJ, Zielinski C. Selecting first-line bevacizumab-containing therapy for advanced breast cancer: TURANDOT risk factor analyses. Br J Cancer. 2014 Nov 25;111(11):2051-7. doi: 10.1038/bjc.2014.504. Epub 2014 Sep 30.

Reference Type: DERIVED

PMID: 25268370 (View on PubMed)

Lang I, Brodowicz T, Ryvo L, Kahan Z, Greil R, Beslija S, Stemmer SM, Kaufman B, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Messinger D, Zielinski C; Central European Cooperative Oncology Group. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol. 2013 Feb;14(2):125-33. doi: 10.1016/S1470-2045(12)70566-1. Epub 2013 Jan 10.

Reference Type: DERIVED

PMID: 23312888 (View on PubMed)

Other Identifiers

CECOG/BC1.3.005

Identifier Type: -

Identifier Source: org_study_id