Clinical trial NCT00600340: 2-arm Trial of Paclitaxel Plus Bevacizumab vs. Capecitabine Plus Bevacizumab
Official title: A Randomized Phase III 2-arm Trial of Paclitaxel Plus Bevacizumab vs. Capecitabine Plus Bevacizumab for the First-line Treatment of Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Locally Recurrent or Metastatic Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Metastatic Breast Cancer
Lead sponsor: Central European Cooperative Oncology Group
Sponsor class: OTHER
First posted: 2008-01-25
Enrollment: 564
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Overall Survival (PP Population)
timeFrame: Time from the date of randomization to the date of death or date last known to be alive, assessed up to approximately 6 years
measure: Overall Survival (ITT Population)
timeFrame: Time from the date of randomization to the date of death or date last known to be alive, assessed up to approximately 6 years
Secondary outcomes:
measure: Observation Time (ITT Population)
timeFrame: Up to approximately 6 years
measure: Best Overall Response (ITT Population)
timeFrame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
measure: Best Overall Response (PP Population)
timeFrame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
measure: Unconfirmed Best Overall Response (ITT Population)
timeFrame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
measure: Unconfirmed Best Overall Response (PP Population)
timeFrame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
measure: Objective Response Rate and Disease Control Rate (ITT Population)
timeFrame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
measure: Objective Response Rate and Disease Control Rate (PP Population)
timeFrame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
measure: Unconfirmed Objective Response Rate and Disease Control Rate (ITT Population)
timeFrame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
measure: Unconfirmed Objective Response Rate and Disease Control Rate (PP Population)
timeFrame: Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
measure: Progression Free Survival (ITT Population)
timeFrame: Time from the date of randomization to disease progression, death or censoring (whichever occurred first), assessed up to approximately 5 years.
measure: Progression Free Survival (PP Population)
timeFrame: Time from the date of randomization to disease progression, death or censoring (whichever occurred first), assessed up to approximately 5 years.
measure: Time to Treatment Failure (ITT Population)
timeFrame: From first drug intake to progression, death or withdrawal from study treatment or study closure (whichever occurred first), assessed up to approximately 4.5 years
measure: Time to Treatment Failure (PP Population)
timeFrame: From first drug intake to progression, death or withdrawal from study treatment or study closure (whichever occurred first), assessed up to approximately 4.5 years
measure: Time to Response (ITT Population)
timeFrame: Time from randomization until occurrence of response, assessed up 1.7 years
measure: Time to Response (PP Population)
timeFrame: Time from randomization until occurrence of response, assessed up 1.7 years
measure: Duration of Response (ITT Population)
timeFrame: Time from first occurrence of CR or PR until disease progression, death or study closure, whichever occurred first, assessed up to 3.4 years after occurrence of response.
measure: Duration of Response (PP Population)
timeFrame: Time from first occurrence of CR or PR until disease progression, death or study closure, whichever occurred first, assessed up to 3.4 years after occurrence of response.
Other outcomes:
Locations:
city: Leoben
country: Austria
facility: LKH Leoben
city: Linz
country: Austria
facility: Hospital Barmherzige Schwestern
city: Linz
country: Austria
facility: AKH Linz, Dep. of Oncology
city: Linz
country: Austria
facility: Hospital Elisabethinen Linz
city: Salzburg
country: Austria
facility: Univ. Klinik, Medicine III
city: Steyr
country: Austria
facility: 2. Med. Abteilung - LKH-Steyr
city: Vienna
country: Austria
facility: General Hospital, Medical University of Vienna
city: Vienna
country: Austria
facility: Hospital Hietzing
city: Sarajevo
country: Bosnia and Herzegovina
facility: Institute of Oncology Sarajevo
city: Plovdiv
country: Bulgaria
facility: Cancer Center Plovdiv
city: Sofia
country: Bulgaria
facility: University Hospital "Queen Joanna"
city: Varna
country: Bulgaria
facility: Interdistrict Oncology Dispensary
city: Osijek
country: Croatia
facility: Department for Oncology, GH Osijek
city: Pula
country: Croatia
facility: General Hospital Pula
city: Rijeka
country: Croatia
facility: University Hospital Centre Rijeka
city: Zagreb
country: Croatia
facility: University Hospital for Tumors
city: Zagreb
country: Croatia
facility: University Hospital Rebro
city: Liberec
country: Czechia
facility: Krajska nemocnice Liberec
city: Nova Ves pod Plesi
country: Czechia
facility: Institut onkologie a rehablilitace na Plesi
city: Olomouc
country: Czechia
facility: Fakultni nemocnice Olomouc
city: Prague
country: Czechia
facility: Charles University Prague, Dep of Oncology
city: Budapest
country: Hungary
facility: Semmelweis Univ. Radiology Clinic
city: Budapest
country: Hungary
facility: National Institute of Oncology
city: Szeged
country: Hungary
facility: Onkotherápiás Klinika,
city: Szombathely
country: Hungary
facility: Markusovszky Teaching Hospital
city: Kfar Saba
country: Israel
facility: Meir Medical Center
city: Petah-Tikva
country: Israel
facility: Rabin Medical Center
city: Tel Aviv
country: Israel
facility: Tel Aviv Sourasky Medical Center, Div of Oncology
city: Tel Hashomer
country: Israel
facility: Sheba Medical Center
city: Tel-Aviv
country: Israel
facility: Assuta Medical Center
city: Riga
country: Latvia
facility: P. Stradins University Hospital
city: Riga
country: Latvia
facility: Riga Eastern Hospital - the latvian Center of Oncology
city: Gdansk
country: Poland
facility: Wojewodzkie Centrum Onkologii
city: Gdansk
country: Poland
facility: Medical University of Gdansk
city: Krakow
country: Poland
facility: Klinika Onkologii CMuJ
city: Lodz
country: Poland
facility: Lodz Oncology Center
city: Rzeszow
country: Poland
facility: Centrum Medyczne Poradnia Onkologiczna
city: Siedlce
country: Poland
facility: Wojewodzki Szpital Specialistyczny
city: Tarnow
country: Poland
facility: Szpital Wojewodzki im Sw. Lukasza
city: Warsaw
country: Poland
facility: Memorial Cancer Center and Institute
city: Wroclaw
country: Poland
facility: Dolnoslaskie Centrum Onkologii
city: Bucharest
country: Romania
facility: Emergency University Bucharest Hospital
city: Bukarest
country: Romania
facility: Institutul Oncologic Bucuresti
city: Cluj-Napoca
country: Romania
facility: Cancer Institute "I. Chiricuta"
city: Iasi
country: Romania
facility: University Hospital St. Spiridon Iasi
city: Sibiu
country: Romania
facility: Clinical County Hospital Sibiu
city: Timisoara
country: Romania
facility: Oncomed-Oncology Practice
city: Belgrade
country: Serbia
facility: Institute for Oncology and Radiology
city: Belgrade
country: Serbia
facility: Clinical Hospital Center " Bezanijska Kosa"
city: Nis
country: Serbia
facility: Clinic of Oncology
city: Sremska Kamenica
country: Serbia
facility: Institute of Oncology
city: Bratislava
country: Slovakia
facility: Nomocnica Sv. Alzbety, Narodny Onkologicky Ustav
city: Bratislava
country: Slovakia
facility: National Cancer Institute
city: Kosice
country: Slovakia
facility: Oncology Institute, Department of Radiotherapy and Onclogy
city: Poprad
country: Slovakia
facility: POKO Porad, s.r.o
Study officials:
affiliation: Dep. of Internal Medicin I, Oncology, Medical University of Vienna
name: Christoph C Zielinski, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.