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

Metastatic Breast Cancer Clinical Trial

— TURANDOT  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00600340
• Other study ID #: CECOG/BC1.3.005
• Status: Completed
• Phase: Phase 3
• Start date: April 2008
• Est. completion date: December 2014

Study information

• Verified date: October 2019
• Source: Central European Cooperative Oncology Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 564
• Est. completion date: December 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

Biological:
• 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
• 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

Locations

Country	Name	City	State
Austria	LKH Leoben	Leoben
Austria	AKH Linz, Dep. of Oncology	Linz
Austria	Hospital Barmherzige Schwestern	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
Bosnia and Herzegovina	Institute of Oncology Sarajevo	Sarajevo
Bulgaria	Cancer Center Plovdiv	Plovdiv
Bulgaria	University Hospital "Queen Joanna"	Sofia
Bulgaria	Interdistrict Oncology Dispensary	Varna
Croatia	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
Czechia	Krajska nemocnice Liberec	Liberec
Czechia	Institut onkologie a rehablilitace na Plesi	Nova Ves pod Plesi
Czechia	Fakultni nemocnice Olomouc	Olomouc
Czechia	Charles University Prague, Dep of Oncology	Prague
Hungary	National Institute of Oncology	Budapest
Hungary	Semmelweis Univ. Radiology Clinic	Budapest
Hungary	Onkotherápiás Klinika,	Szeged
Hungary	Markusovszky Teaching Hospital	Szombathely
Israel	Meir Medical Center	Kfar Saba
Israel	Rabin Medical Center	Petah-Tikva
Israel	Tel Aviv Sourasky Medical Center, Div of Oncology	Tel Aviv
Israel	Sheba Medical Center	Tel Hashomer
Israel	Assuta Medical Center	Tel-Aviv
Latvia	P. Stradins University Hospital	Riga
Latvia	Riga Eastern Hospital - the latvian Center of Oncology	Riga
Poland	Medical University of Gdansk	Gdansk
Poland	Wojewodzkie Centrum Onkologii	Gdansk
Poland	Klinika Onkologii CMuJ	Krakow
Poland	Lodz Oncology Center	Lodz
Poland	Centrum Medyczne Poradnia Onkologiczna	Rzeszow
Poland	Wojewodzki Szpital Specialistyczny	Siedlce
Poland	Szpital Wojewodzki im Sw. Lukasza	Tarnow
Poland	Memorial Cancer Center and Institute	Warsaw
Poland	Dolnoslaskie Centrum Onkologii	Wroclaw
Romania	Emergency University Bucharest Hospital	Bucharest
Romania	Institutul Oncologic Bucuresti	Bukarest
Romania	Cancer Institute "I. Chiricuta"	Cluj-Napoca
Romania	University Hospital St. Spiridon Iasi	Iasi
Romania	Clinical County Hospital Sibiu	Sibiu
Romania	Oncomed-Oncology Practice	Timisoara
Serbia	Clinical Hospital Center " Bezanijska Kosa"	Belgrade
Serbia	Institute for Oncology and Radiology	Belgrade
Serbia	Clinic of Oncology	Nis
Serbia	Institute of Oncology	Sremska Kamenica
Slovakia	National Cancer Institute	Bratislava
Slovakia	Nomocnica Sv. Alzbety, Narodny Onkologicky Ustav	Bratislava
Slovakia	Oncology Institute, Department of Radiotherapy and Onclogy	Kosice
Slovakia	POKO Porad, s.r.o	Poprad

Sponsors (1)

Lead Sponsor	Collaborator
Central European Cooperative Oncology Group

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival (PP Population)	Overall survival (OS) defined as time from randomization to date of death from any cause. Patients without recorded death were censored at the date the patient was last known to be alive. OS was analyzed at two looks, one interim look and the final analysis. Due to group sequential testing, the overall significance level alpha = 0.025 was spent on both looks according to Lan-DeMets spending method with O'Brien-Fleming-type boundaries. Alpha spent at Interim after 47% of information was 0.0010. Alpha spent at final analysis after 99% of information was 0.0250.	Time from the date of randomization to the date of death or date last known to be alive, assessed up to approximately 6 years
Primary	Overall Survival (ITT Population)	Overall survival (OS) defined as time from randomization to date of death from any cause. Patients without recorded death were censored at the date the patient was last known to be alive. OS was analyzed at two looks, one interim look and the final analysis. Due to group sequential testing, the overall significance level alpha = 0.025 was spent on both looks according to Lan-DeMets spending method with O'Brien-Fleming-type boundaries. Alpha spent at Interim after 50% of information was 0.0014. Alpha spent at final analysis after 99% of information was 0.0250.	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	Observation Time (ITT Population)	Median observation time estimated with reverse Kaplan-Meier methods. Observation time (in months) is defined as time from randomization to the day the patient was last confirmed to be alive. In case of patient deaths the time was censored at the day of death.	Up to approximately 6 years
Secondary	Best Overall Response (ITT Population)	The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase	Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Secondary	Best Overall Response (PP Population)	The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase	Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Secondary	Unconfirmed Best Overall Response (ITT Population)	The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment.	Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Secondary	Unconfirmed Best Overall Response (PP Population)	The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment.	Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Secondary	Objective Response Rate and Disease Control Rate (ITT Population)	Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase	Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Secondary	Objective Response Rate and Disease Control Rate (PP Population)	Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase	Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Secondary	Unconfirmed Objective Response Rate and Disease Control Rate (ITT Population)	Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment.	Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Secondary	Unconfirmed Objective Response Rate and Disease Control Rate (PP Population)	Objective response rate (ORR) is defined as the proportion of patients with complete response or partial response. Disease control rate (DCR) is defined as the proportion of patients with complete response, partial response and stable disease. The best overall response according to the RECIST criteria is the best response recorded from the start of the treatment until disease progression/recurrence or within 28 days of last intake of study medication in the Study Treatment Phase. Complete and partial response in this summary did not require a confirmation by a second tumor assessment	Up to disease progression or up to 28 days after last intake of study medication, assessed up to approximately 5 years.
Secondary	Progression Free Survival (ITT Population)	Progression Free Survival (PFS) is defined as time from randomization to date of documented progression or date of death due to any cause, whichever occurred first. Patients without recorded progression or death were censored at the last date they were known to have not progressed. Patients who were randomized and had no post-baseline tumor assessment were censored on the day of randomization. Median PFS, associated stratified Hazard Ratio (HR).	Time from the date of randomization to disease progression, death or censoring (whichever occurred first), assessed up to approximately 5 years.
Secondary	Progression Free Survival (PP Population)	Progression Free Survival (PFS) is defined as time from randomization to date of documented progression or date of death due to any cause, whichever occurred first. Patients without recorded progression or death were censored at the last date they were known to have not progressed. Patients who were randomized and had no post-baseline tumor assessment were censored on the day of randomization. Median PFS, associated stratified Hazard Ratio (HR).	Time from the date of randomization to disease progression, death or censoring (whichever occurred first), assessed up to approximately 5 years.
Secondary	Time to Treatment Failure (ITT Population)	Time to treatment failure (TTF) was defined as time from first drug intake to progression, death or withdrawal from study treatment, whichever occurred first. Patients without an event were censored at the date of the last tumor assessment or last treatment administration, whichever occurred last. Median TTF, associated stratified Hazard Ratio (HR).	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
Secondary	Time to Treatment Failure (PP Population)	Time to treatment failure (TTF) was defined as time from first drug intake to progression, death or withdrawal from study treatment, whichever occurred first. Patients without an event were censored at the date of the last tumor assessment or last treatment administration, whichever occurred last. Median TTF, associated stratified Hazard Ratio (HR).	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
Secondary	Time to Response (ITT Population)	Time to response (TR) was defined as time from randomization until occurrence of response (complete response (CR) or partial response (PR)) according to RECIST criteria. Patients without response were censored after the longest time to response observed in any patient. Median TR, associated stratified Hazard Ratio (HR). Since the median TR was not observed, the number of subjects with a response at given timepoints were reported.	Time from randomization until occurrence of response, assessed up 1.7 years
Secondary	Time to Response (PP Population)	Time to response (TR) was defined as time from randomization until occurrence of response (complete response (CR) or partial response (PR)) according to RECIST criteria. Patients without response were censored after the longest time to response observed in any patient. Median TR, associated stratified Hazard Ratio (HR). Since the median TR was not observed, the number of subjects with a response at given timepoints were reported.	Time from randomization until occurrence of response, assessed up 1.7 years
Secondary	Duration of Response (ITT Population)	Duration of response (DR) was defined as time from date of first occurrence of any response (complete response (CR) or partial response (PR)) until the occurrence of progression of disease or death. Patients with response who neither progressed nor died were censored at the date of their last tumor assessment. Median DR, associated stratified Hazard Ratio (HR).	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.
Secondary	Duration of Response (PP Population)	Duration of response (DR) was defined as time from date of first occurrence of any response (complete response (CR) or partial response (PR)) until the occurrence of progression of disease or death. Patients with response who neither progressed nor died were censored at the date of their last tumor assessment. Median DR, associated stratified Hazard Ratio (HR).	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.