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An open randomized phase III study to compare 8 continuous cycles of chemotherapy with 8 cycles of intermittent (2 times 4 cycles) chemotherapy in first line treatment, in combination with bevacizumab, and second line treatment of patients with HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer.


- candidate number8648
- NTR NumberNTR2589
- ISRCTNISRCTN wordt niet meer aangevraagd.
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR10-nov-2010
- Secondary IDsBOOG 2010-02 Borstkanker Onderzoeks Groep
- Public TitleAn open randomized phase III study to compare 8 continuous cycles of chemotherapy with 8 cycles of intermittent (2 times 4 cycles) chemotherapy in first line treatment, in combination with bevacizumab, and second line treatment of patients with HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer.
- Scientific TitleAn open randomized phase III study to compare 8 continuous cycles of chemotherapy with 8 cycles of intermittent (2 times 4 cycles) chemotherapy in first line treatment, in combination with bevacizumab, and second line treatment of patients with HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer.
- ACRONYMStop&Go
- hypothesisThe primary goal of this non-inferiority trial is to determine if the results obtained with a intermittent chemotherapy regimen (2 x 4 cycles of paclitaxel) are not inferior to the results of a continuous chemotherapy regimen (8 cycles of paclitaxel), both combined with bevacizumab in first line treatment of patients with HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer.
- Healt Condition(s) or Problem(s) studiedMetastatic breast cancer, Bevacizumab , HER2/neu negative tumor, Paclitaxel , Liposomal doxorubicine
- Inclusion criteria1. Female patients ≥ 18 years old;
2. Patients with HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer, who are candidates for chemotherapy;
3. Patients with measurable or evaluable-only disease by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria as determined by the investigator;
4. Documented Estrogen Receptor (ER) / Progesteron Receptor (PR) status;
5. HER2/neu-negative disease as determined by immunohistochemistry or Fluorescence In Situ Hybridization (FISH);
6. Patients with an ECOG Performance Status ≤ 2;
7. Life expectancy of > 12 weeks;
8. Signature of Informed Consent Form by patient.
- Exclusion criteriaPrior Treatment:
1. Previous chemotherapy for HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer;
2. Prior hormonal therapy for HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer that has not been discontinued 1 week before start of study treatment;
3. Prior adjuvant/neo-adjuvant chemotherapy within 6 months prior to first study treatment. However, if the prior adjuvant/neo-adjuvant chemotherapy was taxane based, patients are excluded if they received their last chemotherapy within12 months prior to first study treatment;
4. Prior radiotherapy covering more than 30% of marrow-bearing bone;
5. Patients that have received recent radiation therapy that are not recovered from any significant (Grade ≥ 3) acute toxicity prior to study treatment;
6. Prior therapy with bevacizumab, sorafenib, sunitinib, or other VEGF pathway-targeted therapy.

Current Treatment:
7. Chronic daily treatment with aspirin (>= 325 mg/day) or clopidogrel (>= 75 mg/day);
8. Chronic daily treatment with corticosteroids (dose of >= 10 mg/day methylprednisolone or equivalent), with the exception of inhaled steroids;
9. Current or recent (within 30 days of first study treatment) treatment with another investigational drug or participation in another investigational study.

Hematology, coagulation and biochemistry:
10. Inadequate bone marrow function: Absolute Neutrophil Count (ANC): < 1.5 x 109/L, or platelet count <100 x 109/L or hemoglobin < 6 mmol/L;
11. Inadequate liver function, defined as:
A. Serum (total) bilirubin > 2 x the Upper Limit of Normal (ULN) for the institution;
B. Aspartaat-Amino-Transferase/ Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT) or Alanine-Amino-Transferase/ Serum Glutamic Pyruvic Transaminase (ALAT/SGPT) > 2.5 x ULN (> 5 x ULN in patients with liver metastases);
C. Alkaline phosphatase levels > 2.5 x ULN (> 5 x ULN in patients with liver metastases, or > 10 x ULN in patients with bone metastases).
12. Inadequate renal function, defined as:
A. Serum creatinine > 1.5 x ULN;
B. Creatinine clearance < 50 mL/min (Calculated according to Cockroft and Gault);
C. Urine dipstick for proteinuria > 2+. Patients with >= 2+ proteinuria on dipstick analysis at baseline should undergo a 24 hour urine collection and must demonstrate ≤1g of protein in the 24-hour urine.
13. Patients not receiving anticoagulant medication who have an International Normalized Ratio (INR) > 1.5 or an activated Partial Thromboplastin Time (aPTT) > 1.5 x ULN within 7 days prior to first study treatment. Note: Patients receiving full dose oral or parenteral anticoagulants may be included in the study as long as anticoagulant dosing has been stable for at least two weeks prior to study entry and the appropriate coagulation monitoring tests are within local therapeutic limits.

Other:
14. Known CNS disease, except for treated brain metastases. Treated brain metastases are defined as: having no evidence of progression or haemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose) are allowed. Treatment for brain metastases may include whole brain radiotherapy (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to day 1 are excluded. A brain or MRI scan is required within 28 days prior to day 1 if the presence of untreated brain metastases is suspected;
15. Patients with concurrent active malignancy other than: breast cancer; adequately treated non melanoma skin cancer; or other non-invasive carcinoma or in situ neoplasm, provided that the patient is disease free for > 3 years;
16. 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. 17.Women of childbearing potential (defined as <2 years after last menstruation and not surgically sterile) not using effective, non-hormonal means of contraception (intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly);
18. Major surgical procedure (including open biopsy) within 28 days prior to the first study treatment, or anticipation of the need for major surgery during the course of the study treatment;
19. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to day 1;
20. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to day 1;
21. Any previous venous thrombo-embolism > CTC Grade 3;
22. History of haemoptysis (≥1/2 teaspoon of bright red blood per episode) within 1 month prior to day 1;
23. History or evidence of inherited bleeding diathesis or coagulopathy with the risk of bleeding;
24. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg);
25. Clinically significant (i.e. active) cardiovasculair disease defined as:
A. Cerebro Vascular Accident (CVA);
B. Stroke within ≤ 6 months prior to prior to day 1;
C. Myocardial infarction within ≤ 6 months prior to day 1;
D. Unstable angina;
E. New York Heart Association (NYHA) Grade II or greater;
F. Congestive Heart Failure (CHF);
G. Serious cardiac arrhythmia requiring medication;
H. Relevant pathologic findings in ECG.
26. Left Ventricle Ejection Fraction (LVEF) by MUGA or ECHO < 50%;
27. History of abdominal fistula, Grade 4 bowel obstruction or gastrointestinal perforation, intra-abdominal abscess within 6 months of randomization;
28. Serious non-healing wound, peptic ulcer or bone fracture;
29. Known hypersensitivity to any of the study drugs or excipients;
30. Hypersensitivity to Chinese hamster ovary cell products or other recombinant human or humanized antibodies;
31. Evidence of any other medical conditions (such as psychiatric illness, physical examination or laboratory findings) that may interfere with the planned treatment, affect patient compliance or place the patient at high risk from treatment-related complications.
- mec approval receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingNone
- controlActive
- groupParallel
- Type2 or more arms, randomized
- Studytypeintervention
- planned startdate 11-nov-2010
- planned closingdate1-okt-2013
- Target number of participants420
- InterventionsArm A:
1st line:
1. Paclitaxel and bevacizumab: 8 cycles, unless PD or unacceptable toxicity occurs earlier;
2. Bevacizumab until PD or unacceptable toxicity;
3. At PD patients will go to the 2nd treatment line.
2nd line:
1. Non-pegylated liposomal doxorubicin (Myocet®) (or capecitabine): 8 cycles, unless PD or unacceptable toxicity occurs earlier;
2. At PD patients will go to the 3rd treatment line. If possible, it is advised to cross-over from 2nd line non-pegylated liposomal doxorubicin to 3rd line capecitabine.

Arm B:
1st line:
1. Paclitaxel and bevacizumab: 4 cycles, unless PD or unacceptable toxicity occurs earlier;
2. Bevacizumab until PD or unacceptable toxicity;
3. At PD < 3 months after last administration of paclitaxel patients will go to the 2nd treatment line;
4. At PD ≥ 3 months after last administration of paclitaxel, patients will receive another 4 cycles of paclitaxel and bevacizumab;
5. Bevacizumab until the next PD or unacceptable toxicity;
6. At the next PD patients will go to the 2nd treatment line.
2nd line:
1. Non-pegylated liposomal doxorubicin (Myocet®) (or capecitabine): 4 cycles, unless PD or unacceptable toxicity occurs earlier;
2. At PD < 3 months patients will go to the 3rd treatment line. If possible, it is advised to cross-over from 2nd line non-pegylated liposomal doxorubicin to 3rd line capecitabine;
3. At PD ≥ 3 months after last administration of liposomal doxorubicin (Myocet®) (or capecitabine), patients will receive another 4 cycles of liposomal doxorubicin (Myocet®) (or capecitabine);
4. At the next PD patients will go to the 3rd treatment line.
- Primary outcomePFS is defined as the time from start of treatment to the documented progression that requires the patient to switch to the next treatment line or to death due to any cause.
- Secondary outcome1. Changes in the RAND 36 quality of life scale will be measured;
2. Safety and tolerability;
3. ORR calculated as the proportion of patients with a best overall response of confirmed Complete Response (CR) and Partial Response (PR);
4. DOR calculated as the time from the date of first documented CR or PR to the first documented progression or death due to underlying cancer;
5. OS calculated as the time from the date of randomization to the date of death due to any cause or the date of last contact;
6. Direct medical costs will be calculated using a standard cost method.
- TimepointsRespons evaluation every 12 weeks.
- Trial web sitehttp://www.boogstudycenter.nl
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIES Borstkanker Onderzoek Groep (BOOG)
- CONTACT for SCIENTIFIC QUERIESDr. F.L.G. Erdkamp
- Sponsor/Initiator Breast Cancer Study Group (BOOG)
- Funding
(Source(s) of Monetary or Material Support)
Roche Nederland BV, Breast Cancer Study Group (BOOG), Cephalon
- PublicationsN/A
- Brief summaryAn open randomized phase III study to compare 8 continuous cycles of chemotherapy with 8 cycles of intermittent (2 times 4 cycles) chemotherapy in first line treatment, in combination with bevacizumab, and second line treatment of patients with HER2/neu negative, incurable, metastatic or unresectable locally advanced breast cancer.
- Main changes (audit trail)
- RECORD10-nov-2010 - 26-nov-2010


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