Metronomic Therapy in Metastatic Breast Cancer.

Sponsor

Swiss Group for Clinical Cancer Research (Other)

Overall Status

Completed

CT.gov ID

NCT01131195

Collaborator

(none)

139

Enrollment

Locations

Arms

91.4

Actual Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as paclitaxel, cyclophosphamide, and capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether bevacizumab is more effective when given together with paclitaxel or cyclophosphamide and capecitabine in treating patients with breast cancer.

PURPOSE: This randomized phase III trial is studying the side effects of giving bevacizumab together with paclitaxel and to see how well it works compared with giving bevacizumab together with cyclophosphamide and capecitabine as first-line therapy in treating women with locally advanced, recurrent, or metastatic breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Biological: bevacizumab, Paclitaxel Biological: Bevacizumab, Cyclophosphamide, Capecitabine	Phase 3

Detailed Description

OBJECTIVES:

To determine if bevacizumab and paclitaxel versus bevacizumab, metronomic cyclophosphamide, and capecitabine as first-line therapy causes less medication-related adverse events in women with HER2-negative metastatic, locally advanced, or recurrent breast cancer.
To compare quality of life (QOL) in patients treated with these regimens.
To replicate previous findings of better QOL in patients with complete response or partial response versus stable disease for 6 months or greater.
To determine the predictive value of baseline QOL for the duration of a meaningful change in QOL of patients treated with chemotherapy.
To determine the associations between the QOL endpoints, selected health economics, and clinical endpoints.

OUTLINE: This is a multicenter study. Patients are stratified according to tumor response (measurable vs evaluable disease), WHO performance status (0 or 1 vs 2), and center. Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15 and paclitaxel IV on days 1, 8, and 15. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.
Arm II: Patients receive bevacizumab IV over 30-90 minutes on days 1 and 15, oral cyclophosphamide once daily on days 1-28, and oral capecitabine 3 times a day on days 1-28. Treatment repeats every 4 weeks in the absence of disease progression or unacceptable toxicity.

Patients complete quality-of-life questionnaire (BL-QA) and health economics questionnaires (BL-HEA and EQ-5D) at baseline, during, and after completion of study therapy.

After completion of study treatment, patients are followed up at 1 month, every 3 months for 1 year, and then every 6 months for 1 year.

Study Design

Study Type:

Interventional

Actual Enrollment :

139 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Safety and Tolerability of Bevacizumab Plus Paclitaxel vs. Bevacizumab Plus Metronomic Cyclophosphamide and Capecitabine as First-Line Therapy in Patients With HER2-Negative Metastatic or Locally Recurrent Breast Cancer - A Multicenter, Randomized Phase III Trial.

Actual Study Start Date :

Jul 19, 2010

Actual Primary Completion Date :

Dec 14, 2012

Actual Study Completion Date :

Feb 28, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm A: bevacizumab and paclitaxel Bevacizumab (10 mg/kg) i.v. is given every two weeks. Paclitaxel (90 mg/m2) i.v. is given on days 1, 8, and 15 of a 4 week cycle. Both medications are given until PD, unacceptable adverse event, or consent withdrawal. If an unacceptable adverse event to any of the drugs in this treatment arm occurs the remaining tolerated drug is given until PD, consent withdrawal, or unacceptable adverse event according to local investigators opinion.	Biological: bevacizumab, Paclitaxel Bevacizumab (10 mg/kg) i.v. is given every two weeks. Paclitaxel (90 mg/m2) i.v. is given on days 1, 8, and 15 of a 4 week cycle. Other Names: Avastin
Active Comparator: Arm B: bevacizumab, cyclophosphamide and capecitabine Bevacizumab (10 mg/kg) i.v. is given every two weeks. Cyclophosphamide (50 mg) and capecitabine (3x 500 mg) p.o. are given daily. All three medications are given until PD, unacceptable adverse event, or consent withdrawal. If an unacceptable adverse event to any of the drugs in this treatment arm occurs the remaining tolerated drug(s) is (are) given until PD, consent withdrawal, or unacceptable adverse event according to local investigators opinion	Biological: Bevacizumab, Cyclophosphamide, Capecitabine Bevacizumab (10 mg/kg) i.v. is given every two weeks. Cyclophosphamide (50 mg) and capecitabine (3x 500 mg) p.o. are given daily Other Names: Avastin Xeloda

Arm

Intervention/Treatment

Active Comparator: Arm A: bevacizumab and paclitaxel

Bevacizumab (10 mg/kg) i.v. is given every two weeks. Paclitaxel (90 mg/m2) i.v. is given on days 1, 8, and 15 of a 4 week cycle. Both medications are given until PD, unacceptable adverse event, or consent withdrawal. If an unacceptable adverse event to any of the drugs in this treatment arm occurs the remaining tolerated drug is given until PD, consent withdrawal, or unacceptable adverse event according to local investigators opinion.

Biological: bevacizumab, Paclitaxel

Bevacizumab (10 mg/kg) i.v. is given every two weeks. Paclitaxel (90 mg/m2) i.v. is given on days 1, 8, and 15 of a 4 week cycle.

Other Names:

Avastin

Active Comparator: Arm B: bevacizumab, cyclophosphamide and capecitabine

Bevacizumab (10 mg/kg) i.v. is given every two weeks. Cyclophosphamide (50 mg) and capecitabine (3x 500 mg) p.o. are given daily. All three medications are given until PD, unacceptable adverse event, or consent withdrawal. If an unacceptable adverse event to any of the drugs in this treatment arm occurs the remaining tolerated drug(s) is (are) given until PD, consent withdrawal, or unacceptable adverse event according to local investigators opinion

Biological: Bevacizumab, Cyclophosphamide, Capecitabine

Bevacizumab (10 mg/kg) i.v. is given every two weeks. Cyclophosphamide (50 mg) and capecitabine (3x 500 mg) p.o. are given daily

Other Names:

Avastin

Xeloda

Outcome Measures

Primary Outcome Measures

Incidence of grade 3-5 adverse events [Documentation of AE observed during trial treatment and in follow-up until resolution]
Patients who have experienced at least one of the adverse event grade ≥ 3 according to the NCI CTCAE criteria 4.0 are considered for the primary endpoint.

Secondary Outcome Measures

Objective response (OR) [the best response under trial treatment]
OR is the best response under trial treatment, defined as a complete response (CR) or partial response (PR) as assessed by RECIST v1.1.
Disease control (DC) [best response under trial treatment at 24 weeks after randomization]
DC is the best response under trial treatment, defined as CR + PR + stable disease.
Progression-free survival (PFS) [from randomization until documented tumor progression]
PFS is calculated from randomization until documented tumor progression according to RECIST 1.1 or death of any cause, whichever occurs first.
Overall survival (OS) [the time from randomization to death from any cause]
OS is defined as the time from randomization to death from any cause
Time to specific grade 3-5 adverse events [Time from randomization until the first occurrence of the predefined grade 3-5 adverse events for the primary endpoint.]
Time from randomization until the first occurrence of the predefined grade 3-5 adverse events for the primary endpoint.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed adenocarcinoma of the breast
Locally advanced, recurrent, or metastatic disease
HER2-negative disease
Measurable or evaluable disease
Candidate for taxane-based chemotherapy
No presence or history of CNS metastasis
Clinical suspicion of CNS metastasis must be confirmed by CT or MRI scan
Hormone receptor status not specified

PATIENT CHARACTERISTICS:

Menopausal status not specified
WHO performance status 0-2
Neutrophil count ≥ 1.5 x 10^9/L
Platelet count ≥ 100 x 10^9/L
Hemoglobin ≥ 80 g/L
Bilirubin ≤ 1.5 times upper limit of normal (ULN)
AST ≤ 5 times ULN
Alkaline phosphatase ≤ 2.5 times ULN (≤ 5 times ULN in case of liver metastases or ≤ 10 times ULN in case of bone metastases)
Serum creatinine ≤ 1.5 times ULN
Urine protein < 2+ by dipstick OR ≤ 1 g by 24-hour urine collection
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception during and for 12 months after completion of study therapy
Patients with INR > 1.5 (or Quick ≤ 70%) OR aPTT > 1.5 times ULN within 7 days prior to expected first trial treatment must be receiving anticoagulant medication
Patients receiving full-dose oral or parental anticoagulants may be included in the trial provided anticoagulant dosing has been stable for at least 2 weeks prior to trial entry and the appropriate coagulation monitoring tests are within local therapeutic limits
Must be compliant and geographically proximal for staging and follow-up
No previous malignancy within the past 5 years except for adequately treated carcinoma in situ of the cervix or localized nonmelanoma skin cancer
No known hypersensitivity to trial drugs or its active compound (e.g., fluoropyrimidine), any other components of the trial drugs, or drugs formulated with cremophor EL including hypersensitivity to Chinese hamster ovary cell products or any other humanized recombinant antibodies
No preexisting peripheral motor or sensory neuropathy > NCI CTCAE grade 2 (i.e., moderate symptoms or limiting instrumental activities of daily living)
No history or evidence of inherited bleeding diathesis, coagulopathy with the risk of bleeding, serious nonhealing wound, active peptic ulcer, nonhealing bone fracture, or bleeding metastases
No history of abdominal fistula, grade 4 bowel obstruction, or gastrointestinal perforation or intra-abdominal abscess within the past 6 months
No evidence of other medical conditions that would impair the ability of the patient to participate in the trial or might preclude therapy with trial drugs, including any of the following:
DPD deficiency
Severe respiratory, cardiac, hepatic, or renal disease
Active infection
Uncontrolled diabetes mellitus
Uncontrolled hypertension ≥ 140/100 mm Hg
Myocardial infarction within the past 12 months
Cerebrovascular accident or stroke within the past 6 months
History of hemorrhagic disorders
No psychiatric disorder precluding understanding of information on trial-related topics, giving informed consent, filling out quality-of-life forms, or interfering with compliance for oral drug intake

PRIOR CONCURRENT THERAPY:

No prior chemotherapy for metastatic or locally recurrent breast cancer
No prior radiotherapy for metastatic disease
Prior radiotherapy for the relief of metastatic bone pain allowed provided no more than 30% of marrow-bearing bone was irradiated
At least 12 months since prior bevacizumab or other anti-VEGF therapy
At least 12 months since prior capecitabine, continuous (> 24 hours) fluorouracil infusion, or other oral fluoropyrimidine (e.g., eniluracil/fluorouracil, uracil/tegafur, S1, or emitefur)
At least 12 months since prior taxane-based chemotherapy
At least 6 months since other prior (neo)adjuvant chemotherapy
At least 30 days since prior treatment in another clinical trial
At least 24 hours since prior minor surgical procedures
At least 28 days since prior and no concurrent major surgical procedures (including open biopsy) and no anticipation of the need for major surgery during the first course of this trial
At least 10 days since prior hormone therapy for metastatic disease
No continuous daily treatment with corticosteroid except for inhaled steroids
No concurrent chronic daily aspirin > 325 mg/day
No concurrent chronic daily clopidogrel > 75 mg/day
No other concurrent anticancer treatments
No other concurrent investigational treatments or experimental drugs
No other concurrent drug therapy contraindicated for use with the trial drugs

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Hirslanden Klinik Aarau	Aarau	Switzerland	CH-5001
2	Kantonspital Aarau	Aarau	Switzerland	CH-5001
3	Kantonsspital Baden	Baden	Switzerland	CH-5404
4	Universitaetsspital-Basel	Basel	Switzerland	CH-4031
5	Spitalzentrum Biel	Biel	Switzerland	CH-2501
6	RSV-GNW Spitalzentrum Oberwallis	Brig	Switzerland	3900
7	Kantonsspital Graubuenden	Chur	Switzerland	CH-7000
8	Kantonsspital Frauenfeld	Frauenfeld	Switzerland	8501
9	Kantonsspital Freiburg	Fribourg	Switzerland	1708
10	Hopital Cantonal Universitaire de Geneve	Geneva	Switzerland	CH-1211
11	Centre Hospitalier Universitaire Vaudois	Lausanne	Switzerland	CH-1011
12	Kantonsspital Luzern	Luzerne	Switzerland	CH-6000
13	Oncology Institute of Southern Switzerland - IOSI Ticino	Mendrisio	Switzerland	CH-6850
14	Kantonsspital Olten	Olten	Switzerland	CH-4600
15	Hopital Regional de Sion-Herens-Conthey	Sion	Switzerland	CH -1951
16	Kantonsspital - St. Gallen	St. Gallen	Switzerland	CH-9007
17	Regionalspital Thun	Thun	Switzerland	3600
18	Spital Uster	Uster	Switzerland	8610
19	Kantonsspital Winterthur	Winterthur	Switzerland	8401
20	Onkozentrum - Klinik im Park	Zurich	Switzerland	8002
21	Onkozentrum Hirslanden	Zurich	Switzerland	CH-8008
22	City Hospital Triemli	Zurich	Switzerland	CH-8063
23	UniversitaetsSpital Zuerich	Zurich	Switzerland	CH-8091