Clinical trial NCT01131195: Metronomic Therapy in Metastatic Breast Cancer.
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: HER2-negative breast cancer
recurrent breast cancer
stage IIIB breast cancer
stage IIIC breast cancer
stage IV breast cancer
Lead sponsor: Swiss Group for Clinical Cancer Research
Sponsor class: OTHER
First posted: 2010-05-26
Enrollment: 139
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Incidence of grade 3-5 adverse events
timeFrame: Documentation of AE observed during trial treatment and in follow-up until resolution
Secondary outcomes:
measure: Objective response (OR)
timeFrame: the best response under trial treatment
measure: Disease control (DC)
timeFrame: best response under trial treatment at 24 weeks after randomization
measure: Progression-free survival (PFS)
timeFrame: from randomization until documented tumor progression
measure: Overall survival (OS)
timeFrame: the time from randomization to death from any cause
measure: Time to specific grade 3-5 adverse events
timeFrame: Time from randomization until the first occurrence of the predefined grade 3-5 adverse events for the primary endpoint.
Other outcomes:
Locations:
city: Aarau
country: Switzerland
facility: Hirslanden Klinik Aarau
city: Aarau
country: Switzerland
facility: Kantonspital Aarau
city: Baden
country: Switzerland
facility: Kantonsspital Baden
city: Basel
country: Switzerland
facility: Universitaetsspital-Basel
city: Biel
country: Switzerland
facility: Spitalzentrum Biel
city: Brig
country: Switzerland
facility: RSV-GNW Spitalzentrum Oberwallis
city: Chur
country: Switzerland
facility: Kantonsspital Graubuenden
city: Frauenfeld
country: Switzerland
facility: Kantonsspital Frauenfeld
city: Fribourg
country: Switzerland
facility: Kantonsspital Freiburg
city: Geneva
country: Switzerland
facility: Hopital Cantonal Universitaire de Geneve
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: Luzerne
country: Switzerland
facility: Kantonsspital Luzern
city: Mendrisio
country: Switzerland
facility: Oncology Institute of Southern Switzerland - IOSI Ticino
city: Olten
country: Switzerland
facility: Kantonsspital Olten
city: Sion
country: Switzerland
facility: Hopital Regional de Sion-Herens-Conthey
city: St. Gallen
country: Switzerland
facility: Kantonsspital - St. Gallen
city: Thun
country: Switzerland
facility: Regionalspital Thun
city: Uster
country: Switzerland
facility: Spital Uster
city: Winterthur
country: Switzerland
facility: Kantonsspital Winterthur
city: Zurich
country: Switzerland
facility: Onkozentrum - Klinik im Park
city: Zurich
country: Switzerland
facility: Onkozentrum Hirslanden
city: Zurich
country: Switzerland
facility: City Hospital Triemli
city: Zurich
country: Switzerland
facility: UniversitaetsSpital Zuerich
Study officials:
affiliation: Universitaetsspital-Basel
name: Christoph Rochlitz, MD
role: STUDY_CHAIR
affiliation: Luzerner Kantonsspital
name: Ralph Winterhalder, MD
role: STUDY_CHAIR
References:
citation: Rochlitz C, Bigler M, von Moos R, Bernhard J, Matter-Walstra K, Wicki A, Zaman K, Anchisi S, Kung M, Na KJ, Bartschi D, Borner M, Rordorf T, Rauch D, Muller A, Ruhstaller T, Vetter M, Trojan A, Hasler-Strub U, Cathomas R, Winterhalder R; Swiss Group for Clinical Cancer Research (SAKK). SAKK 24/09: safety and tolerability of bevacizumab plus paclitaxel vs. bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer - a multicenter, randomized phase III trial. BMC Cancer. 2016 Oct 10;16(1):780. doi: 10.1186/s12885-016-2823-y.
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.