Evaluation of Hypertension as a Predictor of Efficacy Bevacizumab in Metastatic Breast Cancer and Colorectal Cancer

Study Overview
=================
Brief Summary
-----------------
This is a multicenter, post-authorization observational with prospective follow-up (EPA-SP) study. Will be involved 137 metastatic breast cancer patients or metastatic colorectal cancer. The hypertension will be evaluated as a predictor of efficacy of bevacizumab associated with chemotherapy, in terms of progression-free survival (PFS) (Main endpoint). The duration of the study will be approximately 42 months.

Detailed Description
-----------------
Hypertension (HT) is the most common side effect seen in trials of bevacizumab in combination with chemotherapy. Based on the hypothesis that the development of hypertension during treatment would be an indicative of the successful blockade of the Vascular Endothelial Growth Factor (VEGF) pathway, different studies have explored retrospectively the relationship between hypertension and the results of treatment with bevacizumab. This study aims to demonstrate the association between hypertension (diagnosed optimally) with efficacy to treatment with bevacizumab prospectively and secondly verify if blood pressure measures taken at home are a reflection of a diagnosis of hypertension. Also have been explored different molecular markers involved in the pathway of VEGF which might be used as predictors of response. Therefore, this study includes the collection of blood samples (serum or plasma) and tumor tissue of patients included in this study, with the aim of exploring biomarkers that correlate with treatment efficacy and toxicity. The diagnosis of hypertension (HT) will be performed using a Holter recording, and standard blood pressure footage will be collected during the first three cycles of treatment given the Common Toxicity Criteria of the National Cancer Institute-NCI CTCAE version 4.0 and the guidelines of the European Society of Cardiology and Hypertension, 2007. Will be collected a sample of primary tumor and blood for patients who previously have consented it. Samples will be sent to a central laboratory for analysis of biomarkers. An interim analysis will be conducted to assess the true incidence of hypertension. Based on this analysis, will be evaluated the need to recalculate the sample size. At the end of the study, will be performed an analysis of correlation of data measured by standard BP (Blood Pressure) and Holter recording footage with the PFS. Moreover will be determined in serum, plasma and tumor tissue and certain biomarkers to correlate with efficacy to treatment with bevacizumab.

Official Title
-----------------
Evaluation Study of Hypertension as a Predictor of Efficacy Bevacizumab (BV) in Combination With Chemotherapy (CT) in Metastatic Colorectal Cancer (MCC) and Metastatic Breast Cancer (MBC).

Conditions
-----------------
Metastatic Colorectal Cancer, Metastatic Breast Cancer

Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: May only participate in the study patients (women and men) who meet all the following criteria: MCC or MBC patients with chemotherapy and bevacizumab established indication. The first line systemic treatment planned for patients with MCC should be based in combination chemotherapy (oxaliplatin / irinotecan plus fluoropyrimidine) associated with bevacizumab. The first line systemic treatment planned for MBC patients should be based on a combination of paclitaxel or capecitabine plus bevacizumab. Presence of measurable or evaluable disease according to RECIST 1.1, for the evaluation of the response to treatment. Equal or more than 18 years old. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Signed written informed consent. Women of childbearing potential must have a negative pregnancy test in serum or urine conducted in the 7 days prior to the administration of chemotherapeutic treatment assigned by your doctor, and accept the use of double barrier contraception during the study (Note : Patients who are not of childbearing age may participate without using contraceptives. Women who are of childbearing age are those who: 1) have reached natural menopause (defined as 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone (FSH) within postmenopausal interval as determined by the laboratory, or 12 months of spontaneous amenorrhea), 2) have undergone bilateral oophorectomy with or without hysterectomy 6 weeks before, or 3) have undergone bilateral tubal ligation). Men also should use an adequate contraception method. Exclusion Criteria: Patients meeting any of the following circumstances will be excluded from the study: Have received prior systemic anticancer therapy with chemotherapy for advanced disease or prior treatment with bevacizumab. Treatment with an investigational agent or biological agent within 30 days prior to inclusion in the study. Contraindications to treatment with chemotherapy and bevacizumab according to summary products characteristics. Background or current history (within five years before the start of treatment) of other malignancies, except for colorectal carcinoma and breast cancer (patients with basal cell carcinoma or squamous cell skin or cervical carcinoma in situ treated curative may be included in the study). Life expectancy less than 3 months. Patients who are pregnant or breastfeeding. Patients with an inadequate organ function (bone marrow, kidney and liver)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Bevacizumab + Chemotherapy<br>Patients who received the addition of Bevacizumab (BV) every 2-3 weeks to Chemotherapy (CT) with either oxaliplatin or irinotecan plus fluoropyrimidines in patients with Metastatic Colorectal Cancer (MCRC), either paclitaxel or capecitabine in patients with Metastatic Breast Cancer (MBC), as first-line therapy. | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With or Without Blood Pressure Increase as a Predictor of Progression Free Survival (PFS) | The incidence of hypertension was studied during treatment with bevacizumab combined with chemotherapy. A Cox regression analysis was performed, entering as a dependent variable the PFS and as independent variable the Arterial Hypertension (AHT) (yes/no). AHT is introduced in the model of Cox as a time-dependent variable since its situation can change as length of the study. The date on which the AHT changes (passes from normotensive to hypertensive). | Up to 3 years | 
| Progression Free Survival (PFS) | The PFS is the time from the patient receiving the first dose of chemotherapy for advanced disease to the date of progression, the administration of a new antineoplastic treatment that does not contain bevacizumab or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With White Coat AHT While at Home | The incidence of white coat arterial hypertension (AHT) was evaluated comparing each of the measurements in medical attention (in a doctor office) with the measurement that was made at home (without a doctor). White Coat Hypertension is a phenomenon in which people exhibit a blood pressure level above the normal range, in a clinical setting, though they do not exhibit it in other settings. | Cycle 1, cycle 2, and cycle 3, up to 9 weeks | 
| Number of Participants With White Coat AHT With 24 Hours Ambulatory BP Measure | The incidence of white coat arterial hypertension (AHT) was evaluated comparing each of the measurements with the measurement that was made in the hospital. Ambulatory Blood Pressure Monitoring (ABPM) is when the blood pressure is being measured as patient moves around, living her normal daily life. White Coat Hypertension is a phenomenon in which people exhibit a blood pressure level above the normal range, in a clinical setting, though they do not exhibit it in other settings. | Baseline, cycle 1, cycle 2, and cycle 3, up to 9 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hypertension, Bevacizumab Response Predictors, Metastatic Breast Cancer, Metastatic Colon Cancer