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

• Sponsor: Spanish Breast Cancer Research Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01733628
• Collaborator: Roche Farma, S.A (Industry)
• Enrollment: 143
• Locations: 10
• Actual Duration (Months): 61.9
• Patients Per Site: 14.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer; Metastatic Breast Cancer

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.

Study Design

• Study Type: Observational
• Actual Enrollment: 143 participants
• Observational Model: Case-Only
• Time Perspective: Prospective
• 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).
• Actual Study Start Date: Oct 23, 2012
• Actual Primary Completion Date: Dec 19, 2017
• Actual Study Completion Date: Dec 19, 2017

Arms and Interventions

Arm	Intervention/Treatment
Bevacizumab + Chemotherapy 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.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With or Without Blood Pressure Increase as a Predictor of Progression Free Survival (PFS) [Up to 3 years]

   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).

2. Progression Free Survival (PFS) [Up to 3 years]

   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.

Secondary Outcome Measures

1. Number of Participants With "White Coat" AHT While at Home [Cycle 1, cycle 2, and cycle 3, up to 9 weeks]

   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.

2. Number of Participants With "White Coat" AHT With 24 Hours Ambulatory BP Measure [Baseline, cycle 1, cycle 2, and cycle 3, up to 9 weeks]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

May only participate in the study patients (women and men) who meet all the following criteria:

1. 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.

2. Presence of measurable or evaluable disease according to RECIST 1.1, for the evaluation of the response to treatment.

3. Equal or more than 18 years old.

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

5. Signed written informed consent.

6. 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:

1. Have received prior systemic anticancer therapy with chemotherapy for advanced disease or prior treatment with bevacizumab.

2. Treatment with an investigational agent or biological agent within 30 days prior to inclusion in the study.

3. Contraindications to treatment with chemotherapy and bevacizumab according to summary products characteristics.

4. 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).

5. Life expectancy less than 3 months.

6. Patients who are pregnant or breastfeeding.

7. Patients with an inadequate organ function (bone marrow, kidney and liver)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital General Universitario de Elche	Elche	Alicante	Spain
2	Complejo Hospitalario Universitario A Coruña	A Coruña		Spain	15006
3	Hospital General Universitario de Alicante	Alicante		Spain
4	Complejo Hospitalario Universitario Reina Sofía	Córdoba		Spain
5	Complejo Hospitalario de Jaén	Jaén		Spain
6	Centro Oncológico MD Anderson	Madrid		Spain
7	Hospital General Universitario Gregorio Marañón	Madrid		Spain
8	Hospital Universitario 12 de Octubre	Madrid		Spain
9	Hospital Universitario La Fe	Valencia		Spain
10	Hospital Universitario Miguel Servet	Zaragoza		Spain

Sponsors and Collaborators

• Spanish Breast Cancer Research Group
• Roche Farma, S.A

Investigators

• Study Director: Study Director, Hospital General Universitario de Elche

Study Documents (Full-Text)

• Study Protocol - Feb 23, 2012

More Information

Additional Information:

• Spanish Breast Cancer Research Group (GEICAM) is a Spanish Breast Cancer Research Group

Publications

None provided.

• Responsible Party: Spanish Breast Cancer Research Group
• ClinicalTrials.gov Identifier: NCT01733628
• Other Study ID Numbers: GEICAM/2011-04; GEI-BEV-2011-02
• First Posted: Nov 27, 2012
• Last Update Posted: Dec 4, 2019
• Last Verified: Dec 1, 2019

• Keywords provided by Spanish Breast Cancer Research Group: Hypertension; Bevacizumab Response Predictors; Metastatic Breast Cancer; Metastatic Colon Cancer
• Additional relevant MeSH terms: Breast Neoplasms; Colorectal Neoplasms; Hypertension

Study Results

Participant Flow

Recruitment Details	From October 2012 to July 2016, 143 patients were included.

Arm/Group Title	Bevacizumab + Chemotherapy
Arm/Group Description	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.
Period Title: Overall Study
STARTED	143
COMPLETED	143
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Bevacizumab + Chemotherapy
Arm/Group Description	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.
Overall Participants	143
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61.18
Sex: Female, Male (Count of Participants)
Female	102 71.3%
Male	41 28.7%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
Spain	143 100%
Eastern Cooperative Oncology Group (ECOG) status (Count of Participants)
ECOG 0	67 46.9%
ECOG 1	72 50.3%
Unknown	4 2.8%
Blood Pressure Systolic (mmHg) [Mean (Full Range) ]
Mean (Full Range) [mmHg]	129.4
Blood Pressure Diastolic (mmHg) [Mean (Full Range) ]
Mean (Full Range) [mmHg]	74.73
Pulse (bpm) [Mean (Full Range) ]
Mean (Full Range) [bpm]	78.92
Women Menopausal Status (Count of Participants)
Postmenopausal women	75 52.4%
Premenopausal women	27 18.9%
Previous arterial hypertension (Count of Participants)
Previous arterial hypertension	43 30.1%
No Previous arterial hypertension	70 49%
Unknown	30 21%
Cancer type (Count of Participants)
Metastatic Colorectal Cancer (MCRC)	65 45.5%
Metastatic Breast Cancer (MBC)	78 54.5%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With or Without Blood Pressure Increase as a Predictor of Progression Free Survival (PFS)
Description	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).
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

There were 30 patients who were not included in Population per Protocol because of the following: 6 patients didn't fulfil inclusion and exclusion criteria, 8 patients didn't received Bevacizumab, 16 patients didn't have Holter assessment performed at baseline and/or at any other study visit.

Arm/Group Title	Bevacizumab + Chemotherapy
Arm/Group Description	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.
Measure Participants	113
No AHT : 0 to 0.5 years	19 13.3%
No AHT : 0.5 to 1 years	11 7.7%
No AHT : 1 to 1.5 years	6 4.2%
No AHT : 1.5 to 2 years	4 2.8%
No AHT : 2 to 2.5 years	1 0.7%
No AHT: 2.5 to 3 years	1 0.7%
Yes AHT: 0 to 0.5 years	94 65.7%
Yes AHT: 0.5 to 1 years	58 40.6%
Yes AHT: 1 to 1.5 years	25 17.5%
Yes AHT: 1.5 to 2 years	13 9.1%
Yes AHT: 2 to 2.5 years	7 4.9%
Yes AHT: 2.5 to 3 years	5 3.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Bevacizumab + Chemotherapy
	Comments
	Type of Statistical Test	Other
	Comments	Type of statistical Test: Inequality
Statistical Test of Hypothesis	p-Value	0.8166
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Progression Free Survival (PFS)
Description	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.
Time Frame	Up to 3 years

Outcome Measure Data

Analysis Population Description

There were 30 patients who were not included in Population per Protocol because of the following: 6 patients didn't fulfil inclusion and exclusion criteria, 8 patients didn't received Bevacizumab, 16 patients didn't have Holter assessment performed at baseline and/or at any other study visit

Arm/Group Title	Bevacizumab + Chemotherapy
Arm/Group Description	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.
Measure Participants	113
Mean (Standard Deviation) [Months]	10.19 (8.77)

3. Secondary Outcome

Title	Number of Participants With "White Coat" AHT While at Home
Description	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.
Time Frame	Cycle 1, cycle 2, and cycle 3, up to 9 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab + Chemotherapy
Arm/Group Description	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.
Measure Participants	113
No AHT	60 42%
Yes AHT	6 4.2%
Missing	47 32.9%
No AHT	73 51%
Yes AHT	10 7%
Missing	30 21%
No AHT	65 45.5%
Yes AHT	6 4.2%
Missing	42 29.4%

4. Secondary Outcome

Title	Number of Participants With "White Coat" AHT With 24 Hours Ambulatory BP Measure
Description	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.
Time Frame	Baseline, cycle 1, cycle 2, and cycle 3, up to 9 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Bevacizumab + Chemotherapy
Arm/Group Description	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.
Measure Participants	113
No AHT	94 65.7%
Yes AHT	14 9.8%
Missing	5 3.5%
No AHT	66 46.2%
Yes AHT	5 3.5%
Missing	42 29.4%
No AHT	83 58%
Yes AHT	9 6.3%
Missing	21 14.7%
No AHT	70 49%
Yes AHT	5 3.5%
Missing	38 26.6%

Adverse Events

Time Frame	All adverse events occurred during the treatment and up to 30 days after the last dose were notified. All Serious Adverse Events (SAEs) that occurred within the first 3 cycles were recorded in the electronic Case Report Form (eCRF). Only those Grade 3-4 adverse events that were related to the treatment that occurred during the first 3 treatment cycles were recorded in the eCRF.
Adverse Event Reporting Description	The Safety Population (SP) included 135 patients who signed the Informed Consent and received at least 1 dose of Chemotherapy combined with Bevacizumab. The Intent to Treat (ITT) Population included 143 patients who signed the Informed Consent. Serious Adverse Events and/or Other (Not Including Serious) Adverse Events (AEs) have been calculated in the SP (n=135), and All-Cause Mortality have been calculated in the ITT population (n=143) as per protocol.
Arm/Group Title	Bevacizumab + Chemotherapy
Arm/Group Description	The Safety Population (SP) included 135 patients who signed the Informed Consent and received at least 1 dose of Chemotherapy combined with Bevacizumab. The Intent to Treat (ITT) Population included 143 patients who signed the Informed Consent. Serious Adverse Events and/or Other (Not Including Serious) Adverse Events (AEs) have been calculated in the SP (n=135), and All-Cause Mortality have been calculated in the ITT population (n=143).
All Cause Mortality
	Bevacizumab + Chemotherapy
	Affected / at Risk (%)	# Events
Total	9/143 (6.3%)
Serious Adverse Events
	Bevacizumab + Chemotherapy
	Affected / at Risk (%)	# Events
Total	22/135 (16.3%)
Cardiac disorders
Acute coronary syndrome	1/135 (0.7%)
ICTUS	1/135 (0.7%)
Gastrointestinal disorders
Diarrhea	5/135 (3.7%)
Gastroenteritis	1/135 (0.7%)
Diverticulitis	1/135 (0.7%)
General disorders
Back pain	1/135 (0.7%)
Fever	1/135 (0.7%)
Malaise	1/135 (0.7%)
Immune system disorders
Neutrophil count decreased	1/135 (0.7%)
Infections and infestations
Skin infection: Cellulitis	1/135 (0.7%)
Lynph Gland Infection	1/135 (0.7%)
Lung infection	1/135 (0.7%)
Penile infection	1/135 (0.7%)
Soft tissue infection	2/135 (1.5%)
Urinary tract infection	1/135 (0.7%)
Metabolism and nutrition disorders
Anorexia	1/135 (0.7%)
Dehydration	1/135 (0.7%)
Musculoskeletal and connective tissue disorders
Abdominal pain	1/135 (0.7%)
Renal and urinary disorders
Urinary tract obstruction	1/135 (0.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/135 (1.5%)
Surgical and medical procedures
Coronary Angiography	1/135 (0.7%)
Other (Not Including Serious) Adverse Events
	Bevacizumab + Chemotherapy
	Affected / at Risk (%)	# Events
Total	57/135 (42.2%)
Blood and lymphatic system disorders
Neutrophil count decreased	12/135 (8.9%)
Neutrophil Count Decreased	3/135 (2.2%)
Blood bilirubin increased	1/135 (0.7%)
Lymphopenia	1/135 (0.7%)
Lymphopenia	2/135 (1.5%)
Cardiac disorders
Hypertension	11/135 (8.1%)
Gastrointestinal disorders
Abdominal pain	3/135 (2.2%)
Diarrhea	1/135 (0.7%)
Diarrhea	1/135 (0.7%)
Diverticulitis	1/135 (0.7%)
Fistulized perianal abscess	1/135 (0.7%)
Mucositis oral	2/135 (1.5%)
Nausea	1/135 (0.7%)
General disorders
Dehydration	1/135 (0.7%)
Fatigue	3/135 (2.2%)
Investigations
GGT increased	8/135 (5.9%)
APTT increased	3/135 (2.2%)
Alanine aminotransferase increased	1/135 (0.7%)
Aspartate aminotransferase increased	1/135 (0.7%)
Hyperkalemia	1/135 (0.7%)
Hyponatremia	1/135 (0.7%)
Metabolism and nutrition disorders
LDL Cholesterol increased	3/135 (2.2%)
Nervous system disorders
Anorexia	1/135 (0.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/135 (0.7%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrome	1/135 (0.7%)
Rash/Desquamation	1/135 (0.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.