Prospective, Randomized, Pharmacological Intervention Study; Evaluating Effect of the Angiotensin II-receptor (AT1) Blocker Candesartan vs Placebo in Prevention of Trastuzumab-associated Cardiotoxicity in Patients Treated With Trastuzumab
Prospective, randomized pharmacological intervention study
Primary objectives:
- to determine whether concurrent ATII-antagonist treatment can prevent trastuzumab-related
cardiotoxicity, defined as a decline in LVEF of more than 15% or a decrease to an absolute
value <45%
Secondary objectives:
- To determine if 'Brain Natriuretic Peptide' (NT-proBNP) and troponin T can be used
as surrogate marker in the monitoring of trastuzumab-associated cardiotoxicity
- To determine genetic variability in relevant genes such as the HER2 gene (by assessing
single nucleotide polymorphisms [SNPs] in the kinase domain) and explore any
correlations with trastuzumab induced cardiotoxicity 3) To determine the reversibility
of a decrease in left ventricular ejection fraction (LVEF) associated with trastuzumab
treatment
Arm I : placebo Arm II : AT1 blocker candesartan (32 mg/day; run in 16 mg during week 1)
Randomization: before chemotherapy treatment period. Study period: chemotherapy period,
trastuzumab treatment period 26 weeks follow up after discontinuation of trastuzumab
treatment and thereafter 1 month follow-up after end of placebo or AT1 blocker.
Candesartan treatment will start the same day as the first infusion of trastuzumab and will
continue up to 26 weeks after the end of treatment with trastuzumab.
Women with primary HER2 positive breast cancer who are considered for adjuvant systemic
treatment with anthracycline containing chemotherapy and trastuzumab.
Before start of anthracycline treatment:
- Medical history, physical examination
- New York Heart Association (NYHA) score
- Cardiac questionnaire
- Electrocardiogram
- MUGA scan
- Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count,
serum creatinine, sodium, potassium, calcium, thyroid stimulating hormone, glucose,
cholesterol, bilirubin, alkaline phosphatase, ASAT/ALAT, LDH, albumin, NT-proBNP,
troponin T analysis
- Pregnancy test
- Genotype analysis
Every chemotherapy cycle
- Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count,
serum creatinine, sodium, potassium, calcium, glucose, bilirubin, alkaline phosphatase,
ASAT/ALAT, LDH, albumin, (NT-proBNP, troponin T analysis)
Before start of trastuzumab treatment:
- Physical examination
- New York Heart Association (NYHA) score
- Cardiac questionnaire
- Electrocardiogram
- MUGA scan
- Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count,
serum creatinine, sodium, potassium, calcium, glucose, bilirubin, alkaline
phosphatase, ASAT/ALAT, LDH, albumin, NT-proBNP, troponin T analysis
After 3, 6 and 9 months trastuzumab:
- Physical examination
- New York Heart Association (NYHA) score
- Cardiac questionnaire
- MUGA scan
- Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count,
serum creatinine, sodium, potassium, calcium, glucose, bilirubin, alkaline phosphatase,
ASAT/ALAT, LDH, albumin, NT-proBNP, troponin T analysis
After 1 year trastuzumab, 26 weeks after the last trastuzumab administration:
- Physical examination
- New York Heart Association (NYHA) score
- Cardiac questionnaire
- Electrocardiogram
- MUGA scan
- Laboratory assessments; hemoglobin, hematocrit, white blood cell count, platelet count,
serum creatinine, sodium, potassium, calcium, glucose, bilirubin, alkaline phosphatase,
ASAT/ALAT, LDH, albumin, NT-proBNP, troponin T analysis
The primary endpoint of the study is the deterioration of the cardiac function defined as a
decline in LVEF of 15% or more to an absolute value below 45% during the year with
trastuzumab.
From previous studies it is estimated that about 30% of the patients treated with
trastuzumab will show deterioration of LVEF.
A total of 200 patients will receive trastuzumab and candesartan or trastuzumab and placebo
in this double blind placebo-controlled study. The number of patients randomized (= before
chemotherapy period) for this trial shall be more than 200 as a small number of patients
might drop out before start of therapy with trastuzumab. This number cannot exactly be
determined beforehand.
Interventional
Allocation: Randomized, Endpoint Classification: Bio-availability Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
The occurrence of cardiotoxicity, defined as a decline in LVEF (MUGA) of more than 15% or a decrease of less than 15% to an absolute value below 45%.
during 1 year trastuzumab therapy and during 26 weeks after discontinuation of trastuzumab
Yes
J.H.M. Schellens, MD PhD
Principal Investigator
The Netherlands Cancer Institute
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
M06HER
NCT00459771
June 2007
June 2013
Name | Location |
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Beth Israel Deaconess Medical Center | Boston, Massachusetts 02215 |