Evaluating the Effect of Candesartan vs Placebo in Prevention of Trastuzumab-Associated Cardiotoxicity
Information source: The Netherlands Cancer Institute
Information obtained from ClinicalTrials.gov on October 19, 2009
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Breast Cancer
Intervention: placebo (Drug); AT1 blocker candesartan (Drug)
Phase: Phase 3
Status: Recruiting
Sponsored by: The Netherlands Cancer Institute Official(s) and/or principal investigator(s):
J.H.M. Schellens, MD PhD, Principal Investigator, Affiliation: The Netherlands Cancer Institute
Overall contact:
J.H.M. Schellens, MD PhD, Phone: +31 20 512 2446, Email: j.schellens@nki.nl
Summary
Evaluating the effect of the angiotensin II-receptor (AT1) blocker candesartan vs placebo in
prevention of trastuzumab-associated cardiotoxicity in patients with primary breast cancer
treated with trastuzumab.
Clinical Details
Official title: 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
Study design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment, Bio-availability Study
Primary outcome: 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%.
Detailed description:
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.
Eligibility
Minimum age: 18 Years.
Maximum age: 79 Years.
Gender(s): Female.
Criteria:
Inclusion Criteria:
- Women aged ≥18 years
- WHO: ≤ 2
- Strongly HER2-positive breast cancer, defined as an immunohistochemistry score of 3+
using the HercepTestTM, or gene amplification by fluorescence in situ hybridization,
or chromogenic in situ hybridization (CISH).
- Serum creatinine <140 umol/l or creatinine clearance > 50 ml/min (by Cockcroft-Gault
formula)
- Thyroid stimulating hormone between 0. 5-3. 9 MU/l
- Blood pressure systolic ≥ 140 mmHg and diastolic ≥ 90 mmHg is acceptable at
randomization. However prior to the first administration of trastuzumab blood
pressure should be regulated and should be systolic ≥ 100 mmHg and ≤ 180 mmHg and
diastolic ≥ 60 mmHg and ≤ 100 mmHg. (blood pressure should be regulated according to
the guidelines of appendix 5)
- LVEF ³ 50% assessed by multigated angiography (MUGA) or cardiac ultrasound
- Adjuvant regimen: trastuzumab start ≥ 3 weeks after day 1 of the last anthracycline
chemotherapy cycle
- Trastuzumab treatment according to standard medical care
- Written informed consent to participate in the study
Exclusion Criteria:
- Prior anthracycline chemotherapy regimen or anti-HER2 therapy, or other prior
biologic or immunotherapy for breast cancer treatment or any malignancy
- Previous malignancy requiring chemotherapy or radiotherapy
- Uncontrolled serious concurrent illness
- Patients with New York Heart Association (NYHA) class II/III/IV congestive heart
failure
- Myocardial infarction < 6 months before randomization
- Treatment with ACE inhibitor, ATII blocker, or lithium. Patients treated with ACE
inhibitor, or ATII blocker can switch (after randomization and during the
chemotherapy period) to alternative antihypertensive therapy; see appendix 5.
- History of hypersensitivity to the study medication
- Pregnancy or breast feeding
Locations and Contacts
J.H.M. Schellens, MD PhD, Phone: +31 20 512 2446, Email: j.schellens@nki.nl
University Medical Center Groningen, Groningen, Netherlands; Not yet recruiting
E.G.E. de Vries, MD PhD
UMC St. Radboud, Nijmegen, Netherlands; Not yet recruiting
W. vd Graaf, MD, PhD
Medisch Centrum Leeuwarden, Leeuwarden, Netherlands; Not yet recruiting
W.E. Fiets, MD, PhD
Canisius-Wilhelmina Hospital, Nijmegen, Netherlands; Not yet recruiting
C.M.P.W. Mandigers, MD, PhD
Slotervaart Hospital, Amsterdam, Netherlands; Not yet recruiting
M. Soesan, MD
Isala Klinieken, Zwolle, Netherlands; Not yet recruiting
A. Honkoop, MD PhD
Medisch Spectrum Twente, Enschede, Netherlands; Not yet recruiting
W. Smit, MD, PhD
The Netherlands Cancer Institute, Amsterdam 1066 CX, Netherlands; Recruiting
J.H.M. Schellens, MD, PhD
Additional Information
Starting date: June 2007
Last updated: June 20, 2007
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