Evaluating the Effect of Candesartan vs Placebo in Prevention of Trastuzumab-associated Cardiotoxicity

Netherlands Cancer Institute (NKI)

Status and phase

Completed

Phase 3

Conditions

Breast Cancer

Treatments

Drug: Placebo

Drug: AT1 blocker candesartan

Study type

Interventional

Funder types

Other

Industry

Identifiers

NCT00459771

M06HER

2006-001707-11 (EudraCT Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment

210 patients

Sex

Female

Ages

18 to 79 years old

Volunteers

No Healthy Volunteers

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