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

Breast Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00459771
• Other study ID #: M06HER
• Secondary ID: 2006-001707-11
• Status: Completed
• Phase: Phase 3
• First received: April 11, 2007
• Last updated: December 1, 2014
• Start date: June 2007
• Est. completion date: December 2014

Study information

• Verified date: December 2014
• Source: The Netherlands Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 210
• Est. completion date: December 2014
• Est. primary completion date: December 2013
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 79 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Bio-availability Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Breast Cancer

Intervention

Drug:
• AT1 blocker candesartan
AT1 blocker candesartan, 32 mg oral QD
• Placebo
Placebo, 32 mg, oral QD

Locations

Country	Name	City	State
Netherlands	Medisch Centrum Alkmaar	Alkmaar
Netherlands	Flevoziekenhuis	Almere
Netherlands	Onze Lieve Vrouwe Gasthuis	Amsterdam
Netherlands	Slotervaart Hospital	Amsterdam
Netherlands	The Netherlands Cancer Institute	Amsterdam
Netherlands	Wilhelmina Ziekenhuis	Assen
Netherlands	Jeroen Bosch Hospital	Den Bosch
Netherlands	Deventer Ziekenhuis	Deventer
Netherlands	Medisch Spectrum Twente	Enschede
Netherlands	Martini Ziekenhuis	Groningen
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Ziekenhuis de Tjongerschans	Heerenveen
Netherlands	Medisch Centrum Leeuwarden	Leeuwarden
Netherlands	Antonius Ziekenhuis	Nieuwegein
Netherlands	Canisius-Wilhelmina Hospital	Nijmegen
Netherlands	UMC St. Radboud	Nijmegen
Netherlands	VieCuri Medisch Centrum voor Noord-Limburg	Venlo
Netherlands	Streekziekenhuis Koningin Beatrix	Winterswijk
Netherlands	Isala Klinieken	Zwolle

Sponsors (3)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute	AstraZeneca, Roche Pharma AG

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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