Microarray Analysis in breast cancer to Taylor Adjuvant Drugs Or Regimens, a randomized phase III study

ISRCTN ISRCTN61893718
DOI https://doi.org/10.1186/ISRCTN61893718
Secondary identifying numbers N/A
Submission date
20/12/2005
Registration date
20/12/2005
Last edited
02/09/2024
Recruitment status
No longer recruiting
Overall study status
Completed
Condition category
Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data

Plain English summary of protocol

Not provided at time of registration

Contact information

Dr S.C. Linn
Scientific

Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital
Departments of Molecular Biology and Medical Oncology
Plesmanlaan 121
Amsterdam
1066 CX
Netherlands

+31 (0)20 5122951
s.linn@nki.nl

Study information

Study designRandomized controlled trial
Primary study designInterventional
Secondary study designRandomised controlled trial
Study setting(s)Hospital
Study typeOther
Scientific titleMicroarray Analysis in breast cancer to Taylor Adjuvant Drugs Or Regimens, a randomized phase III study
Study acronymMATADOR, BOOG 2005-02, CKTO 2004-04
Study objectivesCurrent study hypothesis as of 29/04/2013:
To define gene expression profiles that can predict a disease-free survival (DFS) advantage for either dose dense therapy, or docetaxel-containing chemotherapy.

Previous study hypothesis until 29/04/2013:
With microarray analysis of primary breast cancers of patients who participate in this study one can identify gene expression profiles that can predict a disease-free survival advantage for either dose dense therapy, docetaxel, and/or 6 versus 4 courses of chemotherapy.
Ethics approval(s)Netherlands Cancer Institute, 15/03/2004, ref: EV04-87
Health condition(s) or problem(s) studiedBreast cancer
InterventionCurrent interventions as of 29/04/2013:
Randomization to one of the treatment arms (6 cycles TAC or AC dd)

ACdd:
doxorubicin 60 mg/m2 i.v. bolus and cyclophosphamide 600 mg/m2 i.v. bolus on day 1 every 2 weeks.
TAC:
Doxorubicin 50 mg/m² as an i.v. bolus on day 1, followed by cyclophosphamide 500 mg/m2 as i.v. bolus and, after 1 hour, docetaxel 75 mg/m² as 1 hour i.v. infusion on day 1 every 3 weeks.
Both Arms:
- prophylactic pegfilgrastim 6 mg s.c. given 1 day after completion of administration of each chemotherapy cycle;
- Radiotherapy, if indicated;
- Endocrine treatment for at least 5 years, (according to the most recent Dutch national guidelines)starting 1 to 6 weeks after radiotherapy or 3 to 6 weeks after chemotherapy for patients with positive estrogen and/or progesterone receptors.

HER2 positive patients
For HER2 positive patients we recommend to treat these patients outside the context of this study. Only in case of an increased risk of cardiotoxicity, the HERA study schedule is an alternative, in which case patients could participate in the MATADOR study.
Both Arms:
For HER2 positive patients with increased risk of cardiotoxicity, who are going to receive trastuzumab according to the schedule of the HERA study, trastuzumab should be given for 52 weeks, and should start within 7 weeks from day 1 of the last chemotherapy cycle or within 6 weeks from the end of adjuvant radiotherapy, whichever is last.

Previous interventions until 29/04/2013:
2 randomizations:
1. To one of the treatment arms (TAC or AC dd)
2. To 4 or 6 courses of chemotherapy (second randomization only open for patients with 1-3 positive axillary lymph nodes)

AC dd: doxorubicin 60 mg/m2 iv bolus and cyclophosphamide 600 mg/m2 iv bolus on day 1 every 2 weeks.
TAC: Docetaxel 75 mg/m2 1 hour i.v. infusion on day 1 in combination with doxorubicin 50 mg/m2 i.v. bolus and cyclophosphamide 500 mg/m2 i.v. bolus on day 1 every 3 weeks.

Both Arms:
1. Prophylactic pegfilgrastim 6 mg sc given 1 day after completion of administration of each chemotherapy cycle
2. Radiotherapy, if indicated
3. Endocrine treatment for 5 years, starting 1 to 6 weeks after radiotherapy or 3 to 6 weeks after chemotherapy for patients with positive estrogen and/or progesterone receptors.
Intervention typeMixed
Primary outcome measureCurrent primary outcomes as of 29/04/2013:
To define gene expression profiles that can predict a disease-free survival (DFS) advantage for either dose dense therapy, or docetaxel—containing chemotherapy.

Previous primary outcomes until 29/04/2013:
To define gene expression profiles that can predict a disease-free survival advantage for either dose dense therapy, docetaxel, and/or 6 versus 4 courses of chemotherapy.
Secondary outcome measuresCurrent secondary outcome measures as of 29/04/2013:
Is docetaxel-doxorubicin-cyclophosphamide (TAC) better than doxorubicin-cyclophosphamide dose-dense (AC dd) concerning DFS, RFS, breast cancer specific survival and all cause survival?
Objectives of optional side studies:
1. To determine whether the proteomic profile of patients, with primary breast cancer, relates to patient demographic characteristics, tumor stage, tumor biologic characteristics or tumor genetic (micro-array) profile
2. To identify a proteomic pattern that positively or negatively predicts relapse according to the genetic profile of the primary tumor (micro-array analysis) in each treatment arm
3. To identify a proteomic pattern in follow-up serum samples that can predict for relapse

Previous secondary outcome measures until 29/04/2013:
1. Is TAC better than AC dd regarding disease free survival and overall survival?
2. Are 6 courses better than 4 regarding disease free survival and overall survival?

Objectives of optional side studies
1.To determine whether the proteomic profile of patients, with primary breast cancer, relates to patient demographic characteristics, tumor stage, tumor biologic characteristics or tumor genetic (micro-array) profile
2.To identify a proteomic pattern that positively or negatively predicts relapse according to the genetic profile of the primary tumor (micro-array analysis) in each treatment arm
3.To identify a proteomic pattern in follow-up serum samples that can predict for relapse
Overall study start date01/10/2004
Completion date19/11/2012

Eligibility

Participant type(s)Patient
Age groupAdult
Lower age limit18 Years
SexFemale
Target number of participants600
Total final enrolment664
Key inclusion criteriaCurrent inclusion criteria as of 29/04/2013:
1. Women with pT1-T3, pN0-3b, M0 adenocarcinoma of the breast (TNM classification 2002). Women with a macrometastasis in the sentinel node, who did not receive an axillary dissection (pN1(sn)), are only eligible if radiotherapy of the axilla is included in the treatment plan (for instance experimental arm AMAROS study);
2. Known HER2 and estrogen receptor status.
3. Frozen tumor tissue available (or tumor tissue sent in RNAlater to NKI-AVL).
4. primary surgery (defined as date of last surgical intervention) < 6 weeks before randomisation, or radiotherapy < 5 weeks before randomisation.
5. Good performance status (WHO < 1)
6. normal hematology, normal renal and liver function tests (see below).
7. no history of heart failure.
8. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures during study treatment (chemotherapy and hormonal therapy).
9. no conditions that may compromise follow-up.
10. informed consent.
11. At least 18 years old and able to undergo intensive chemotherapy (in the study of Martin et al. employing the TAC regimen (1d) age < 65 years was required).
12. Laboratory requirements: (within 14 days prior to registration)
12.1. Hematology:
12.1.1. Neutrophils ≥ 1.5 109/L;
12.1.2. Platelets ≥ 100 109/L;
12.1.3. Hemoglobin ≥6.0 mmol/L;
12.2. Hepatic function:
12.2.1. Total bilirubin ≤ 16 umol/L;
12.2.2. ASAT (SGOT) and ALAT (SGPT) ≤ 1.5 UNL;
12.2.3. Alkaline phosphatase ≤ 2.5 UNL;
12.3. Renal function:
12.3.1. Creatinine ≤ 120 µmol/L;
12.3.2. If limit values, the calculated creatinine clearance should be ≥ 60 mL/min.

Previous inclusion criteria until 29/04/2013:
1. Women with pT0-T3, pN 1-3b, M0 adenocarcinoma of the breast (TNM classification 2002). Women with a macrometastasis in the sentinel node, who did not receive an axillary dissection (pN1(sn)), are only eligible if radiotherapy of the axilla is included in the treatment plan (for instance experimental arm AMAROS study).
2. Frozen tumor tissue available (or tumor tissue sent in RNAlater to NKI-AVL)
3. Primary surgery <6 weeks before randomisation, or radiotherapy <5 weeks before randomisation
4. Good performance status; WHO <1
5. Normal hematology, normal renal and liver function tests (see below)
6. No history of heart failure
7. Patients of childbearing potential must implement adequate non-hormonal contraceptive measures during study treatment (chemotherapy and hormonal therapy)
8. No conditions that may compromise follow-up
9. Written Informed consent
10. Able to undergo intensive chemotherapy (in the study of Nabholtz (1) age <65 years was required)
11. Laboratory requirements: (within 14 days prior to registration)
Hematology:
i. Neutrophils >1.5 x 10^9/l
ii. Platelets >100 x 10^9/l
iii. Hemoglobin >6.0 mmol/l
Hepatic function:
i. Total bilirubin <16 µmol/L
ii. ASAT (SGOT) and ALAT (SGPT) <1.5 UNL
iii. Alkaline phosphatase <2.5 UNL
Renal function:
i. Creatinine <120 µmol/l
ii. If limit values, the calculated creatinine clearance should be >60 ml/min
Key exclusion criteriaCurrent exclusion criteria as of 29/04/2013:
1. Prior systemic anticancer therapy for any cancer (immunotherapy, hormonal therapy, chemotherapy)
2. Prior radiation therapy for breast cancer
3. HER2 positive breast cancer (except for patients who are going to be treated according to HERA study (1c)
4. Pregnant, or lactating patients
5. Pre-existing motor or sensory neurotoxicity of a severity > grade 2 by NCI criteria
6. Other serious illness or medical condition:
6.1. Congestive heart failure or unstable angina pectoris, previous history of myocardial infarction within 1 year from study entry, uncontrolled hypertension or high-risk uncontrolled arrhythmias
6.2. History of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent
6.3. Active uncontrolled infection
7. Past history of invasive breast cancer or past or current history of neoplasm other than breast carcinoma, except for:
7.1. Curatively treated non-melanoma skin cancer
7.2. In situ carcinoma of the cervix
7.3. Ipsilateral ductal carcinoma in-situ (DCIS) of the breast
7.4. Lobular carcinoma in-situ (LCIS) of the breast
8. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry
9. Male patients

Previous exclusion criteria until 29/04/2013:
1. Prior systemic anticancer therapy for any cancer (immunotherapy, hormonal therapy, chemotherapy)
2. Prior radiation therapy for breast cancer
3. Pregnant, or lactating patients
4. Pre-existing motor or sensory neurotoxicity of a severity > grade 2 by NCI criteria
5. Other serious illness or medical condition:
5.1 Congestive heart failure or unstable angina pectoris, previous history of myocardial infarction within 1 year from study entry, uncontrolled hypertension or high-risk uncontrolled arrhythmias
5.2 A history of significant neurological or psychiatric disorders including psychotic disorders, dementia or seizures that would prohibit the understanding and giving of informed consent
5.3 Active uncontrolled infection
6. Past or current history of neoplasm other than breast carcinoma, except for:
6.1 Curatively treated non-melanoma skin cancer
6.2 In situ carcinoma of the cervix, cipsilateral ductal carcinoma in-situ (DCIS) of the breast,
6.3 Llobular carcinoma in-situ (LCIS) of the breast
7. Concurrent treatment with other experimental drugs. Participation in another clinical trial with any investigational not marketed drug within 30 days prior to study entry.
8. Male patients
Date of first enrolment01/10/2004
Date of final enrolment19/11/2012

Locations

Countries of recruitment

  • Netherlands

Study participating centre

Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital
Amsterdam
1066 CX
Netherlands

Sponsor information

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI AVL)
Hospital/treatment centre

Plesmanlaan 121
Amsterdam
1066 CX
Netherlands

+31 (0)20 5129111
y.rhemrev@nki.nl
ROR logo https://ror.org/03xqtf034

Funders

Funder type

Industry

Sanofi-Aventis

No information available

Amgen
Government organisation / For-profit companies (industry)
Alternative name(s)
Amgen Inc., Applied Molecular Genetics Inc.
Location
United States of America
Koningin Wilhelmina Fonds

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to shareYes
IPD sharing plan summaryOther
Publication and dissemination planNot provided at time of registration
IPD sharing planThe gene expression data will be available after publication. The patient level data have been submitted to the Early Breast Cancer Trialists's Group, also called the Oxford Overview. This database is not publicly available (https://www.ctsu.ox.ac.uk/research/ebctcg).

Study outputs

Output type Details Date created Date added Peer reviewed? Patient-facing?
Results article results 27/11/2017 16/01/2019 Yes No
Results article results 01/10/2018 16/01/2019 Yes No
Results article 29/06/2024 02/09/2024 Yes No

Editorial Notes

02/09/2024: Publication references added.
23/04/2019: The total final enrolment has been added from the results publication.
17/01/2019: IPD sharing statement added.
16/01/2019: Publication references added.
29/04/2013: The following changes were made to the trial record:
1. The overall trial end date was changed from 30/09/2008 to 19/11/2012.
2. The target number of participants was changed from 1200 to 600 after an amendment that had been approved by the medical ethical committee.

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