Condition category
Cancer
Date applied
23/02/2010
Date assigned
06/04/2010
Last edited
06/04/2010
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Dr Luca Gianni

ORCID ID

Contact details

Fondazione IRCCS Istituto Nazionale Tumori
Via Venezian
1
Milano
20133
Italy
+39 (0)2 2390 2789
luca.gianni@istitutotumori.mi.it

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

FM-B04-01

Study information

Scientific title

European Cooperative Study of Primary Systemic Therapy in Women with Operable Breast Cancer and T > 2 cm: a multicentre open-labelled trial with two separate parallel studies

Acronym

ECTO II

Study hypothesis

The primary efficacy variable of this protocol consisting in two separate and parallel phase II studies is the rate of pathological complete remissions (pCR = absence of invasive cancer cells at pathological examination) assessed at surgery after primary systemic therapy in ER-negative (Study 1) and in ER-positive (Study 2) early breast cancer.

In ER-negative tumours, prior experience revealed that after 4 cycles of AT (doxorubicin [Adriamycin®] and paclitaxel [Taxol®]) followed by 4 cycles of CMF (Cyclophosphamide, Methotrexate, Flourouracil), the rate of pCR was 46%. Patients eligible for Study 1 will be randomly allocated to one of three arms and for each study regimen an absolute increase of the pCR rate of at least 15% . An important secondary endpoint of the study is to decide which of the three regimens is the most promising. This will be addressed based on a randomised phase II trial design proposed by Simon et al. in 1985 and updated in 2002. For ER-negative tumours a pCR rate > 50% is considered to be of clinical interest. Therefore, the null hypothesis is set at 50% vs an alternative hypothesis of a pCR rate of 65%. In order to have a 90% probability of selecting a treatment regimen if it has at least a 15% better activity than the others, 105 patients are to be randomly assigned to each of the three regimens. This would assume that the response rate in the less efficacious arm(s) is 50%. No formal comparison between the three arms is planned. Instead, the regimen(s) with the best response rate will be declared the “winner(s)” provided its (their) response rate is greater that 50%. From the above, a total of 315 patients with ER-negative tumours would be needed. At the first stage of accrual, a total of 42 patients are needed for each of the three regomens and accrual to the study will be continued for those of the arms where at least 23 pCR have been documented.

In ER-positive tumours, prior experience revealed that after 4 cycles of AT followed by 4 cycles of CMF, the rate of pCR was 11%. Patients eligible for Study 2 will be randomly allocated to one of three arms and for each study regimen an absolute increase of the pCR rate of at least 15%. An important secondary endpoint of the study is to decide which of the three regimens is the most promising. This will be addressed based on a randomized phase II trial design proposed by Simon et al. in 1985 and updated in 2002. For ER-positive tumours a pCR rate > 10% is considered to be of clinical interest. Therefore, the null hypothesis is set at 10% vs an alternative hypothesis of a pCR rate of 25%. In order to have a 90% probability of selecting a treatment regimen if it has at least a 15% better activity than the others, 57 patients are to be randomly assigned to each of the three regimens. This would assume that the response rate in the less efficacious arm(s) is 10%. No formal comparison between the three arms is planned. Instead, the regimen(s) with the best response rate will be declared the “winner(s)” provided its (their) response rate is greater that 10%. From the above, a total of 171 patients with ER-positive tumours would be needed. At the first stage of accrual, a total of 28 patients are needed for each of the three regimens and accrual to the study will be continued for those of the arms where at least 4 pCR have been documented.

Ethics approval

Independent Ethics Committee of the Istituto Nazionale Tumori of Milano (Coordinating Center) approved on the 24th February 2005 (ref: INT 21/05)
All other centres will seek ethics approval before recruiting participants.

Study design

Multicentre open-labelled trial with two separate parallel studies

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

No available in web format, please use contact details below to request a patient information sheet.

Condition

Early invasive unilateral breast cancer larger than 2 cm in diameter

Intervention

1. Patients in Study 1 will randomly receive one of the three following regimens
1.1. AT: doxorubicin (60 mg/ m^2) plus paclitaxel (200 mg/m^2) every 3 weeks for 4 cycles sequentially followed by CMF: cyclophosphamide (600 mg/m2^), methotrexate (40 mg/m^2) and fluorouracil (600 mg /m^2) by intravenous administration on day 1 and 8, every 4 weeks for 4 cycles.
1.2. AT: doxorubicin (60 mg/ m^2) plus paclitaxel (200 mg/m^2) every 3 weeks for 4 cycles sequentially followed by CM: cyclophosphamide (600 mg/m^2), methotrexate (40 mg/m^2) by intravenous administration on day 1 and 8 every 4 weeks for 4 cycles plus Capecitabine (Xeloda® [X]) to be administered orally from day 1 to day 14 of each cycle at the dose of 1850 mg/m^2 (to be divided in two daily doses, within half an hour from breakfast and dinner, with a glass of water) for 4 cycles.
1.3. AC: doxorubicin (60 mg/ m^2) plus cyclophosphamide (600 mg/m^2) every 3 weeks for 4 cycles sequentially followed by Paclitaxel (100 mg/m^2) on day 1 and 8 every 3 weeks for 4 cycles plus Capecitabine (Xeloda® [X]) to be administered orally from day 1 to day 14 of each cycle at the dose of 1850 mg/m^2 (to be divided in two daily doses, within half an hour from breakfast and dinner, with a glass of water) for 4 cycles.

Patients in Study 2 will randomly receive one of the three following regimens
1) AT: doxorubicin (60 mg/ m^2) plus paclitaxel (200 mg/m^2) every 3 weeks for 4 cycles sequentially followed by CMF: cyclophosphamide (600 mg/m2^), methotrexate (40 mg/m^2) and fluorouracil (600 mg /m^2) by intravenous administration on day 1 and 8 every 4 weeks for 4 cycles. Exemestane will be administered daily at the oral dose of 25 mg from the first day of doxorubicin and paclitaxel till the day of surgery. Luteinizing Hormone-Releasing Hormone (LH-RH) analogues must be delivered in premenopausal patients to achieve total estrogen blockade.
2) AT: doxorubicin (60 mg/ m^2) plus paclitaxel (200 mg/m^2) every 3 weeks for 4 cycles sequentially followed by CM: cyclophosphamide (600 mg/m^2), methotrexate (40 mg/m^2) by intravenous administration on day 1 and 8 every 4 weeks for 4 cycles plus Capecitabine (Xeloda® [X]) to be administered orally from day 1 to day 14 of each cycle at the dose of 1850 mg/m^2 (to be divided in two daily doses, within half an hour from breakfast and dinner, with a glass of water) for 4 cycles. Exemestane will be administered daily at the oral dose of 25 mg from the first day of doxorubicin and paclitaxel till the day of surgery. LH-RH analogues must be delivered in premenopausal patients to achieve total estrogen blockade.
3) AC: doxorubicin (60 mg/ m^2) plus cyclophosphamide (600 mg/m^2) every 3 weeks for 4 cycles sequentially followed by paclitaxel (100 mg/m^2) on day 1 and 8 every 3 weeks for 4 cycles plus capecitabine (Xeloda® [X]) to be administered orally from day 1 to day 14 of each cycle at the dose of 1850 mg/m^2 (to be divided in two daily doses, within half an hour from breakfast and dinner, with a glass of water) for 4 cycles. Exemestane will be administered daily at the oral dose of 25 mg from the first day of doxorubicin and cyclophosphamide till the day of surgery. LH-RH analogues must be delivered in premenopausal patients to achieve total estrogen blockade.

Surgery (followed by radiotherapy if breast conserving) is scheduled after completion of the systemic therapy in all patients.

Although disease-free and overall survival are not the main objectives of this study, we recommended that all patients be followed for at least the first 5 years after the end of the planned treatment to comply with Good Clinical Practice (GCP) rules on long-term safety of study drugs.

Intervention type

Drug

Phase

Phase II

Drug names

AT: Doxorubicin (Adriamycin®), paclitaxel (Taxol®); CMF: cyclophosphamide, methotrexate, flourouracil; X: capecitabine (Xeloda®); exemestane (Aromasin®)

Primary outcome measures

Pathological complete response in breast (pCR), defined as the absence of invasive cancer cells at pathological examination, measured when all patients complete surgery

Secondary outcome measures

1. Overall response rate measured when patients complete primary systemic therapy
2. Tolerability and safety of all proposed regimens

Overall trial start date

30/06/2005

Overall trial end date

18/12/2008

Reason abandoned

Eligibility

Participant inclusion criteria

1. Female patients, presenting for the first time with unilateral operable breast cancer larger than 2.0 cm in largest diameter, who have not received any previous treatment for an invasive malignancy
2. Histologically proven diagnosis of invasive breast cancer
3. Estrogen receptor status assessed as negative (Study 1) or positive (Study 2)
4. Age greater than or equal to 18 years
5. Eastern Cooperative Oncology Group (ECOG) Performance Status less than or equal to 1
6. Availability of Human EGF (Epidermal Growth Factor) Receptor 2 (HER2) status on immunohistochemistry
7. Availability of progesterone receptor status
8. Primary tumour lesion measurable on largest diameter by clinical and/or radiological examination. Presence of suspected multifocal disease does not exclude the patient
9. Patients must have completed all instrumental and laboratory evaluations within 4 weeks prior to study entry
10. Signed written informed consent (approved by the Institutional Review Board [IRB]/ Independent Ethics Committee [IEC]) obtained prior to any study specific screening procedures
11. Able to comply with the protocol

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

Total planned recruitment of 486 patients, 315 in Study 1 and 171 in Study 2

Participant exclusion criteria

1. Pregnant or lactating women. Documentation of a negative pregnancy test must be available for premenopausal women with intact reproductive organs and for women less than one year after the menopause
2. Women of childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception. For example: intra-uterine device or barrier method of contraception in conjunction with spermicidal jelly
3. Evidence of metastases or locally advanced breast cancer
4. Bilateral breast cancer
5. Absence of ER assessment
6. Previous treatment with chemotherapy or hormonal therapy or any prior therapy with any investigational drug for any type of malignancy
7. Previous extensive radiotherapy or major surgery for any malignancy
8. Previous or concomitant malignancy of any type, except adequately treated basal cell carcinoma of the skin or in situ cervix cancer
9. Patients with New York Heart Association (NYHA) class greater than or equal to II heart disease
10. Patients with a left ventricular ejection fraction (LVEF) below 50% by Multiple Uptake Gated Acquisition (MUGA) scan or echocardiography
11. Pre-existing motor or sensory neuropathy of grade greater than 1 for any reason
12. Patients with a history of hypersensitivity due to administration of drugs containing polyoxyethylene castor oil (Cremophor EL) (e.g., cyclosporin), or hardened castor oil (e.g., vitamin preparations for injection, etc.)
13. Other serious illness or medical condition including:
13.1. History of documented congestive cardiac failure
13.2. Angina pectoris requiring antianginal medication
13.3. Evidence of transmural infarction on ECG
13.4. Poorly controlled hypertension (e.g. systolic greater than 180 mm Hg or diastolic greater than 100 mm Hg; however, patients with hypertension which is well controlled on medication are eligible)
13.5. Clinically significant valvular heart disease
13.6. High-risk uncontrolled arrhythmias
14. Patients with a history of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant and precluding informed consent or adversely affecting compliance to study drugs
15. Serious uncontrolled infections (bacterial or viral) or poorly controlled diabetes mellitus
16. Any of the following abnormal baseline haematological values:
16.1. Neutrophils less than 1.5 x10^9/L
16.2. Platelets less than 100 x 10^9/L
17. Any of the following abnormal laboratory tests:
17.1. Serum total bilirubin greater than 1.25 xULN (upper limit of normal) (except for patients with clearly documented Gilbert’s syndrome)
17.2. Alanine transaminase (ALT) or aspartate transaminase (AST) greater than 1.25 x ULN
17.3. Alkaline phosphatase greater than 1.25 x ULN
17.4. Serum creatinine greater than 1.5 x ULN

Recruitment start date

30/06/2005

Recruitment end date

18/12/2008

Locations

Countries of recruitment

Austria, Germany, Italy, Russian Federation, Spain

Trial participating centre

Fondazione IRCCS Istituto Nazionale Tumori
Milano
20133
Italy

Sponsor information

Organisation

Fondazione Michelangelo (Italy)

Sponsor details

Via Venezian
Milano
20133
Italy
+39 (0)2 2390 3071
pinuccia.valagussa@istitutotumori.mi.it

Sponsor type

Charity

Website

http://www.fondazionemichelangelo.org

Funders

Funder type

Charity

Funder name

Michelangelo Foundation (Fondazione Michelangelo) (Italy)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes