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TEAM II A randomised, multicentre, prospective, phase III trial investigating
TEAM IIa: Neoadjuvant hormonal therapy with exemestane for three versus six months.
and / or
TEAM IIb: The efficacy and safety of the addition of ibandronate to adjuvant hormonal therapy in postmenopausal women with hormone receptor positive early breast cancer.



- candidate number2269
- NTR NumberNTR785
- ISRCTNISRCTN17633610
- Date ISRCTN created28-dec-2006
- date ISRCTN requested18-dec-2006
- Date Registered NTR27-sep-2006
- Secondary IDsBOOG 2006-04 
- Public TitleTEAM II A randomised, multicentre, prospective, phase III trial investigating
TEAM IIa: Neoadjuvant hormonal therapy with exemestane for three versus six months.
and / or
TEAM IIb: The efficacy and safety of the addition of ibandronate to adjuvant hormonal therapy in postmenopausal women with hormone receptor positive early breast cancer.
- Scientific TitleA randomised, multicentre, prospective, phase III trial investigating
(a) Neoadjuvant hormonal therapy with exemestane for three versus six months
and / or
(b) The efficacy and safety of the addition of ibandronate to adjuvant hormonal therapy in postmenopausal women with hormone receptor positive early breast cancer.
- ACRONYMTEAM II
- hypothesisTEAM IIa: Six months of neoadjuvant therapy with exemestane is superior to three months with respect to the rate of downsizing in postmenopausal women with ER positive (> 50% of tumour cells positive) primary breast cancer.

TEAM IIb: Adjuvant systemic therapy combined with oral ibandronate results in an improved 3-years disease free survival compared to adjuvant systemic therapy without ibandronate in postmenopausal women with hormone receptor positive primary breast cancer.
- Healt Condition(s) or Problem(s) studiedBreast cancer
- Inclusion criteriaTEAM IIa:
1. Female patients with histologically, by core needle biopsy-proven, invasive adenocarcinoma of the breast.
2. Any tumour with a size >= 2 cm (except cT4d = inflammatory breast cancer).
3. Indication to receive adjuvant hormonal therapy according to most recent NABON guideline.
4. ER expression > 50% (PgR either positive or negative).
5. Postmenopausal women; postmenopausal defined as:
5.1 Age >= 50 and amenorrhoea for > 1 year.
5.2 Bilateral surgical oophorectomy and no HRT (any age is acceptable).
5.3 Age < 50 with natural amenorrhoea >1 year at breast cancer diagnosis (and uterus in situ).
5.4 Postmenopausal due to chemotherapy will be excluded.
5.5 In case of doubt about menopausal status, assessment of FSH, LH and estradiol has to be performed to define the menopausal status.
6. WHO performance status 0 or 1.
7. Absence of any psychological-, familial-, sociological- or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
8. Accessible for follow-up for the duration of the trial.
9. Before randomisation, patients must be capable of understanding the trial and give written informed consent according to ICH/GCP and local IRB guidelines.

TEAM IIb:
1. Histological confirmed invasive adenocarcinoma of the breast.
2. Stage I-III breast cancer.
3. Completed adequate surgical treatment.
4. (Neo)adjuvant chemotherapy, radiotherapy and / or trastuzumab are allowed.
5. Indication to receive adjuvant hormonal therapy according to most recent NABON guideline.
6. ER and / or PgR receptor positive (ER expression >= 10% and/or PgR >= 10%).
7. Known HER2 status.
8. Adequate renal- and hepatic function as assessed by laboratory testing within four weeks prior to enrolment.
8.1 Renal function;
Creatinine <= 120 µmol/L.
If limit values, the calculated creatinine clearance should be >= 30 mL/min with the Cockcroft and Gault-formula.
8.2 Hepatic function;
Total bilirubin <= 1.5 UNL
ASAT (SGOT) and ALAT (SGPT) <= 2.5 UNL
Alkaline Phosphatase <= 2.5 UNL
9. Postmenopausal women;postmenopausal defined as:
9.1 Age >= 50 and amenorrhoea for > 1 year.
9.2 Bilateral surgical oophorectomy and no HRT (any age is acceptable).
9.3 Age < 50 with natural amenorrhoea >1 year at breast cancer diagnosis (and uterus in situ).
9.4 Postmenopausal due to chemotherapy will be excluded.
9.5 In case of doubt about the menopausal status, assessment of FSH, LH and estradiol has to be performed to define the menopausal status.
10. WHO performance status 0 or 1.
11. Absence of any psychological-, familial-, sociological- or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
12. Accessible for follow-up for the duration of the trial.
13. Before randomisation, patients must be capable of understanding the trial and give written informed consent according to ICH/GCP, and local IRB guidelines.
- Exclusion criteriaTEAM IIa:
1. M1 disease by clinical examination according to the NABON guideline.
2. Multicentric breast cancer (including CIS).
3. Bilateral breast cancer (including CIS).
4. cT4d tumour (inflammatory breast cancer).
5. Hormone replacement therapy during the last 12 months.
6. One of the following diseases:
6.1 Uncontrolled cardiac disease.
6.2 Psychiatric disorders preventing proper informed consent.
6.3 Concomitant malignancies within the last five years, except for adequately treated carcinoma in situ of the uterine cervix or basal squamous cell carcinoma of the skin.
6.4 Prior invasive breast cancer or CIS within the last 15 years.
6.5 Other serious illnesses that may interfere with subject compliance, adequate informed consent or determination of causality of adverse events.
7. Concurrent participation in another clinical study that may interfere with the results of the trial involving investigational agents within thirty days of treatment from this study, unless this is agreed by the Study Coordinators.
8. More than three weeks after date of histological biopsy of primary breast cancer.

TEAM IIb
1. M1 disease by clinical examination according to the NABON guideline.
2. Bilateral invasive breast cancer (including CIS).
3. Patients having shown progressive disease in TEAM IIa (preoperative hormonal treatment with exemestane).
4. One of the following diseases:
4.1 Uncontrolled cardiac disease.
4.2 Psychiatric disorders preventing proper informed consent.
4.3 Patients with untreated oesophagitis, gastric ulcers or IBD.
4.4 Concomitant malignancies within the last five years, except for adequately treated carcinoma in situ of the uterine cervix or basal squamous cell carcinoma of the skin.
4.5 Prior invasive breast cancer and / or CIS within the last 15 years.
4.6 Other serious illnesses that may interfere with subject compliance, adequate informed consent or determination of causality of adverse events.
5. History of disease with influence on bone metabolism, including:
5.1 Pagets disease of the bone.
5.2 Primary hyperparathyroidism (patients cured by surgery may be included if interval >= 1 year).
6. Hormone replacement therapy during the last 12 months.
7. Current active dental problems including dental abscess or infection of the jawbone (maxilla or mandible), or a current or prior diagnosis of osteonecrosis of the jaw requiring maxillo-facial surgery.
8. Recent (within 4 weeks of study entry) or planned dental or jaw surgery (e.g. extraction, implants). Recent dental fillings, teeth scaling and polishing or minor gingival surgery do not exclude the patient.
9. Concurrent participation in another clinical study that may interfere with the results of the trial involving investigational agents within thirty days of treatment from this study, unless this is agreed by the Study Coordinators.
10. More than 5 weeks after final surgery or after end of adjuvant chemotherapy.
- mec approval receivedyes
- multicenter trialyes
- randomisedyes
- masking/blindingNone
- controlActive
- groupParallel
- Type[default]
- Studytypeintervention
- planned startdate 1-okt-2006
- planned closingdate1-okt-2010
- Target number of participants2478
- InterventionsTEAM IIa:
Patients will be randomised (1:1)between three versus six months of neoadjuvant therapy with exemestane (25 mg once daily). After surgery, patients may be randomised in the adjuvant part of the study (TEAM IIb) if the adjuvant inclusion criteria are met.

TEAM IIb:
Patients will be randomised (1:1) to oral ibandronate (50 mg once daily) for three years added to standard adjuvant systemic treatment or to standard adjuvant systemic therapy only. Hormonal treatment will be according to the most recent NABON guideline. Exemestane will be used as aromatase inhibitor.
- Primary outcomeTEAM IIa:
Objective response rate (immediately prior to surgery) of the primary breast tumour, assessed by palpation, which is preferably performed by the same person.

TEAM IIb:
Three years disease free survival.
- Secondary outcomeTEAM IIa:
1. Objective response rate of the breast tumour by mammography (RECIST).
2. Objective response rate of the breast tumour assessed by ultrasound (RECIST).
3. Objective response rate of the breast tumour assessed by MRI (RECIST).
4. Objective response rate of the regional lymph nodes assessed by ultrasound (RECIST).
5. Pathological complete response rate of primary breast cancer.
6. Pathological complete response rate of eventually positive lymph nodes.
7. Number of patients who required a mastectomy before neoadjuvant therapy and for whom breast conserving surgery became feasible after neoadjuvant therapy (independent of actual surgical treatment received).
8. Number of patients who required a mastectomy before neoadjuvant therapy and who received breast conserving surgery after neoadjuvant therapy.
9. Determination of predictive factors able to predict clinical and pathological response. 10. Collection of tumour samples for translational research to improve diagnostics and treatment of breast cancer.

TEAM IIb:
1. Time to and rate of bone metastases as first occurrence, in patients treated with these regimens.
2. Time to and rate of bone metastases, per se, in patients treated with these regimens.
3. Time to and rate of visceral and other distant metastases in patients treated with these regimens.
4. Time to and rate of local- and locoregional recurrences in patients treated with these regimens.
5. Time to and rate of contralateral breast cancer in patients treated with these regimens.
6. Five years disease free survival.
7. Overall survival (all cause mortality and breast cancer specific mortality) in patients treated with these regimens.
8. Safety and toxicity of ibandronate in patients treated with this bisphosphonate.
9. Specific prognostic indicators for the development of bone metastases and factors that are able to predict specific benefit from ibandronate treatment in these patients using tissue micro-array and other modern techniques.
- Timepoints
- Trial web sitehttp://www.ikcnet.nl
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIESProf. Dr. C.J.H. Velde, van de
- CONTACT for SCIENTIFIC QUERIESProf. Dr. C.J.H. Velde, van de
- Sponsor/Initiator TEAM II Study Group
- Funding
(Source(s) of Monetary or Material Support)
Leiden University Medical Center (LUMC)
- PublicationsN/A
- Brief summaryTEAM IIa
BACKGROUND: Clinical trials in patients with hormone receptor positive breast cancer have shown that neoadjuvant hormonal therapy accomplished relevant clinical and ultrasound response rates resulting in an improved rate of breast conserving surgery. Aromatase inhibitors are superior to tamoxifen in this setting. However, the optimal duration of neoadjuvant hormonal therapy has never been investigated in a phase III trial. Moreover, at present it is unknown who will benefit from neoadjuvant exemestane.
INTERVENTION: Patients will be randomised (1:1) between three versus six months of neoadjuvant therapy with exemestane (25 mg once daily). After surgery, patients may be randomised in the adjuvant part of the study (TEAM IIb) if the adjuvant inclusion criteria are met.
PRIMARY OBJECTIVE: Objective response rate (immediately prior to surgery) of the primary breast tumour, assessed by palpation
SIDE STUDIES:
* Translational research

TEAM IIb
BACKGROUND: Clinical trials have shown that bisphosphonates reduce the rate of skeletal related events and the incidence of new bone metastases in breast cancer patients with bone metastases. Two trials in patients with early breast cancer suggest that the bisphosphonate clodronate might prevent or delay bone metastases. One other trial produced conflicting results. At present, the value of adjuvant bisphosphonates is unclear. It is assumed that more potent bisphosphonates, such as ibandronate, may have greater potential to prevent bone metastases.
INTERVENTION: Patients will be randomised (1:1) to receive hormonal treatment with or without oral ibandronate (50 mg once daily) for three years. Hormonal treatment will be according most recent NABON guideline. Exemestane will be used as aromatase inhibitor.
PRIMARY OBJECTIVE: Three years disease free survival.
SIDE STUDIES:
* Translational research
* Life style study
- Main changes (audit trail)TEAM II A

Major amendment:
The main amendment is the transition from a randomized phase III study (3 vs 6 months neo-adjuvant exemestane) to a non-randomised, prospective phase II study (all patients receive 6 months neo-adjuvant exemestane). The reasons for this major change are explained below.
First, the inclusion rate has been less prosperous than expected: in the first 2 years, 34 patients have been randomized. An important reason for this low accrual is that patients as well as their physicians are motivated to opt for 6 months treatment and they prefer to continue the neoadjuvant treatment outside the study. Second, as the tumor remains in situ and accessible for examination (palpation, radiology), the neoadjuvant setting provides the unique model for testing the hypothesis in the same patient. The primary end point will remain clinical tumor response.
Due to this amendment, the statistical sample size calculation has changed. Based on recent literature (Bardanas A., et al. Br J Cancer 2009; 100:442-9), a clinical response rate is expected of 36% and 60% after 3 and 6 months neoadjuvant therapy with exemestane, respectively. These figures are supported by two other studies: 66% clinical response rate after 4 months in a relative young Japanese cohort with relative small tumors (Takei H., et al. Breast Cancer Res Treat 2008; 107:87-94) and 69% clinical response rate after 6 months in an Italian cohort more comparable with our intended patient population (Mustacchi G., et al. Ann Oncol 2009;20:655–9). To detect a difference of 24% with a two-sized 95%- confidence interval of 10%, 78 patients are needed. To compensate for a 5% drop-out rate, a total of 82 patients will be included.

Minor amendments:
1. Hormone replacement therapy during the last 12 months is currently an exclusion criterion. This is amended to Hormone replacement therapy for treatment of menopausal symptoms not stopped at least 4 weeks prior to registration. Patients < 55 years of age should have postmenopausal values of FSH, LH and estradiol. (Chapter 6.2).
2. More than three weeks after date of diagnostic histological biopsy of primary breast cancer is currently an exclusion criterion. Due to logistics problems, this is amended to More than six weeks (Chapter 6.2)
3. An important advantage of neoadjuvant systemic therapy is the downsizing of the primary tumor. In some instances, this may lead to a complete clinical response i.e. the tumor is not detectable by physical examination or radiological assessment. Although these patients have an excellent prognosis, an operation remains necessary to obtain adequate local control (Mieog et al., Br J Surg 2007; 94:1189-200). The placement of radiopaque clips to mark the primary tumor in patients who receive neoadjuvant chemotherapy and breast-conservation therapy is associated with better local control (Oh JL, et al., Cancer 2007; 110:2420-7). Therefore, the placement of tumor-marker clips is warranted in patients who respond well to neoadjuvant systemic therapy. This option is included in this amendment (Chapter 7). As the precise method of placement and choice of marker is not described in current NABON guideline (www.oncoline.nl), this is left to the scrutiny of the local investigator.

TEAM IIb
Major amendment:
In contrast to our expectations based on our previous TEAM study and the population of new postmenopausal breast cancer patients in The Netherlands, only 258 patients have been randomised in the first 2 years. Instead of 45 patient per month, the inclusion rate is about 10 patients per month. Due to this low accrual rate, it will take too long to answer the questions as stated in the protocol. We therefore lowered the sample size from 2058 to 1116 patients, by changing three statistical parameters, thereby maintaining the objectives of the trial (Chapter 18):
1) the power has been lowered from 90% to 80%
2) the inclusion period has been extended from 4 to 6 years
3) the DFS has been increased from 91% vs 94% to 92 vs 95% based on data from the TEAM trial (Jones SE et al., abstract 15, SABCS 2008) It is important to state that the appropriateness of the TEAM IIb trial has been emphasized in the past year. Recent literature showed positive results in estrogen-responsive early breast cancer premenopausal patients who used zoledronic acid (Gnant M., et al N Engl J Med 2009; 360:679-91. These promising results will probably increase the inclusion rate in our trial.

Minor amendments:
1. Deletion of the Lifestyle substudy. Since the number of patients included so far is much lower than expected, this substudy will be connected to another trial.
2. More than five weeks after final surgery or after end of chemotherapy is currently an exclusion criterion. Due to logistics problems, this is amended to More than nine weeks after final surgery or after end of adjuvant chemotherapy, or after end of adjuvant radiotherapy, whichever comes last (Chapter 15.2).
3. Hormone replacement therapy during the last 12 months is currently an exclusion criterion. This is amended to Hormone replacement therapy for treatment of menopausal symptoms not stopped at least 4 weeks prior to randomisation. Patients < 55 years of age should have postmenopausal values of FSH, LH and estradiol. (Chapter 15.2).
4. Currently, a new prescription of ibandronate should be send to Apotheek Zorg every three months. This is amended to yearly, with 2 repeat prescriptions (Chapter 16.6).
5. Currently, patients with HER2 overexpression should receive exemestane upfront. This has been amended to high risk patients in accordance with the latest NABON guidelines (Chapter 3.1).
6. In the patient information a section has been added concerning the logistics of the ibandronate delivery (Appendix G, page 107).
- RECORD27-sep-2006 - 15-jun-2013


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