A011106: ALTernate approaches for clinical stage II or III Estrogen Receptor positive breast cancer NeoAdjuvant TrEatment (ALTERNATE) in postmenopausal women: A Phase III Study

Summary

This clinical trial was designed to examine the pathologic outcomes of patients whose neoadjuvant treatment course is determined using an early marker of endocrine resistance (namely, Ki67 after 4 or 12 weeks of neoadjuvant therapy) as well as assessing clinical outcome of patients whose disease burden after completing neoadjuvant endocrine therapy is classified as Modified PePi 0.

a treatment cycle is defined to be 4 weeks in length.
First Phase of the trial: neoadjuvant comparison phase; 400 eligible patients will be randomized to one of the 3 following treatment arms:

arm i: anastrozole arm: anastrozole daily for 6 cycles* followed by surgery.
- For the modified PePi 0 group, adjuvant anastrozole is to be administered for 54 cycles (approximately 4.5 years after surgery is completed). adjuvant chemotherapy is not recommended.
- For the modified PePi non-0 group it is recommended that adjuvant chemotherapy and endocrine therapy of the treating physician's choice be administered. Patients may participate in other adjuvant pharmaceutical trials.

arm ii: Fulvestrant arm: Fulvestrant on days 1 and 15 of cycle 1 and day 1 of cycles 2-6* followed by surgery.
- For the modified PePi 0 group, adjuvant fulvestrant is to be administered for 18 cycles (approximately 1.5 years) after surgery is completed and when fulvestrant treatment is complete begin anastrozole for an additional 36 cycles (approximately 3 years). adjuvant chemotherapy is not recommended.
- For the modified PePi non-0 group it is recommended that adjuvant chemotherapy and endocrine therapy of the treating physician's choice be administered. Patients may participate in other adjuvant pharmaceutical trials.

arm iii: anastrozole + Fulvestrant arm: anastrozole daily in combination with fulvestrant on days 1 and 15 of cycle 1, and on day 1 of cycles 2-6*, followed by surgery.
-For the modified PePi 0 group, adjuvant fulvestrant plus anastrozole are to be administered for 18 cycles (approximately 1.5 years) after surgery is completed and when fulvestrant treatment is complete continue anastrozole for an additional 36 cycles (approximately 3 years post surgery). adjuvant chemotherapy is not recommended.
- For the modified PePi non-0 group it is recommended that adjuvant chemotherapy and
endocrine therapy of the treating physician's choice be administered. Patients may participate
in other adjuvant pharmaceutical trials.

Second phase of the trial: Modified PePi 0 Validation Phase
During the study period between the completion of the randomization of 400 eligible patients to each of the 3 treatment arms and completion of analysis of their endocrine resistance data, all patients registered onto the study will be enrolled onto arm i.

Based on the findings of the analysis, one of the following will occur:
- only arm i will be open to enrollment.
- arm i and one of the fulvestrant containing arms (ii or iii) will be open to enrollment.
- arm i, arm ii and arm iii will all be open to enrollment
* in both phase of the trial, if a patient is found to have endocrine therapy resistant disease, defined by Ki67 [Greater Than] 10% at the 4-week or the 12-week biopsy, the patient will discontinue neoadjuvant endocrine protocol therapy, and it is recommended that the patient be switched to 12 weeks of neoadjuvant paclitaxel (the neoadjuvant Chemotherapy Group) as outlined in Section 8.1 of the protocol, or alternatively another regimen containing a taxane and/or anthracycline or CMF regimen administered per nCCn Guidelines, and then proceed to surgery. if patient would not be a candidate of neoadjuvant chemotherapy, the patient may proceed to surgery.

* neoadjuvant Chemotherapy Group: Paclitaxel 80mg/m2 iV on days 1, 8, 15 and 22 every 4 weeks
for 3 cycles followed by surgery oR chemotherapy regimen according to nCCn Guidelines.

Participant Eligibility

1. Female >= 18 years of age.
2. ECOG performance status 0-2.
3. Postmenopausal, verified by:
- Post bilateral surgical oophorectomy, or
- No spontaneous menses > 1 year or
- No menses for < 1 year with FSH and estradiol levels in postmenopausal range, according to institutional standards
4. Pathologic confirmation of invasive breast cancer diagnosed by core needle biopsy.
5. Clinical T2-T4c, any N, M0 invasive breast cancer, by AJCC 7th edition clinical staging, with the goal being surgery to complete excision of the tumor in the breast and the lymph node.
The extent of disease is a solitary lesion where the lesion is:
- palpable
- its size can be measured bidimensional by tape, ruler or caliper technique, and
- its largest tumor diameter is at least 2.0 cm (that is considered measurable by the WHO criteria)
Note:

* Patients with contralateral ductal carcinoma in situ and/or invasive breast cancer are not eligible.

* Patients with multifocal/multi-lesional breast cancer are not eligible if more than one lesion is invasive breast cancer in the same breast.
6. Invasive breast cancer is estrogen receptor (ER) positive with an Allred score of 6, 7 or 8 by local institution standard protocol. If an Allred Score is not reported on the diagnostic pathology report, ER positivity in > 66% cells is eligible. If ER positivity is < 66%, the staining intensity (weak, intermediate, strong) is needed to calculate the Allred Score to determine eligibility.
7. Invasive breast cancer is HER2 negative defined as 0 or 1+ by IHC or with a FISH ratio
(HER2 gene copy/chromosome 17) < 2 if IHC 2+ by local institution standard protocol.
8. Documentation of mammogram and ultrasound (including DCIS and invasive cancer) of the diseased breast performed within 42 days prior to registration. Mammogram for the unaffected contralateral breast is required within 12 months prior to registration.9. Laboratory values (<=14 days prior to registration)
Absolute Neutrophil Count (ANC) > 1,000/mm3
Platelet Count > 100,000/mm3
Total Bilirubin < 1.5 x upper limits of normal (ULN) Creatinine <1.5 x upper limits of normal (ULN) Serum ALT < 2.5 x upper limits of normal (ULN)
10. Tissue acquisition: Patient must agree to provide the required research biopsies at baseline, week 4 and at surgery for integral and integrated biomarker and correlative studies.