PrECOG 0102-Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Fulvestrant (Faslodex) plus Everolimus in Post-Menopausal Patients with Hormone-Receptor Positive Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy

Summary

This is a Phase ii study. 25 sites will be activated. 130 patients will be enrolled. There will be a balanced 1:1 randomization of everolimus:placebo (e.g., for every patient randomized to receive everolimus, one patient will be randomized to receive placebo).

Dosing and administration:

Fulvestrant (arm a and arm B)

induction Phase:

Cycle 1 (28 day cycle) - Patients will receive fulvestrant 500 mg iM (two-250 mg injections each dose) on day 1 and 15.

note: Cycle 1 is the only time fulvestrant is given on day 15. if patient previously received one cycle of fulvestrant (day 1 and day 15) prior to study entry as permitted in inclusion Criteria #8, patient should receive fulvestrant 500 mg on day 1 only.

Cycle 2, and thereafter (28 day cycles) - Patients will receive fulvestrant 500 mg iM (two-250 mg injections) on day 1 of all subsequent cycles for a maximum of 12 cycles.

everolimus or Placebo (arm a and arm B):

* The study drug everolimus/placebo will be self-administered (by the patients themselves). The local investigator will instruct the patient to take the study drug exactly as specified in the protocol. everolimus/placebo should be administered orally once daily, preferably in the morning, at the same time every day with or without food. everolimus/placebo tablets should be swallowed whole with a glass of water. The tablets must not be chewed or crushed. in cases where tablets cannot be swallowed, the tablets should be disintegrated in water just prior to being taken. approximately 30 mL (2 tablespoons) of water should be put into a glass. The tablets should then be added and the contents stirred gently (for a maximum of 7 minutes) until the tablets are disintegrated. The contents should then be drunk. if the patient vomits after taking the study drug, they should not take another tablet that day. if the patient forgets to take the medication and remembers by 10 PM, they may take the dose. otherwise, skip that dose and begin as usual the next day.
* everolimus/placebo will be administered orally as once daily dose of 10 mg (two- 5 mg tablets) continuously from study day 1 until progression of disease or unacceptable toxicity for 12 cycles. See Section 5.5 regarding duration of therapy (including guidelines for treatment beyond Cycle 12).
* if vomiting occurs, no attempt should be made to replace the vomited dose.
* all dosages prescribed and dispensed to the patient and all dose changes during the study must be recorded.
* PreCoG, or their designee, will be responsible for blinding, drug randomization, and management of the electronic interactive web registration (iWR) system. Both tablets will be blinded and identified by kit number only. The iWR system will assign the proper kit to the patient based on the patient randomization. Conditions for study drug will be described on the medication label.
* Both everolimus and placebo will be provided by novartis. everolimus is formulated as tablets for oral administration of 5 mg strength. Both placebo and everolimus tablets are blister-packed under aluminum foil in units of 10 tablets per blister card, which should be opened only at the time of administration as drug is both hygroscopic and light-sensitive.
* Dose modifications should be made prior to dose calculation at the beginning of each cycle and reasons recorded in source documents and on appropriate case report forms.

Randomization:
arm a: induction Phase
fulvestrant 500 mg iM (two- 250 mg injections each dose) day 1 and 15 of cycle 1, then 500 mg iM (two- 250 mg injections) day 1 of all subsequent cycles (every 28 days for 12 cycles) plus everolimus 10 mg (two- 5 mg tablets) Po QD x 12 cycles

arm B: induction Phase
fulvestrant 500 mg iM (two- 250 mg injections each dose) day 1 and 15 of cycle 1, then 500 mg iM (two- 250 mg injections) day 1 of all subsequent cycles (every 28 days for 12 cycles) plus placebo 2 tablets Po QD x 12 cycles

Participant Eligibility

1. Must be willing to sign a protocol-specific informed consent.
2. Patients must be 18 years of age or older.
3. Patients must have an ECOG Performance Status 0 or 1 (see Appendix B: ECOG Performance Status Scale).
4. Patients must have histologically or cytologically confirmed adenocarcinoma of the breast.
5. Patients must have stage IV disease or inoperable locally advanced disease.
6. Patients must have ER and/or PR-positive disease as determined by their local pathology or reference laboratory by ASCO-CAP criteria.51 Tumors must be HER-2/neu negative or equivocal by standard ICH/FISH or ICH/CISH methodologies by ASCO-CAP criteria.52
7. Patients must be Aromatase Inhibitor (AI) resistant, defined as:

* relapsed while receiving adjuvant therapy with an aromatase inhibitor (anastrozole, letrozole, or exemestane) or,

* progressive disease while receiving an aromatase inhibitor for metastatic disease.
Note: Patients may have received an endocrine agent (e.g., Tamoxifen) between the time of progression on an AI and registration. Patients previously treated with two or more prior cycles of fulvestrant are not eligible. Patients who have received one prior cycle (dose on day 1 and day 15) of fulvestrant within 28 days of randomization are eligible as long as they meet other eligibility criteria.
8. Patients who have received one prior cycle (dose on day 1 and day 15) of fulvestrant within 28 days of randomization are eligible so long as they meet other eligibility criteria.

* patients previously treated with two or more prior cycles of fulvestrant are not eligible
9. Patients must be female and postmenopausal, defined as:

* a history of at least 12 months without spontaneous menstrual bleeding or,

* prior bilateral salpingo-oophorectomy, with or without hysterectomy or,

* age >= 55 years with a prior hysterectomy with or without oophorectomy or,

* age <55 years with a prior hysterectomy without oophorectomy or unknown status, with a documented FSH level in postmenopausal range within 4 weeks of randomization or,

* receiving a gonadotropin releasing hormone analog (GnRH) to suppress ovarian function (e.g., goserelin 3.6 mg q 4 weeks).
10. Patients may have received up to one prior systemic chemotherapy regimen for metastatic disease.
11. Adequate organ function, as evidenced by ALL the following obtained within 4 weeks of randomization*:

* total white blood cell count (leukocytes, WBC) >= 3.0 x 109/L, absolute neutrophil count (ANC) >= 1.5 x 109/L and platelet count >= 100 x 109/L

* hemoglobin >= 9 g/dL

* serum bilirubin <= 1.5 x ULN

* AST or ALT <= 2.5 x ULN (<= 5 x ULN in patients with liver metastases)

* serum creatinine <= 1.5 x ULN

* serum albumin >= 3 g/dL

* fasting serum cholesterol <= 300 mg/dL OR <= 7.75 mmol/L AND fasting triglycerides <= 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.

* PT with INR <= 1.5 (Anticoagulation is allowed if target INR <= 1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for >2 weeks at time of randomization.)
*Please see study table in Section 7.0 for labs that may need to be repeated within <= 7 days of Cycle 1 Day 1 (C1D1).
12. Patients may have measurable disease, non-measurable disease (e.g., bone only metastases), or both per RECIST Version 1.1 Criteria. Measurable lesions are defined as those that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm by chest x-ray, as >= 10 mm with CT scan, or >= 10 mm with calipers by clinical exam. All tumor measurements must be recorded in millimeters (or decimal fractions of centimeters). Note: Tumor lesions that are situated in a previously irradiated
13. Patients with basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix within the past five years must have been treated with curative intent. Patients with a history of prior malignancy are eligible provided they were treated with curative intent and have been free of disease for >3 years.