MLN0128 in Combination With Fulvestrant in Women With Advanced or Metastatic Breast Cancer After Aromatase Inhibitor Therapy

The drug being tested in this study is called MLN0128. MLN0128 is being tested to treat
postmenopausal women with advanced or metastatic estrogen receptor (ER) positive, human
epidermal growth factor receptor-2 (HER2) negative breast cancer that has progressed during
or after aromatase inhibitor (AI) therapy. This study will evaluate the efficacy and safety
of combination of fulvestrant + daily MLN0128 and fulvestrant + weekly MLN0128 compared with
fulvestrant alone.

The study will enroll approximately 153 patients. Participants will be randomly assigned (by
chance, like flipping a coin) to one of the three treatment groups—which will remain
undisclosed to the participant and study doctor during the study (unless there is an urgent
medical need):

- Fulvestrant 500 mg

- Fulvestrant 500 mg + MLN0128 4 mg

- Fulvestrant 500 mg + MLN0128 30 mg

All participants will receive either fulvestrant 500 mg intramuscularly (IM), fulvestrant 500
mg + MLN0128 4 mg daily or fulvestrant 500 mg + MLN0128 30 mg weekly.

This multicenter trial will be conducted worldwide. Participants will make multiple visits to
the clinic, and end of treatment (EOT) visit which will occur 30 to 40 days after receiving
their last dose of study drug or before the start of any subsequent anticancer therapy. After
EOT, participants will be followed for progression free survival (PFS) and overall survival
(OS).

Inclusion Criteria:

1. Female participants aged 18 years or older who are postmenopausal.

2. Histologically proven diagnosis of breast cancer with evidence of metastatic disease
or locoregional recurrence. 3. Histological confirmation and documentation of estrogen
receptor (ER)-positive status (≥1% positive stained cells). 4. Histological or
cytological confirmation and documentation of human epidermal growth factor receptor-2
(HER2)-negative status by local laboratory testing using criteria in the American
Society of Oncology (ASCO)/College of American Pathologists (CAP) Clinical Practice
Guideline update.

3. Measureable disease

4. Progressive Disease (PD) during prior aromatase inhibitor (AI) therapy.

5. Have a history of brain metastasis provided that all of the following criteria are
met:

- Brain metastases have been treated.

- No evidence of PD for ≥3 months before the first dose of study drug.

- No hemorrhage after treatment.

- Off dexamethasone treatment for ≥4 weeks before the first dose of study drug.

- No ongoing requirement for dexamethasone or anti-epileptic drugs.

6. Eastern cooperative oncology group (ECOG) performance status of 0 or 1.

7. Clinical laboratory values as specified below within 4 weeks before the first dose of
study drug:

- Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥1.5*10^9/L;
platelet count ≥100*10^9/L; hemoglobin (Hgb) ≥9 g/dL.

- Total bilirubin ≤1.5*the upper limit of the normal range (ULN), aspartate
aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5*ULN (≤5*ULN if
liver metastases are present).

- Creatinine clearance ≥40 mL/min based on Cockcroft-Gault estimate or based on a
12- or 24-hour urine collection.

- Fasting serum glucose ≤130 mg/dL and fasting triglycerides ≤300 mg/dL.

Exclusion Criteria:

1. Prior therapy with mechanistic target of rapamycin (mTOR), phosphoinositide-3-kinase
(PI3K), or dual PI3K-mTOR inhibitors, serine/threonine-specific protein kinase (AKT)
inhibitors, or fulvestrant.

2. Prior treatment with >1 line of chemotherapy for metastatic breast cancer or for
locoregional recurrence that was not amenable to resection or radiation therapy with
curative intent.

3. Experienced PD on >2 endocrine therapies for metastatic breast cancer or for
locoregional recurrence that was not amenable to resection or radiation therapy with
curative intent.

4. Life-threatening metastatic visceral disease (defined as extensive hepatic involvement
or symptomatic pulmonary lymphangitic spread).

5. Poorly controlled diabetes mellitus defined as hemoglobin A1c (glycosylated
hemoglobin; HbA1c) >7%; participants with a history of transient glucose intolerance
due to corticosteroid administration may be eligible if all other inclusion/exclusion
criteria are met.