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

An Open-Label Phase 2 Study of MLN0128 (A TORC1/2 Inhibitor) in Combination With Fulvestrant in Women With ER-Positive/HER2-Negative Advanced or Metastatic Breast Cancer That Has Progressed During or After Aromatase Inhibitor Therapy

The primary purpose of this study is to compare the progression free survival (PFS) of participants treated with the combination of fulvestrant plus daily sapanisertib and fulvestrant plus weekly sapanisertib versus participants treated with single-agent fulvestrant.

The drug being tested in this study is called sapanisertib. Sapanisertib 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 sapanisertib and fulvestrant + weekly sapanisertib 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 + Sapanisertib 4 mg
• Fulvestrant 500 mg + Sapanisertib 30 mg

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

This multicenter trial will be conducted Spain and the USA. 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.

5. Measurable disease defined as either of the following:

   • At least 1 extra-osseous lesion that could be accurately measured in at least 1 dimension.
   • The lesion must have measured ≥20 mm with conventional imaging techniques or ≥10 mm with spiral CT or MRI. Lymph nodes must be ≥1.5 cm in the short axis to be considered measurable.
   • Bone lesions (lytic or mixed [lytic plus sclerotic]) in the absence of measurable disease as defined above. Note: Participants with sclerotic/osteoblastic bone lesions only, in the absence of measurable disease, were not eligible.

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

7. 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.

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

9. 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.