Safety and Efficacy Study of MLN0128 in Combination With Exemestane or Fulvestrant in Postmenopausal Women With ER/PR+ Metastatic Breast Cancer

Inclusion Criteria

Each patient must meet all of the following inclusion criteria to be enrolled in the study:

Phase 1b and Phase 2

1. Advanced or metastatic breast cancer.

2. Histological or cytological confirmation of ER+ status (defined as > 1% positive tumor
cells), and histological or cytological confirmation of HER2-negative (HER2-) status
by local laboratory testing using criteria in the American Society of Oncology
(ASCO)/College of American Pathologists (CAP) Clinical Practice Guideline update.[44]

3. Female patients 18 years of age or older who:Are postmenopausal for at least 1 year
before the Screening visit, where menopause is defined by: Age ≥ 55 years and 1 year
or more of amenorrhea

Age < 55 years and 1 year or more of amenorrhea, with an estradiol assay < 20 pg/mL
oSurgical menopause with bilateral oophorectomy

Note: Ovarian radiation or treatment with a luteinizing hormone-releasing hormone
agonist (goserelin acetate or leuprolide acetate) is not permitted for induction of
ovarian suppression.

4. Patients who have a history of brain metastasis are eligible for the study provided
that all the following criteria are met:

- Brain metastases which have been treated

- No evidence of disease progression for ≥ 3 months or hemorrhage after treatment

- Off-treatment with dexamethasone for 4 weeks before administration of the first
dose of MLN0128

- No ongoing requirement for dexamethasone or anti-epileptic drugs

5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.

6. Clinical laboratory values as specified below within 4 weeks before the first dose of
MLN0128:

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

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

- Creatinine clearance ≥ 50 mL/min based either 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

7. Left ventricular ejection fraction (LVEF) within 5 absolute percentage points of
institutional standard of normal as measured by echocardiogram (ECHO) or multiple
gated acquisition scan (MUGA) within 4 weeks before the first dose of MLN0128 (ie, if
the institutional standard of normal is 50%, LVEF may be as low as 45% to be eligible
for the study).

8. Able to provide paraffin blocks or a minimum of 10 unstained slides of available
archival tumor tissues (paraffin blocks are preferred). If archival tumor tissue is
not available, a tumor biopsy may be performed before the patient begins treatment
with MLN0128. If fewer than 10 slides are available or the tumor content/area
requirements are not met, study eligibility will be determined upon discussion with
the sponsor.

9. Ability to swallow oral medications, willingness to perform mucositis prophylaxis, and
suitable venous access for the study-required blood sampling.

10. Voluntary written consent must be given before the performance of any study related
procedure not part of standard medical care, with the understanding that consent may
be withdrawn by the patient at any time without prejudice to future medical care.

Phase 1b Only: In addition to the previously mentioned inclusion criteria, each
patient must meet the following inclusion criterion to be enrolled in the phase 1b
portion of the study:

11. Patients may have SD or disease progression during their most recent treatment with
exemestane or fulvestrant, or everolimus in combination with either exemestane (any
country) or fulvestrant (US only). Exemestane or fulvestrant in combination with
MLN0128 can also be initiated as a new line of therapy.

Phase 2 Only: In addition to the previously mentioned inclusion criteria, each patient
must meet all of the following inclusion criteria to be enrolled in the phase 2
portion of the study:

12. Measureable disease defined as follows:

- At least 1 extra-osseous lesion that can be accurately measured in at least 1
dimension. The lesion must measure ≥ 20 mm with conventional imaging techniques
or ≥ 10 mm with spiral CT or MRI, or

- Bone lesions (lytic or mixed [lytic plus sclerotic]) in the absence of measurable
disease as defined above

13. Patients must have had disease progression during treatment with everolimus in
combination with either exemestane (any country) or fulvestrant (US only) (duration of
treatment ≥ 4 weeks) and must have tolerated everolimus treatment in combination with
exemestane (any country) or fulvestrant (US only) adequately according to the treating
physician's judgment. Everolimus in combination with exemestane or fulvestrant is not
required to be the most recent treatment before enrollment, but progression on the
most recent anticancer therapy is required for enrollment.

Exclusion Criteria

Patients meeting any of the following exclusion criteria are not to be enrolled in the
study:

Phase 1b and Phase 2

1. Prior anticancer therapy or other investigational therapy within 2 weeks before
administration of the first dose of MLN0128 (except for exemestane or fulvestrant,
which should be continued). Treatment with everolimus must be discontinued 2 weeks
before administration of the first dose of MLN0128.

2. Chronic concomitant therapy with bisphosphonates or denosumab for the prevention of
bone metastases. Concomitant treatment with bisphosphonates or denosumab is permitted
for treatment of osteoporosis or management of existing bone metastases if initiated
at least 4 weeks before administration of the first dose of MLN0128.

3. Initiation of treatment with hematopoietic growth factors, transfusions of blood and
blood products, or systemic corticosteroids (either IV or oral steroids, excluding
inhalers) within 1 week before administration of the first dose of MLN0128 (patients
already receiving erythropoietin on a chronic basis for ≥ 4 weeks are eligible).

4. Previous treatment with dual PI3K/mTOR inhibitors or TORC1/2 inhibitors.

5. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI
disease, or for an unknown reason that may alter the absorption of MLN0128.

6. Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) > 7%;
patients with a history of transient glucose intolerance due to corticosteroid
administration may be enrolled in this study if all other inclusion/exclusion criteria
are met.

7. Other clinically significant co-morbidities, such as uncontrolled pulmonary disease,
active central nervous system disease, active infection, or any other condition that
could compromise participation of the patient in the study.

8. Known human immunodeficiency virus infection.

9. History of any of the following within the last 6 months before administration of the
first dose of MLN0128:

- Ischemic myocardial event, including angina requiring therapy and artery
revascularization procedures

- Ischemic cerebrovascular event, including transient ischemic attack and artery
revascularization procedures

- Requirement for inotropic support (excluding digoxin) or serious (uncontrolled)
cardiac arrhythmia (including atrial flutter/fibrillation, ventricular
fibrillation, or ventricular tachycardia)

- Placement of a pacemaker for control of rhythm

- New York Heart Association Class III or IV heart failure

- Pulmonary embolism

10. Significant active cardiovascular or pulmonary disease before administration of the
first dose of MLN0128, including:

- Uncontrolled hypertension (ie, systolic blood pressure > 180 mm Hg; diastolic
blood pressure > 95 mm Hg)

- Pulmonary hypertension

- Uncontrolled asthma or oxygen saturation < 90% by arterial blood gas analysis or
pulse oximetry on room air

- Significant valvular disease; severe regurgitation or stenosis by imaging
independent of symptom control with medical intervention; or history of valve
replacement

- Medically significant (symptomatic) bradycardia

- History of arrhythmia requiring an implantable cardiac defibrillator

- Baseline prolongation of the rate-corrected QT interval (QTc; eg, repeated
demonstration of QTc interval > 480 ms, or history of congenital long QT
syndrome, or torsades de pointes)

11. Diagnosed or treated for another malignancy within 2 years before administration of
the first dose of MLN0128 or previously diagnosed with another malignancy and have any
evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in
situ of any type are not excluded if they have undergone complete resection.

Phase 1b Only: In addition to the previously mentioned exclusion criteria, patients
meeting the following exclusion criterion are not to be enrolled in the phase 1b
portion of the study:

12. More than 3 prior chemotherapy regimens for locally advanced or metastatic disease.

Phase 2 Only: In addition to the previously mentioned exclusion criteria, patients
meeting the following exclusion criterion are not to be enrolled in the phase 2
portion of the study:

13. More than 1 prior chemotherapy regimen for locally advanced or metastatic disease.