Dual mTOR Inhibitor MLN0128 in Advanced Castration-Resistant Prostate Cancer (CRPC) Patients

To be included in this study, patients should have histologically confirmed castration
resistant metastatic prostate cancer with evidence of disease progression. Patients must
have been in a castrate state either by orchiectomy or by GnRH analogues. In detail, they
should meet all of the following criteria

Inclusion Criteria:

- Histologically confirmed prostate cancer with progressive metastatic disease based on
any of the following: i) a rise in PSA, ii) transaxial imaging, or iii) radionuclide
bone scan.

1. PSA - a minimum of 3 consecutive rising levels, with an interval of ≥

1 week between each determination. The last determination must have a minimal
value of ≥ 2 ng/mL and be determined within two weeks prior to enrollment.

2. Measurable Disease - patients showing new or progressive soft tissue masses on CT
or MRI scans as defined by the PCWG2 criteria21

3. Radionuclide bone scan - at least two new metastatic lesions.

- Detectable metastases by bone scan, CT-scan or MRI.

- Ongoing androgen depletion therapy with a Gonadotropin Releasing Hormone (GnRH)
analogue or inhibitor, or orchiectomy (i.e., surgical or medical castration).

For patients who have not had an orchiectomy, there must be a plan to maintain effective
GnRH-analogue therapy for the duration of the trial.

- Castrate levels of serum testosterone < 50 ng/dL determined within 4 weeks prior to
starting treatment.

- Patients who are receiving an anti-androgen as part of their first-line hormonal
therapy must have shown progression of disease off the anti-androgen prior to
enrollment.

- At least 4 weeks must have elapsed from the use of androgen receptor antagonists
(i.e., flutamide, nilutamide, bicalutamide, enzalutamide ); 5-α reductase inhibitors
(i.e., finasteride, aminoglutethimide); abiraterone acetate; estrogens; nitrosoureas,
mitomycin C, isotype therapy, ketoconazole, chemotherapy and other anti-cancer
pharmacologic therapy prior to beginning protocol therapy.

- At least 8 weeks must have elapsed from the use of Strontium-89, Radium-223,
Samarium-153, or immunotherapy (e.g., Provenge) prior to beginning protocol therapy.

- At least 4 weeks must have elapsed from the use of any investigational agent prior to
beginning protocol therapy.

a. Note: Prior treatment with PI3K/mTOR pathway inhibitors prohibited.

- At least 4 weeks must have elapsed from major surgery.

- Toxicities related to prior therapy must either have returned to ≤ Grade 1, baseline
or deemed irreversible.

- Patients with treated, non-progressive epidural disease are eligible.

- KPS performance status 70-100% (50-60% is allowed only if due to bone pain)

- At least 18 years of age, with a life expectancy at least 3 months.

- Patient must be willing to comply with study procedures.

- Physical and laboratory test findings

1. Adequate hepatic function with serum bilirubin ≤ 1.5 times the upper
institutional limits of normal (ULN), ALT and AST ≤ 2.5 x ULN. Patients with a
history of Gilbert's syndrome may be enrolled if the total bilirubin is < 3 mg/dL
with a predominance of indirect bilirubin

2. Adequate renal function with serum creatinine ≤ 1.5 x ULN.

3. Adequate hematologic function with absolute neutrophil counts ≥ 1,500 cell/mm3
and platelets ≥ 100,000 cells/mm3 and hemoglobin value ≥ 9 g/dL (Note: patients
whose anemia has been corrected to a hemoglobin value ≥ 9 g/dL with blood
transfusions are allowed).

4. Electrolytes (including potassium, sodium, and serum calcium corrected for
albumin or ionized calcium) must be within normal limits.

- Left ventricular ejection fraction (LVEF) no more than 5 absolute percentage points
below the institutional standard of normal as measured by echocardiogram (ECHO) or
multiple gated acquisition scan (MUGA) within 4 weeks prior to first study drug
administration (ie, if the institutional normal is 50%, subject's LVEF may be as low
as 45% to be eligible for the study)

Exclusion Criteria:

Patients that meet any of the criteria listed below will not be eligible for study entry:

- History of, or current known metastases in the brain or untreated spinal cord
compression;

- History of another malignancy within the previous 2 years except for the following:

1. Adequately treated basal cell or squamous cell skin cancer, superficial bladder
cancer,

2. Adequately treated Stage I or II cancer currently in complete remission, or any
other cancer that has been in complete remission for at least 2 years;

- Prior treatment with PI3K/mTOR pathway inhibitors;

Diabetes mellitus on active treatment, or subjects with either of the following:

1. Fasting blood glucose (FBG) ≥ 126 mg/dL (7.0 mmol/L), or

2. HbA1c ≥ 6.5%;

- Use of herbal products that may decrease PSA levels (i.e., saw palmetto) or
systemic corticosteroid greater than the equivalent of 10 mg of prednisone per
day during the 4 weeks prior to screening or plans to initiate treatment with the
above during the entire duration of the study;

- Any history of unstable angina, myocardial infarction, New York Heart Association
(NYHA) Class III or IV heart failure, and/or pulmonary hypertension;

- Significant active cardiovascular disease including:

a. Uncontrolled high blood pressure (ie, systolic blood pressure > 180 mmHg, diastolic
blood pressure > 95 mmHg) b. Grade 3 or higher valvular disease c. Grade 3 or higher atrial
fibrillation d. Grade 3 or higher bradycardia e. Endocarditis f. Pulmonary embolism g.
Recent cerebrovascular accident within 6 months prior to enrollment

- A requirement for positive inotropic support (excluding digoxin) or serious
uncontrolled cardiac arrhythmia (including atrial flutter/fibrillation) within 1 year
prior to screening

- A pacemaker or implantable cardiac defibrillator

- Known history of infection with human immunodeficiency virus (HIV), based on medical
history (screening labs to rule out HIV infection are not required);

- Any other condition that, in the opinion of the Investigator, would impair the
patient's ability to comply with study procedures.