A Phase 2 Study of the Dual mTOR Inhibitor MLN0128 in Patients With Metastatic Castration-Resistant Prostate Cancer (CRPC)

Study start date: March 1, 2014

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.