Clinical trial NCT02091531 (phase 2, status: completed)
Conditions: metastatic castration-resistant prostate cancer
ICD codes: C61, D29.1, D40.0, Z15.03, Z80.42, Z85.46, Z12.5
Drugs: mln0128
SMILES: COC1=CC(NC2=NC=C3CN=C(C4=C(C=CC(Cl)=C4)C3=N2)C2=C(F)C=CC=C2OC)=CC=C1C(O)=O
Eligibility criteria:

        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.