Clinical trial NCT01717898 (phase 1/phase 2, status: terminated)
Conditions: castrate-resistant prostate cancer
ICD codes: C61, D29.1, D40.0, Z15.03, Z80.42, Z85.46, Z12.5
Drugs: bez235, prednisone, abiraterone acetate
SMILES: CN1C(=O)N(C2=C1C=NC1=CC=C(C=C21)C1=CN=C2C=CC=CC2=C1)C1=CC=C(C=C1)C(C)(C)C#N, [H][C@@]12CC=C(C3=CC=CN=C3)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CC=C2C[C@@H](O)CC[C@]12C, [H][C@@]12CC=C(C3=CC=CN=C3)[C@@]1(C)CC[C@@]1([H])[C@@]2([H])CC=C2C[C@@H](O)CC[C@]12C
Reason stopped: 
    dose limiting toxicities on lowest dose level
  
Eligibility criteria:

        Inclusion Criteria:

        Patients eligible for inclusion in this study have to meet all of the following criteria:

          1. Patient has provided a signed study Informed Consent Form prior to any screening
             procedure.

          2. Patient is ≥ 18 years of age on the day of consenting to the study.

          3. Patients must have histologically confirmed adenocarcinoma of the prostate.

          4. Radiographic evidence of disease (bone scan, CT scan, ultrasound or MRI acceptable)
             that is amenable to image-guided biopsy must be present.

          5. Patients must have castrate levels of testosterone (< 50 ng/dL) on GnRH analogues or
             have had prior orchiectomy. GnRH analogues must be continued while on study.

          6. Progressive disease as demonstrated by a rising PSA or radiographic progression per
             PCWG2 criteria.

          7. Asymptomatic or minimally symptomatic disease: No use of opiate analgesics (EXCLUDING
             codeine or dextromethorphan) for cancer related pain within 28 days of day 1, cycle 1.

          8. Phase II Cohort 1: No prior Abiraterone Acetate therapy

          9. Phase II Cohort 2: Immediate prior Abiraterone Acetate therapy is required. No
             intervening therapy is allowed between Abiraterone Acetate therapy and study therapy.

         10. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

         11. Men of reproductive potential who have not had a radical prostatectomy must agree to
             use an effective contraceptive method. Patients who have had a prostatectomy are
             sterile and do not need to use contraception.

         12. Patient has adequate bone marrow and organ function as shown by:

               -  Absolute neutrophil count (ANC) ≥ 1.0 x 109/L

               -  Platelets ≥ 100 x 109/L

               -  Hemoglobin (Hgb) ≥ 9.0 g/dL

               -  INR ≤ 2

               -  Serum creatinine ≤ 1.5 x ULN

               -  Total serum bilirubin ≤ 1.5 x ULN (in patients with known Gilbert Syndrome, a
                  total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)

               -  AST and ALT ≤ 3 x ULN (or ≤ 5.0 x ULN if hepatic metastases are present)

               -  Fasting plasma glucose (FPG) ≤ 140mg/dL [7.8 mmol/L]

               -  HgbA1c ≤8% (Patients with diabetes mellitus not actively being treated and
                  patients with an HgbA1c level between 7-8% will be required to have home glucose
                  monitoring three times weekly during the first cycle. Patients may also be
                  referred to a diabetes specialist as indicated.)

        Exclusion Criteria:

        Patients eligible for this study must not meet any of the following criteria:

          1. Patient has received previous treatment with PI3K and/or mTOR inhibitors.

          2. Phase II Cohort 1: Prior Abiraterone Acetate therapy is an exclusion

          3. Prior therapy with any of the following for >1 month: MDV-3100, Orteronel,
             ketoconazole or other drugs given with the intention to inhibit CYP 17.

          4. Patient has active uncontrolled or symptomatic CNS metastases. Note: A patient with
             controlled and asymptomatic CNS metastases may participate in this trial. As such, the
             patient must have completed any prior treatment for CNS metastases > 90 days
             (including radiotherapy and/or surgery) prior to start of treatment in this study and
             should not be receiving chronic corticosteroid therapy for the CNS metastases.

          5. Patient has a concurrent malignancy or has had a malignancy in the last 3 years prior
             to start of study treatment (with the exception of adequately treated basal or
             squamous cell carcinoma or cervical carcinoma in situ).

          6. Patient has received wide field radiotherapy (including therapeutic radioisotopes such
             as strontium 89) ≤ 28 days or limited field radiation for palliation ≤ 14 days prior
             to starting study drug or has not recovered from side effects of such therapy.

          7. Patient has had major surgery within 28 days prior to starting study drug or has not
             recovered from major side effects of the surgery.

          8. Patient has active cardiac disease including any of the following:

               -  Left Ventricular Ejection Fraction (LVEF) < 50% as determined by Multiple Gated
                  acquisition (MUGA) scan or echocardiogram (ECHO)

               -  QTcF > 480 msec on screening ECG

               -  Unstable angina pectoris

               -  Ventricular arrhythmias except for benign premature ventricular contractions

               -  Supraventricular and nodal arrythmias requiring a pacemaker or not controlled
                  with medication

               -  Conduction abnormality requiring a pacemaker

               -  Valvular disease with documented compromise in cardiac function

               -  Symptomatic pericarditis

          9. Patient has a history of cardiac dysfunction including any of the following:

               -  Myocardial infarction within the last 6 months, documented by persistent elevated
                  cardiac enzymes or persistent regional wall abnormalities on assessment of LVEF
                  function.

               -  History of documented congestive heart failure (New York Heart Association
                  functional classification III-IV)

               -  Documented cardiomyopathy

         10. Family history of congenital long or short QT, or known history of QT/QTc prolongation
             or Torsades de Pointes (TdP).

         11. Patient with medically documented history of active major depressive episodes, bipolar
             disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of
             suicidal attempt or ideation, or homicidal ideation.

         12. Active or uncontrolled infection of hepatitis B or hepatitis C.

         13. Inadequately controlled hypertension (i.e., SBP > 180 mmHg or DBP > 100 mmHg).

         14. Patient has impairment of gastrointestinal (GI) function or GI disease that may
             significantly alter the absorption of BEZ235 (e.g. ulcerative diseases, uncontrolled
             nausea, vomiting, diarrhea grade ≥ 2, malabsorption syndrome or small bowel
             resection).

         15. Use of any chemotherapy, investigational agents, immunotherapy, or hormonal therapy
             other LHRH agonists within 28 days of the start of treatment on protocol. Use of bone
             targeted agents including bisphosphanates and RANK ligand inhibitors is allowed if on
             stable dose; Xgeva or Zometa cannot be started within 28 days of initiating study
             therapy.

         16. Systemic corticosteroids except as part of on label treatment prostate cancer
             regimens.

             Note: Topical applications (e.g., rash), inhaled sprays (e.g., obstructive airways
             diseases), eye drops or local injections (e.g., intra-articular) are allowed.

         17. Patient is undergoing active treatment for diabetes mellitus.

         18. Patient is being treated at start of study treatment with any of the following drugs:

               -  Drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A4
                  including herbal medications (see Appendix 1 for a list of prohibited CYP3A4
                  inhibitors and inducers)

               -  Drugs with a known risk to induce Torsades de Pointes (see Appendix 3 for a list
                  of prohibited drugs)

               -  Warfarin and coumadin analogues

         19. Patient is consuming Seville oranges, grapefruit, grapefruit hybrids, pomelos and
             exotic citrus fruits (as well as their juices) during the last 7 days prior to start
             of treatment. Regular orange juice is permitted.

         20. Immunocompromised patients, including known seropositivity for HIV (testing is not
             mandatory).

         21. Patient has other concurrent severe and/or uncontrolled medical condition that would,
             in the investigator's judgment contraindicate his participation in the clinical study
             (e.g. uncontrolled diabetes, chronic pancreatitis, active chronic hepatitis etc.).

         22. Patient is not able to understand or to comply with study instructions and
             requirements or has a history of non-compliance to medical regimen.

         23. Patients in whom, in the opinion of the treating physician, should receive cytotoxic
             chemotherapy with docetaxel.